市販後調査及び観察研究の報告①

市販後調査及び観察研究の報告①
OSSELAER ET AL.
BL000 00MPONENTS
A prospective observational cohort safety study of 5106 platelet
transfusions with components prepared with photochemical
pathogen inactivatlon treatment
Iean C. Osselaer,Nathalie Messe,Tor Heruig,Iose Bueno, Emma Castro, Aurora Espinosa,
Patrizia Accorsi, Kaus Junge, Michele Jacquet, JocelyneFlament, and Laurence Corash
n late 2002 a photochemical trearment (PCT)
process(INTERCEPTBlood Systems,Cerus Europe
I
BV leusden, Netherlands) for inactivation of pathoI
-L gens and white blood cells that may contaminate
platelet (PUf) components receivedCE Mark registration
and becme availablefor routine usewithin certain European countries. During the clinical development of tllis
technology, mndomized controlled trials were conducted
in selectedpatient populations ftequently supported with
PLI transfusions during periods of thromboci'topenia.''z
By necessityfor conduct of the clinical tliats, these studies
primadly enrolled patiens with hematology-oncology
disorders.The tria.lsfocused on posttransfusion PLI count
incrementsr and on assessmentsof hemostatic efficacvin
f
MATERIALS
AND METHODS
ABBBEVIATIONS: DSMB = data ahd satety monitoring board;
HPC(S) = hemovigiluce plan coordinator(s);
PCT = photochemical tleatment.
Flom the Blood ltilsfusion
Center, Clitriques Universitates de
Mont Godime, Universitd Catholique de tpuvain, Yvo[,
Belgiw;
Haukeland Univarsity Hospital, Bergen, Notray;
Centlb de Tlmstusidn, Cru Roja Espa-fiola,Maddd, Spain; St
Olav Hospital, Tlondhelm, NoNa)4 Crntro Tlasfusionale,
Ospeda.ledi Pescda, Pescara, ltaly; Omega Mediation,
Offenbach, Gemany; Tlansfu sion Thelapies, Bdter H€althcare,
Nivelles, Belgiu; and Medical Mairs, Cerus Corp., Concord, .
California,
Addr5s reprint reques6 lor Lauence Corash, MD, Medical
Affai$, Cerus CoD.,24ll
Stuwell Drive, Concord, C.\94520;
e-mail; lary-coroh@cerus.com,
Supported by research g!et6 from Cerus Corp.
Disclosures: tocelFe Flament was o employee of Bder
Healthcare Cory. duihg
conduct of the study, Iauence
Corash
was atr employee ofC€rus Corp. duing conduct ofthe study.
Received for publication April 16, 2007; rcvisioD received
December 3, 2007, and accepted DeceDber 6, 2007,
dol 10.1rll/j.1537-2995.2008.01643.x
TRANSEUSION 2008;48:l06l '1071
Volum●48.」une 2008 TRANSFuS10N 1061
studyd€slgn
General
Blood trmsfusion cbnters with the INTERCEPT Blood
Systdm for PLIs.for routine production of PLI components were invited to participate in this study. Patients in
clinica.lcare institutionswho receivedPIJIsprepued with
PCTwere specificallymonitored for adversehealth efects
for 24 hours after each umsfusion; however,tlere was no
time limitation on.reporting adverseevents after uansfusion, The sole lnclugion criterion for enrollment ms
receipt of at least one PUf component prepared with PCT:
Patientswho receivedPLI transfusionsadministered in an
outpatient clinic were obseruedfor approximately 6 hours
after trmsfusion and assessedbefore discharge. Study
persomel contacted outpatient umsfusion recipients the
following day to complete t}le.assessmentwith the standud data record fom. There were no other inclusion
or exclusion cdteria. Patients in this study received only
PLI components prepared with pathogen inactivation
ueatment.
The study ms designed as a prospective, singie
cohort observational study to be comistent with European Hemovigililce Network recommendations for surveillance of advdrse leactions to tlusfusion of labile
blood components and with those of lational trmsfusion
1062 TRANSFUSIONVolume,48,
June2008
seruices.ss
Study centersuansfusing PLI components prepared with PCT for pathogen inactivation 0NTERCEPT
Blood System for Platelets) in rcutine clinical practice
were requ€sted to complete a repon for each PLI transfusion regardless.of whether or not an adverse event
occured following transfusion. Tmnsfusions associated
with serious adverse events were repotted in greater
detail, Patients were assigned a center specific study
number to preserueanonymiry
Conduct of tha study
In each study center blood transfusion seruice,hemovigilance plan coordinators (HPCS) were designated as
responsiblepersonsfor the conduct of the hemovigilance
plan and coordinated all the related activides on site.
These HPCs,with expertise in transfusion medicine, were
responsiblefor oversightof data collection,ensuringdata
completion, reviewing assessmentsfor relation to PLI
transfusion, and completion of reporting information on
any adverse event after PLI transfusion regardless of
potential relation to the transfusion.
Before initiation of the sudy, clinjcal care personnel
were trained to the studyprotocol andthe specificform for
data collecdon.For eachstudy PLI component issuedfor
transfusion, a specific transfusion report form was issued
with the PLI component (Fig. l), This form was eomFleted
by the primary care physician and returned to the HPC in
the blood center.Theprimilycarc attending physician was
responsiblefor assessingthe relation of.adverse events to
the PLI transfusion. The HPC reviewed the completed
forms md contacied tlie prinary carc physician if data
were incomplete or assessmen6ofrelation did not match
the reported clinical data. The HPC had accessto patient
medical mre recordsto query Emsfuslon reports.The ultimate decision for assessmentof the relation of adverse
even$ to the PLT uansfusion was the resoonsibilitv ofthe
primarytrcating physician. HPC6were chdged with popu.
ladngthe database,by completingelectronicdata entry.In
centerswheie electronic data entrywas not possible,paper
forms were submitted and a sponsor representativa:populated the database The active HPCSwere Dr P Accorsi,
Pescila ltaly (Site02); Dr J.L. Bueno, Madrid Red Cross,
Spain (Site04); Dr A. Espinosa, Tlondheim, Nomay
(Site03); DrT. Heri'ig, Bergen,Noruay (Site08);and Drr.C.
Osselaer,
Mont Godinne,Belgium(Site0l).
A data and safety monitoringboard (DSMB) ms con.
stituted to rcview the studyprotocol and provide oversight
of the study.The DSMB reviewed an inteTim ilalysis of the
data after 2500transfusions and the final report after 5106
Eansfusions,
Study ropon lorms
The report form used for this study wu dweloped on the
basis of hemovigilance rcport forms a.lreadyin use and
ｍト
BACKGFOUND: lnactlvationol palhogensand whlte
blood cells.inplatslet(PLT)componentswith ame
toslen and UVA light (INTEFCEPT,Cerus EuropeBV)
has enteredclinicalpractlcsin Europeanblood centers.
A prospeclivecohon study was implementedto characterize the safety profileol thls new PLT @mponenlin a
broad patienl population.
STUDY OESIGNAND METHODS:Apheresisor butfycoal PLT componentswer€ leukoreduced,suspended
In approximately35 per@nl plasmaand 65 perceni PLT
additivesolutlon,and tr6atedwilh me INTERCEPT
prccess. Blood centeG were requestedto completea
safety dala lom atter €ach l€nslusion,
RESULTS:Data for 5106 INTERCEPTcomponents
sdministeredlo 651 oatienlswere monilored.A lotal ot
5051 (98.9%)transtusionsand 609 (93.5%)pationts
had no reporled reaclions.Fitty-five(1.1%)lranstusions
w€re assoclatodwlth adve€e ev6nts,and 42 (0.8%)
were possibly,probably,or relatedto lhe PLT transtuslon. Advers8evenls occurredin 42 (6.470)palients,
but in only 32.(4.9%)patientswas a causalrelationshlp
to PLT transfusionestabllshsd.One reaclionwas'
sedous,and no dealhswer€ relaledto PLTtranstusion.
Among lh6 transfusionsreactions,th€ most frequent
clinicalevents in descendinglrequencywere chills,
fever, dermatologicreacllons,dyspnea,nauseaor vomIting,and hypotonsion.No episodesof lransfusionr'6laledacute lung injurywgre reporled.
CONCLUSIONS:In this cohorl study,99.2percenlot
lranslusionswere withoutreactionsattribuledto PLTS.
INTERCEPTPLTSexhibllsda sdfetyprofilesimilar
lo lhat previouslyreportedtor convenlionalPLT
componenls.
patients with relatively stable tfuomboc]4openia requiring iepeated PL;f transfusions.2Based on the design of
these clinical ffials, the number of patients studied was
determined by the statistical power required to assessthe
primary endpoints. In the European trial of whole bloodderived bufli-coat PLI components' 52 patients received
3ll PCT PUI component transfusions. To assesshemostatic efficacy,a larger study was conduct€d in the United
Statesin which 318 pauents received 2678 PCT PLT component uansfusions. In both studies ilatients were
assessedspecifically for acute transfusion reactions for
6 hours after study transfusions and for other adverse
events for either 72 or 28 daysr after the last study PLI
transfusion. In both studies the incidence of acute tans.
fusion reactions after receipt of photochemically treated
PLISwas low and the safety profile was similar to that of
conventional PLTs.s
In general,prospectivestudiesretardingrhe saferyof
PLI transfusion havebeen limited. The largestprospective
PLI transfusion study before tht! SPRINTstudt'r was the
TRAPstudy of PLT alloimmunization, which enrolled 533
patients treated with 6379transfusions,but this Studydid
not specifically€emine safety,{After CE Mark registration
ofthe INTERCEPTsystem,an observationalcohon safety
study was im-plementedto prcspectively collect informa.
tion on at least 5OO0PLT trmsfusions to extend the safery
proflle of PLI components prepared with PCT administered to a broad patient popuJadon.
SAFETY O「 PCT PLT COMPONENTS
OSSELAER ET AL
PLATELET TRANSFuS!ON REPORT
Patient
Sex:FO
Age:
DELAYEplTRANsFUS:oN ttEACI:ON RE'ORT
lNTERCEPT P:atel● t Characterlstics and Transfusion
M0
;
Ager
Typel
Hosplal name and cily`
AphsGslsptatslets
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ebreleG
Characte&t6:
O
O
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Olradialed
Phm3d€pbt€d
O
Oth6r,spedfy
Anlisgnmalded
O
_
R6portlng dat6 |
BIood Bankid
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Reporternam6:
し
ocalonl
l o MOdiCa1 0 1oU 0
sur9■
●Utpa10nt 0 0,1可
_=___
Signature
Start datg of the delayod transfusion r€action:
Repoder name:
Dat6 and time otlransfusionr
Susp€ctsdor contlrmed dlaqnosis
Slgmtor.l
Did th€ prtlent sxpgrioncsany acut€advers€tnnstuslon rgactlonwithin 24 hoursaftertrangfugion?
Yeg Et
tl no, stophere
No B
,ty€s : Startdat€andtimeol adversereaclion:
００ ●
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Un70に
P03SiOV Rolalod
0 g
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2O
3 O
! D
l60lal6d dysfunclion wihoul cllni€l
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D6,th
or blologlcal mantrgstatlon
lif€-throatening
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Products transfussd that can b€ related to thls event (bydocroaring
ulじ
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u
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Transfuaion.related laboratory abnomaliti€s
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Conclusion/Diagnosls/Additional
examinstions(€.q.X.Rav...
Please keop a copy of this report in the patient tile and do not forget to complote a 'loelayed Transtusion
Roactlon Repgrt" it any delayed tranEfusion reaction occurg (e,9, GVHD, ...)
Rg. t, C8e report fom
for reportlng rcsponses to PLT trusfuslons
and classlffcatlon of adrers€ wents.ajftertrusfusion,
Voluいo48,」une 2008 TRANSFuS:ON 1063
Please keep e copy of this report in the patient file
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〓０﹁＾
尽計ごｏ
ｏ
﹁
■９ｏ■■あど，ｏ
●
∽‘Ｒｃ一
，お０■︻ｒ，´
３一
Ｆ●
●
ｏ
６●
３●∽
一ｏ
５，
ｏ
ド︻
ｏ
ｏ
ａｏ●
ｏＲ〓ｃ
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０●こ〓ｏＬるｏ
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ョ
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75
０＞﹁ｍ↓く０﹁ ●０ ↓ ●●■ ００〓ヽ０２ｍ２﹁●
SAFETγ OF PCT PLT COMPONEN'S
TABLE 2. Pallent 6xposur6 lo sludy PLT
Nu"ber of pat●
nts
N u n b e o′1 9 1 u d v ui ●
ro a口
sn s ′
e n d p r O p o r t ( %o )。
Rece ved al,●
ast on●
ludy tranず
●
uslon
651 11∞ )
R●●
●,ved O,Iy,lran,“
s10n
271(416)
R●●
●lved more than l trahstusioぃ
From 2 to 10ヤ
ansfuJons
271(41o).
From ll to 20 trans:usonS
`77.2)
From 21 to 40 trans,sbnS
33 15 1)
From 4イlo 60 transfusOns
ll(17)
Fron 61 t●
80 translusbns
3(12)
From 81 lo 100 tra“
l●
91ぃ
´
7● 1)
M o ゎ! h a 出
00 173nguSbns
3 0 51
Number ol ilansfuslons per patlont
Mlan t SD
78±
16:2
Range
,156
Modian
2
IABLE 3, Adverss evants rslated to PLT
trangfuslong classltled a5 traretslon reactlonsr
ovent(olぃ`●
●￨。b9oNatbn) Nomber。
Ch‖Is
Fever
u“icatta
pysPr..a
101わ
oⅢl■3peC“
19d)
Skin rash(n。
Naus●a/vonhln9
訥評m uisg“í
HypotensiOn
events reponed thatwere excluded as related to the Emsfusion (Table4), and 2 of these transfusions had serious
adverse events reported that wete excluded as related to
the transfusion.
On aper-patient basis,42palients (6.5%)experienced
adverse events after study'uansfusions. Eight patienG
(1.2%) experienced adverse events after two differcnt
study transfusions, md I patient (0.15%) had adverse
events after six,difrerent study tEnsfusions, Among the
patients experiencing adrerse events aftir transfusion, 32
patients (4.990)experienced adverse events attributed to
the study PLf transfusion (possibly related, probably
related, or related) and were classified as patients with a
transfusion reaction. Thrce of the 42 patients had sedous
adverseeventsafter PtI trarsfrEion, but for only I patient
w6 the seridus adverseevent attributed to the PLI $ans.
fusion. Of rhe 42 transfusion reactions in 32 padents, 33
transfusions were associated with a single symptdm
ind/or sign, I with two, md l.with six Anong these 42
transfusiors classified as resulting in tansfusion reac,tions; the time to the first reactjon was valiable (Table5).
Only 4 tEnsfusions were preceded by medication to
reduce potential trilsfusion reactions (antihistamines
and corticosteroids for 3 and corticosteroids alone for I
transfusion).
Translusions assoclated wlth suspected bacterial
sepsis
Five tansfusions were associatedwifi chills md filer or
h!?otension that met institutiona] criteria for suspicion of
uansfu sion-associated sepsis, resulting in bacterial cultures of PLlI components and patients (Table 6). Twentyone other PLI components were cu.lturedbased on blood
center survei.llancepractice, but were not associatedwith
suspectedsepsis,and a.Llof these were steiile.
TABLE 4, Advers€ evenls classltled as unrelalod to PLT trsn€tuslons
01-010
01‐
008
01つ96
01・
099
Oヽ■68
01Ю98
01・
106
01‐
170
200
01・
01‐
389
421
01・
427
01・
395
01・
Adve66 evenls'
Faw, chllls, nausoa, vomlting
transtusions
ritstreaclion
betorE
}liu"l""l",l"=15
TABLE & iranstusiona assoclated wiih
'susDocledbact€rial seosis
Palent,D
Ⅵ lai s10ns
Cunure resun
01‐
007
36:W38ぴ
C
Pa30nt blood oullre no9auv●
8P・150/80
ve
ure nega‖
0'ヽ
039
3al´ 61°C
Paヽ ont bbod cu“
SP 140/80
464
Afebい
ro
PC
culuro
noga,ve
に,seぃ
01・
hypo、
9nsion
.
178
39,C12 hr arler Pc cu"ure n9ganv.
01‐
8P120/80
098 _370/39 9C
PC neg。
01・
“
ぃ .dentJ abs,oss
i BP 60/40
' 8P = blood pfossure; PC = plalelBl Componont.
′ovents(%)
14(186)
14(186)
●( 5 3 )
4(5,3)
3(4o)
0(40)
3(40,
3140)
Adve€e ov€nls (n = 75) rgporlad Bfler PLT translusionsattrib.
ul€d to th9 trssfusion and classifi9das par{ of a lransfusion
reaclion hvolvlng 42 of 5l06 lransfusions.
Paient
Serious advergs events afier PLT transfusion
TABLE 5. Numbgt gl ttudy translusions betoro
th€ flret transtuslon reaction
１２３４５田綬爛
of adwrse events associated with Eansfusion reactions
(Table3). One of 42 (rmsfusions was reported with a
serlous adverse event, Grade 3, causally related to PLf
transfusion. Nl of the other tnnsfusion-related adverse
events were Grade l. Thirteen Uansfusions had adverse
OSSELAER ET AL.
Causlityt
Probably unrolated
Ca「 dほC arrhythnl●
tod
Probably un7oは
PrObably unrolated
HypOtenい on
Chms
PrObably un子
Olated
Ch‖ 3,headache
Probably unrela●
d
疇 V01o'“S,い
ソp●enSOn,ooSIわo
υ areはed
,7●
0yspn“ .●a,Sea,v●“￨"ng
baЫy unreは
led
Fev● òわ‖s
PrObably unrelatod
Chms
prObably unrelated
Chms,nau9oa,vom聞 ng
Pr●
bably unielaled
Fever,oyspぃ ea.chost‐
abdomitt pan PrObabv unrelated
Chms
Probaoly unrelated
Chms l
unに
●t“
Grad€t
1
Basis for causaiity assesment
Prior intoctionuider treatment
Condltionbefore iransfusian
Hypoienslonbefore i€nsfusion
Anxiety cfEis, not v€dtiod as chilig, Do fover
F9v€f betore lransfusionwith Dior Infoction
Pdor sepsis dua io dehtal abscesss
Indwellingcatheter infoctiondocumsnted
Febdle nBulropeniabefofe transfusion
Ev6nt sfier RBC transtusion
Coincid€ntwith other medications
Os€t 2 hr Eft6r iBnstugid, blood cultures negative
O6€t 76 mln after lansruslon, blood N,lures negalive
No t€vgr incr4$, PLT unll culturo regative
AdveEe ev6nt5 repodgd aftgr PLT transfusion.
t CaBd relalion to trssluslon a9 assessed by pdmary care physlcian.
t AdveBe ev6nl svgrity grade whgfer GBd€ 0 = lsolatEd dygfwclion wilh@t cl;nicald biologi€l manitoslation;Gradg 1 = absence of
lmmodiato gr long-lem llfa.threateningconsequsn€; Gr€de 2 = long-lem lire-lhteatening@nsequon@; Grade 3 = lmmediate lifelhreatenlng @nsqq€n€i Grado 4 e d€alh.
Volun●48,June 2008 TRANSFuSiON loo7
Patient 01-007 had chills; fevet and ur(icaria after a
transfusion. Culture of a tubing segment was positive
for micrococms, but blood cultue ftom the patient
was negative. The utimria was attdbuted to antibiotic
medication, The tubing segment clrtwe rcSult was considered a laboratory contaminant. P€tient 01"039 exped"
enced chiLls without fever, but with dyspnea after a
umsfusion. No other slmptoms or signs were reported.
Culture of the administration tubing set was positive for
coagulase-negativestaphylocgccus, but blood cultues
from the patient were negative. Patient0l-464 experienced posltlansfusion hypotension. Culture of a
detached tubing segment was positive for Smphylococcus
warneri, bul cultu€ of the .PLT component and blood
cr:ltures were negalive. Patient0l-178 developed fever
and chills after a P.II Eansfusion with a positive blood
culturc for Escherichlacoli. culture of the PLT component, howeverr was nsgative. Patlent0l-098 developed
fever (39.9"C)with chills and hypotension l2 hours after
a PLT transfusion. Blood culture was posltive for lhe
presence bf Actinornyces,but qultue of the associated
PLT component was negative; Subsequently,the source
of sepsiswas idertiffed as a dental abscess.In summary,
no posttansfusion adverse ev€nts suspicious for
tmnsfusion-associaied sepsis were cohfumed witi
c-oncomitant-positivePLI component and patient blood
cultutes.
1068 TRANSFUSIONVolume48, June2008.
Three serious adverse events were reported after PLT
uansfusion. Patjent0l-096 had severe hemodynamic
instability after liver biopsy associatedwith bleeding and
was tImsferred to intensire care.After the onset of hem- .
orrhage, she received a study PLI timsfusion followed by
severe hypotension (blood pressure, 4212?j hean :nte,
92 beats/min). She was treated with fresh-frozen plasma
(FFP), vasopressors,and fibrinogen and recovered. The
primary care physician assessedfte event as probably
uroelated to the PLf [ansfusion and aftributed the
hypotension secondary . to hepatic hemorrhage wi&
hemodtramic instabi.liry
Patient0l-098, recelving chemotherapy for acute
Ieukemia, experienced f*er. chills, and hypotension
l2 hours after his 3lst PLI transfuslon. Subsequent blood
cultures were pirsitive for the pr€senccotActinor(yces,but
the PLI component culture was negatiw. The source of
sepsiswas attributed to a dental abscessand was classified as uruelated to the PLI oansfusion,
Patie;t 0l-464 developed hemorrhilge during mitral
va.lvesurgery ud was treated with PtT transfusions and
methylene blue FFP He expeiiencedhypotension afterthe
second study transfusion. Cultures of the PLT component
and blirod culturcs were negative. On6 day later the
patient experienced a second hypotension episode after'
bansfusion of red blotrd cells (RBCs).The investtgator\g
attributed the event a6 an allergic adverseevent related iol\
the PLI tnnsfusion. The pati€nt had no other allergic
slmptoms. The patient recoveredand was discharged in
good condidon.
Risk tactors associated wlth tranEfuslon reactlons
Both patient and PUL componenl characteristics were
analyzed for association with tmnsfusion reactions, The
analysesshowed that 6.0 percent ofmale patients expedenced at least one transfusion reactioh and 7.3 percent df
the female patients experienced.at least one transfusion
reaction (p = 0.59; odds ratio lORl, I.I9). Stratification by
age showed tbat 4.6 percent of the patiants older than
64years qf agq presented with at least one lrmsfusion
reaction compared to 8.3 percent of patients b€low
64 yea$ of age (p = 0.06; oR, 0.5a). Flnally, 8.8 Fercent of
patients with a prior history oftransfuslon experienced at
Ieast one reaction while only 4.5 percent of patients with
no prior transfusion hjstory experienced at least one reaction (p = 0.07;OR, 1.99).Thesefactors may be confounded
with the diagnostic category of the patients; however,
there were no signncant associadonsbetlveen diagnostlc
category and tahsfusion reactions. Most of the transfusions with attributed reactions were associated with
apheresis preparauons. Only one random-donor PLT
component Ms reported with a Eansfusion reaction, but
this low incidence of reactionswab most likely due to the
SAFETY OF PCT PLT COMPoNENTS
disproportionate use of apheresis components in this
study and not a true effect ofprepalation method.
Extenl ot exposure belore the tlrst transtusion
reaction
Among the 42 tEnsfusions associatedwith a transfusion
reaction, rcadions occurred after single and mtrltiple
tranifusions (Table 5). These data suggest that repeated
exposure to INTERCEPTPLfs did not increase the likelihood of a transfusion reaction. Arnong the 10 patients
without a previoustransfusion history who experienced a
transfusion reaction, 3 patients had an event at the fust
PIT tmnsfusion, I after the 4th, and 6 patients after more
thm 5 transfusions. Patient 01-l13 experienced the fust
reaction (unicalia and flushing) after the l39th INTERCEPT transfusion. Thus, for this patient population
without prior blood product exposure,the fisk of a $ansfusion reaction after INTERCEPTPLIs did not appear to
incredsewith increased exposue.
DlSCUSSION
Generally when a new type oflabile blood component is
introduced Lrto routine clinical practice, initial information cbaracterizing the safety profile is derived from a
limited number of obsewations during the clinical development phase,3The intfoduction ofPCT PLTSinto loutine
clinical practice provided an opponunity to collect more
information on the tolerability and safery ofPCTPLTSin a
broader patient popdation and under routine clinical
conditioru in contEst to a clinical tdal enyiroment. This
approach is consistent with the recent recommendation
flom a consnsus conference lhat new blood safety tecbnologies should be evaluated with postmarketing hemovigilancestudies.ro.
A prospective observational study with obl.igatory
reporting for all uansfusions regardless of outcome ws
designed to assesEthe safetyprofile ofPCT PLTsin routine
clinica.l practice, The data from the present study represent the largest prcspective experience to date for record.
ing potential adverse events associated with PLT
transfusions compared to.prior studies of rctrospective
design and limited size.rr'raThis study was planned.to be
consistent with European hemovigilance pracdces in
which reponing of all grades of transfusion.associated
reactlons has been emphasized.s6 [n contrast to passive
hemovigilance studies, in this study obligatory reporting
for all PLT trilsfusions was required irrespective of
outcome. This study focused on adverse eventslhat could
be linked to PLT transfusions, specifically in the first
24 hours bfter transfusion, but there were no specific
llmitations on when adverse events cou.ld be reported
afrer uansfusion, Thls study captured information on
rcpeated (ransfusions withln patients to determinepoten-
tial effeits of repeated exposure to this new q4re of PLT
component.
. A potential limitation ofthis studywas the absenceof
a concutent contlol group receivlng conventional PLI
components wlth which to determjne a comparative incidence of acute tBnsfusion reactions..Arother limitation
was the polential for overreporting due to the absenceof
a blinded design and the increased awareness among
obseryers that a new type of PLI component was under
evaluation.
Thesepotential limitations were addressedln several
ways. A large portion of the trmsfusions were administered at the Mont Godime Blood Transfusion Center
which had prcspectively collected data for both PLI and
RBC transfusions during an l8-month period before
routine implementation of PLt components rreated with
pathogen inactivation. After the uriiversal introduction of
$eated PLI components into clinical use atthis center,the
methods for RBCsdid not change. During both periods
of observation, PLI ASs were ued to reduce exposure to
alJogeneicplasma.rsThus, in this centet we were able to
compare the prevalenceoftransfusion assbciatedadverse
events with the sme group of obsewers for one component with a new intervention (PCT PLTS)md another
componentthat wasunchanged(RBCs),Basedon a com'
peison of the two observation periods, Osselaer and
coworkerersreported a significant reduction in rbactions
to treated PLf components, from 1.3 to 0.9 percent
(p = 0.02), while the incidence of reactions to RBCSwas
equal in both periods {0.4%). The experjence from this
two-period, two-componenr analysis suggested that
obseryer sensitivjty for overrepoitjng did not gccur In
addition, these data prwided a background rate for acute
uansfusion reactions for leukoreduced PLf components
with PLTAS(I.3% of trmstusions).
Other estimates on the background prevalence of
transfusion reactions can be obtained from the litentue.
On a per-transfusion basis, the prevalence has been
reported to nnge from 18 to 3l perent; however, tlese
studies were conducted some yeils ago with variable
methods ofPLT preparation,rr'r6'rB
More recendy,the incidence of moderate md severe transfusion reactions has
been reported from the TRAPstudi which examined 8769
PLf transfusionsin 598 patients during induction therapy
for acute leukemia.reThe overalj lncidence of reacrions
was 2.2 percent of tilsfusions, md 22 percent of patients
experienced at least one transfusion reaction. In comparison to the TRAPtdal, in this study in wNch all grades
of reactions were reported, both the proportion of
transfusions associated with a reaction {0.890)and the
propoftion of. patients t4.99o) dperiencing at least
one transfusion reacuon causally attributed to a PLT
component were lower
Another comparison can be made with data from the
hemovigi.lancenetwork in France.5In that study, which
ヽ
′
01●
ne 43.」uno 2008 7RANSFuS10N 1009
OSSELAER ET AL.
reported data for transfsion reactions during 2 years in
which the leportipg system was fust implemented, an
incidence of four eventsper iOO0PLTcomponents (0.4%)
was reported. This may be an underestimate, howevet
since each whole-blood PLI concentrate in a pool was
tabu.lated as an individual component. More recently,
Kerkhofis and colleaguesla compared the incidence of
uansfusion reactions for leu-koreducedpooled PLT com. ponents in plasma and plasma with AS in a study of 168
patients and 765.transfusions. They observed an incidence of.5.5 percent of transfusions with reactions for
PLTsin plama versus 2.4 percent of transfusions for PLTs
in a mixture of plasha and AS. On a per-patient basis,
9.5 percentofpadents transfusedwith PLTsin plasma-ASs
had reactions compared to 15.5percent of patients supported with PLTssuspendedin plasma
In this study, which is the largesr prospective PLI
transfusion srudy to date specifica.llydesig{led td caprue
all gradesofuamfusloh reactions,tre prevalence ofreactions per timsfusion and per patient was at the lower
rmge of those reported in studieswith conventional com,
ponents.Youngerpatlent ageand prior expsure to blood
transfusions were risk factors trending to a higher incidence of Eilsfusion reactions. Recently,a higher rate of
transfusion reactibns also was reported in a hemovigilance suwey of pediatdc hematology patients.20
Prior dposure to INTERCEPTPLT trmsfusions did
not inffease the likelihood of a trmsfusion leaction. In
comparison to. other studies of PLI components in
plasma-As mixtirres, the incidence of transfusion reactions on a per.patientbasis forcomponents preparcd with
PCTwas reduced funher. lmportantly, this study eruolled
a substantial number of patients with hematologyoncology disorders treated with complex therapies and
suppqned with rcpeated PLf transfusions as well as swgical padents requting PLI support. No incidents of
TRALI, tEnsfusion-uansmitted bacterial sepsis, or death
associatedwith acutetmnsfusion reactionswere obseived
in this study. B*ed on this experiencein a broad patient
population, PLI components prepued with PCTwere well
tolented in routine cltrical practice.The types and severity of acutri reactions to PLI components preparcd with
palhogen inactivation keatment were consistent with
previous reports of adverse events to.conventional PLI
components, md the data from rhis study provide addi.
tiona.ldata on the saJetyof PUf components ueated with
amorosalenand IIVA lighr.
ACKNOWLEDGMENTS
The Dataand SafetyMonitoringBoardwascomposedof the fol'
lowingmembers:Dr Hiley KleiD,Divisionof Trusfusion Medicine,Natlonaltnstituts of Health,Beth6da,MD; Dr PaulNess,
ltanstusionMedicileDivisioD;The
lohnEHopkiirsHospiral,Bal.
timore,MD; Dr lacqueeCinqualb_re,
CHU de Hautepien€,Strast070 TRANSFUSION
48,Jun62OOg
Volume
boug,
Frucel
Dr Miguel Lozuo,
Hemotherapy ud
Hospita.l Clinic Provincial,
Hemostasis, Barcelona, Spain; DtDantele
Sondag, Sewice Francophone du
Sant, Brussels, Belgium;
DrPaul Strenge$, Intemationa.l Society fot Blood Trusfusion,
AjnEterdam, Netherleds;and
ri6,
Aheli€n
Red Crss,
Dr Roge! Dodd, Hollud
Rockville,
Laborato.
MD. The authors
DrAntonio Iacone. CentroTl6fuslonale,
thank
Ospeda.ledi Pescaa, for
reviewing the manuscripl
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EniiSht H. Factors influencing nioderate to severe reactions to PLI transfusions: exp€dence of the TRAP muhicenter clinical rrial, Trssfu sion 2003;43:I545-S2.
Kerkhofs tH, E&enboom JC, Schipperus MS, En
Wordragen-Vlaswi*el Rr, Brod R, Hfley MS, de Vries
Argelini.Tibert MF, Curde C, Slaedts M, Corash LM,
Rasongles P. Safety ofpla(elet componenb prepaEd wi&
photochemical treatment (INTERCEPT) tran6fused to
nR, Bdge R, En Rhenen Di, BEnd A. A muricrDte! randomjred study of tbe eficacy of tresfusions with platelets
pediatdc oncolo gy-hemarology patienrs, T!ansfu sion
2007;43(S3):224. lt
∞ト
Volumo 48,」
uno 2008 TRANSFuS!ON 11071
販後調査及び観察研究の報
3'6 1 C Oselaera,αl
サ
oumJ cOml翻
18器
膳期￨&]拙
湯
:蠍
鶴♀
programme
An activehaemovigilance
characterizing
the safety
profileof 7437platelettransfusions
prepared
with amotosalen
photochemical
treatment
J. C. Osselaer,rJ. P. Cazenave.2M. Lambermont,3 O. Garraud,'M, Hidajat,s L. Barbolla,6R, Tardivel,t L, Defoin,r C. Wallcr,2
L Mendel: J, P, Raidqt ? G, Kardel,2 R, De Meuter,r p. Fabrigli,. D, Dehenau,s J. L. Arroyo,6 F, padr6n,6 H. Gouezec,T
M. Corral,s M. Jacquet,e D. sundin,e L Line €t L Corashe
lSlooiihontfuion
Cente,CliniqusL)nivetsitohsde MontGodilne,lJnift$itt Cothotique
de touvojn,ywiLgalgjun
2tR Atsoce,
Ftunce
St.asboutg,
lsetuia du Song,
gelgionfedC.osrfros( U.iwGity Hosp,to,,
8/ussers.
BcJg;um
'
Au@ryneLoir( st. Et'c4nqFronce
EFS
sElood Trunsfuiaa. AZ
St JsnAV, Btugge,Belgium
'C.nto de Hemate@pio
yHcmodon;n dc Costt,o y L.on,vottodaild,spoin
'ff5 Iretoqne,ReoncsFronce
sHosp{tai
Unl46itor;o dr Sotomoh@,Sotononco.
SDoi
n
'gCerus
Corporotiotr,Corcod, CA,U5,4
V(,(5,t臓匂ぃiliみ
Methods The focus of this ongoing haemovigllanceprogramme is to dooment all
AEs asociat€d with PCT-PLItransfusion.Data collectedforA_Esiiclude: tine ofevent
aftet starting transfusion,clinical descriptions,i/ital signs, rsults frorn radiographs
and bacterial cultures,went sderity (Grade0-4) and causalrelationshipto pCT-PLT
tmnsfusion.
ResultsOne thousandfour hundred_
parients(nean 60years, range l-96) received
PCI-PLI tnnsfusions.The majodty of the patients(53.40lo)
had haematolos/ioncoloA/
diseass and requiredconventionalchemotlerapy(44.8%)or stem-celJ
traniplantation
(8 6%). Sixty'eight PCT-PLTtnnsfusions were associatedwith AI. Acute tnnsfusion
reactions (ATR),classifredas an AE possiblyrelated,probably related;or relatedto
PCT-PLTtransfusionswere infrequent (r = 55, 55/.743?= 0.706)and most were of
Grade t sweriry. Thirty-nine patients(39/1400= 2.8%)experi€nctdone or moreATRS.
The most frequently reportedsignslsymptomswere chil)s, fever,urticaria,dyspnoea,
nausea end vomiting. Five Als were consideredsevere (l Gnde 2); however,no
causalrelatidnshipto PCT-PLTtransfusion
was found. Repeatedqposure to pCI-pLI
did rot increasethe iikelihood olan Afi. No casa oftransfusion-relatedacutelung
injury and no deathsdue to PCT-PLT
transfusions
were reported.
Betived: 25 Octobet2CA7,
td isEd24 Dtcr hbc, 2007,
rccepted24 Decenb.( 2007,
publishedonIine 30 ) onuory 2Ng
ConclusionsRoutinetansfusion ofPCI-PLT is well-toleratedin a wide ranqe of
patients.ATRSrelatedto PCT-PLT
transfusionwereinfrequentand mostwercof;ild
sweriry.
Key words: PCT,platelets,haemovigiJance,
safefy,INTERCEPT.
Correspoadflc(LilyLin,Cr(usCorporation,
2411StanwellDrive,Concord,
CA94520,USA
lIn@cc(utcom
E-marl:
Materials and methods
@20oSThr Authods)
prblishingLtd.,uot songuinisffi;;;, ;l;::,
Joumafconpilation
o zrjogBtackweil
０ト
Background An activ€ haemovigilance prognmme was implemented to suryey
adversewens {A.E)associatedwith transfusionof platelets photocheinjcaltyheated
with amotosa)enand ultraviolet A (PCT-PLT).
The results of 5106transfusionshave
already been reported.Here we report the results of an additional 243? pCI-pLT
transfusions,
Introduction
INIERCEPT
BloodS,srenwusesa phorochenical
rreatnenl
General shrdy design
nethodology [PCT: amotosalenplus ultraviolet A fitvA)
Iightlto inactjvate
virus€s,
protozoa,
bacteria,
andleucocl.tes This was a prospecliveobseruationalactivehaemovigilance
in plalelet [PLT)and plasna components.The PLT system study.The objectiveof this study was to documentthe
receivedCEMark registntion in Europein 2002.Several transfusion
safetyprofrlefor approximarely
7500pCT-pLT
centresin Bellium, Spain,Nomay and Italy b€ganroutine
componentspreparedwith the INTERCEPT
Blood Systemil
productiof,of FCT-PLTin 2003.An activ€ haemovigilance for platelets(CerusEuropeBV, Leusden,the N€theilands).
programmewas imnediatelyimplementedto prospectively Thesecomponents
wereprepared
in thrercentres
ir Belgjum
collectinformationon PCT-PLT
transfusions
administered (CTSUCL Mont Godinne,CTSDrabant-Hainaut
and AZ
patients
to
ln routjnectinicalsetlings.Prior to CEMark
Sint JaD AV), three cenBesin Fmnce (EFS-Alsace.
EFSregistration,the safety data of PCT-PUIwere primailly
Auvergne-Loire
andEFS-Bretagne),
andonecentrein Spain
'obtalnedfrom
controlledclinicaltrials with a limitednumber
{CHEMCfLValladoiid)and admlnistered
to thrombocytopenic
ofpatientsand pr€determined
clinica)and safetycnd-points patientsunderstandardclinicalpmcticeiir hospitals.
There
[l-3], The postmarketinghaemovigilanceproglammeprowereno randomization
requirements,
no inclusionctlteria
videda neam.td eliend the characteizarion
of the safery abd no exclusioncriteriaoi patientsotherthar the need
profileofPCT-Plf in routineuse and in a broadpatient
to receivea platrlct transfusion, Baselinedemographical
populatiotr.
Thercsultsofth€ fi6t 5 106PCI-PLTtnnsfusions infomation was collectedon all studypanicipanis.Patjents
have alriady beenrepoited[4]. With additionalcentrcsin
wo€ assigneda centre-specifKstudy numberto prcserye
Belgim, SpainaildFrance
stating withthe routineproduction anonymity.
ofPCT-PLT,
the database
ofthis haemovigilance
piogramme
Patientswho Keiwd bansfusioroof PCT-PLT
weremonihasbren expanded{51.
toredfor any Als afterthe start ofeach platelettransfusion,
In March 2oF, the CanadianBlood Servicesand Himawhjch is consistentwith EurcpeanHaemovigilance
Network
o€anizeda consensus
Quebec
conference
to providerccom- Komdendatiotrs for suNeillanceof AE to transfusionof
mendatjons
andguidedecision-making
aboutnewiathogen labilebloodcomponents,
and with thoseof nationaltransinactivationtecbnotogi$ [5]. The panel, consistsof nine
fusion services[7,8].However,in this study,repoftingwas
healthcare
profssionalsand membersofthe public,slressed obligatoryfor all PCT-PLT
tnnsfusionsiD eachparticipating
the iEiportanccof postmarketing
suweillancestudiesin the
clinical site.A transfusionRport was rcquiredfor eachpLT
introductionofnew technologies
for blood sfety. Thepanet
transfusiontegardlessofwhether or not an AE occurred,In
reconmended
that specifrc
studiesshouldbe mandated
by
caseof ocorrenceof ari AE.additionalclinicalandbiological
the reglrlatory
authodtiesandsupportedby thc nanufactureF informationwaScollectedto allow diagnosisard assessment
and/or the blood suppliers.Postmarketingsurueillancefor
ofcausality and severity.The data in the final database
adverse/eactionsto pathogeninactivationproductgshould
werc anonynousand were reportedon a per-transfusjon
belinkedto the mtional haemovigilancts)6temsif possible. baslsaswell ason a per-patientbasis.Tnnsfi.tsions
associated
Depending
on the new pathogeninactivationtechnologjes with seriousAEs were reportedJn great€rdetail,
implinented,specificadditionalsuryeillanceoutcomes
nay be identifiad,Thepanelalsosuggestedthat Chronjcally
Study repon forms
tnnsfusedpatientsmight.serveas an ideal surveillance
populationto identjfylong-termtoxicjtiesofpathogenThe Rpon fom used for this haemovigilanceprograilme
inactivatedproducts,
wasdwelopedon rhebasisof haemovigilance
Rpon form
The actjvehamovigilanceprogrammedescribedin this
alreadyin use,Information wis collectedin sevenl broad
study is in concordanceuith thse recommendations, categoric:patientdemogruphic/diagnosis
dara,plateletcomAhhoughthis prcgnmme is not directlylinked to a specifrc ionant characteistics.
tnnsfu sionryentsanddosm€ntation
countryhiiemovigilance
systemnor designedto replaceany
of all AIs followtngtrasfusion.An aate tnnsfusionreaction
existinghaemovigilance
system,the fomat of data collec(ATR)wasdefrnedasan AE po$ibly relared,probab)yrelated,
tion is modelledaftilthedata collectionformatofthe French or Rlatedto a PCT-PLT
tnnsfusion.
haenovigilancesysten for documentationof transfusion
AEsweregrudedfor clinicalseverirywilhin rhe foilowing
incidenb[7J,Thefocusof the cuBentprogramme
is on a]l
categories:Gmde0, isolateddysfunctionwithout cijnical or
advere events(AE),seriousot non-serious,ocruring after
biologicalnanifestation;Gmde l, absenceoflmmddiateor
the startofPCT-PLTtnnsfusion.
Followjngthe recentreport
long-termlife-thrcateningeffects:GrudeZ, long-tem lifeof 5106PCT-PLT
tnnsfusions[e],herewe reponthe results threatening effects; Grade 3, immediate life-threatening
ofan additional
7437transfusions
ofPCT-PLT.
effmbi andqnde 4, deati. Foreachtransfrsion,the following
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Haenovigilance of photochemicaltreatedplatelets 319
Tablc2 Clinicelrha€ctrri3ti6 ot advcEcevrntsIAEI
On a pcr-transfulionb$ir, (0,b= r x 100/7437)
AF att“
buted
to phteにts
Anv AEs (ATR〕。 SAr
t 。口。
meF・
S(く01%)010 007ol
Numberwith et laa( oncrvant 63(0 9qo1 55(0700)
Signtsymptoms'
8 ( 0 1 0 / o ) 0 ( < 0 1 )0 7 。 O(0%) ‐
Fwtr
4510601〕40(OSOb)
2(く
Ol%)―
Chills
2(く
Itching
0 : , % 〕2 ( く
01%〕 0 ( 0 リー
, k 0 1 0 7 o ) 。( O S o l
1(く01%)―
Hypotansion
14(020o) 14(02%〕
0(0%) =
uiticarie
5 ( く0 1 % ) 5 ( く 0 1 % )
0(0%) ―
SkinEsh
1(く010b)‐
8(01%) 0(く l110o)
oFpnoca
1 ( く0 1 0 o ) 0 ( O O b l
1(く010o)=
RespiEtory
distrcss
81●
1 % ) 5 k O i O r o ,3 “0 1 % ￨ ―
Neu*a/vomlting
6(く
0,Oo) 1(く
0(030
Lowcrbackpain
01%)
・
pain
1(く010o, 1に 01%)
O100o} ‐
Chcsvabdominal
Shoct
Tpchycardie
Other
￨(く01%) 。 0“〕
4k01%)0(く
01%)
14102%) 11(01111
4(く010b)―
,((01%)―
3(く
01%)―
Serious adverse events fouowing plateld't
tansfuslon
0n. pcr-pati.nt basis, (90= D x 100/1400)
Anv AFs(ATR)。
45(320b1
SAR`
to plateletsIや
39(2 SOrc) 4(03%) 0(00¨
)
7(05%) 5(04%)
00%) ―
1 ( 0く1 9 7―
●12噛 23● 0呵
o〕
1(く
01%〕 ,(くol“〕 0 { 0 % ) ―
1(く
1(く
01%)O101●l
0197o)―
13(0 9Cb1 13(09“〕
4 10 3qo1
4(03%)
8106%1 61040/o'
1(く。1%)0(0鳴
510:4%l' 3102“)
2 1 1 1 % ) , k O 」% )
ikO,￨￨サ ,“ 0'%)
3(02¨) O10%)
O1020711 2(0,qol
12(09ql1
10(0700)
O rO%) ―
0 001ol ‐
1(く01%, ―
1に 01%)―
2(ll i“
〕‐
O100bl
―
o“nl _
3(020b) ―
,(く0,・ll ―
3(02噛 ■
.
long-tarh life threatehihg,
immediate
lifc thrcetcningor dcath.
seriousadvcr avant(sAE)r
rrlatcd.or rclaredto tT-PLTt6nlfusron.
tausal rabtionshipthatliaspo$ibly.r.latcd,D.obably
plr AE,
cxa.cdnumblrotA[ dueto multiplcobscwadsiqns/symptoms
"Nunbcfofsign{symptomsceh
Characteristics of clinical signs and sJmptoms
associated with adverse evant
On a per-transfusionbasis,the most frequently observed
(> 0.1%ofthe total 7437transfusions)
were
symptoms/signs
fever, chills, urticaria, dyspnoea,nauseaand/or vomiting
{Table2). Tbe individual incidenceof eachof the following
was< o.l%r itching,hypotension,
skin rash,
signs/symptoms
r€spiEtory distEss,lower back pajD, cbest or abdominal
pain, shock atrd tachygadia. All additional symptoms
includedin thc categoryof othet such as refractoinessto
plarelettEnsfusion,hypertension,cephalea,
pain in the leg,
flush, malaise,cyanosis,oxygen desatuntionand yolume
overload
werealsorcported
but with an individualincidence
pnncipallyas
of Ie$ than0.lqio.
MostofATRSweredescribed
Cradet chillsandunjcaria{Table2).
On a per-patientbasis,.the most frequentlyobserved
s)4nptoms/signs
PO.5% ofthe total l40O patjeDts)were
fevet thills, unicariaanddyspnoea(Table2).Apprcximately
o.l-0.4olbofthe population(froh 2 to 5114oolexperienced
the following sigN/symptoms:skin rash,nausea/vomiting,
shock,iowerbackpain andtachycardia.
Clinicalrefiactorinss
to transfusion,hypertension,,headache
and flushing were
additionalsymptomsreportedih the categoryof'other: Less
than0.1q/oof the studypopulation(only I / 1400)axp€rienced
thr followingsigns/symptoms
surb ashypotension,itching,
respintory distressand chest/abdominalpain. Symptoms
suchaspulseincrease,
legpain,cyanosis,
oxygendsaturation,
malaiseand/or volume overloadwere also reportedin the
categoryof'other'. Most of the ATRSconsistedof various
combinarionsof feverl0.4o,b).
chills (2.00/o),
unicarla(0 9obi,
(0 2ry01.
skin rash(0.30b),
dyspnoea(o 4o,h).
nausea/vomiting
tachycadia(0'10/0)
and otheresymptons{0 7%)(Table2).
0 2008 The Authorlsl
"θ
“"iS(2008)94,315-323
on o 2008 31ackwc‖
Publishing ltd:,ν
レ sα
Joumal compna●
During the cotrrsebf this suryeillanc€, five seriousAEs
were repoft€dfollowing transfusion of PCT-PLT{0 07%,
9io,bCI:0.0-0.2).TheseseriousAEs wereassessed
by the
investigatoFas being 'unrelatedor probablyu!rclated:to
the PCT-PLT
transfusions
andwerc attibuted to proBression
9f underlyingillncs.
PatientB0l-201 wasadmitted.tohospitalfdr a presumed
pulmonaryinfectionpostchemotherapy.
Additionalcomorbidltiesatthe time of admissionweresepticshock,acute
r€nal insufficiercy, neutropenia and thlonbocytopenia.
Intnvenous(i.v,)antibiotictherapywasinitiatedandmultiple
transfusionsof blood products (including PCT-PLI were
administered,
one hour after administrationof the second
plateletunit,thepatientcomplain€dof dyspnoea,
respintory
wasfoundto beh)rpolensive
distress
andtachycardic,-severe
voluDe overloadwas detemined to be the aetiolog/ and
treatmentwith oxygen,diuretics,and dialysiswas initiat€d.
Theeventwasawsed by the irvestjgatorto be unrelatedto
the PCT-PLT
tnnsfusion.
PatieDtJOI-382experieaced
chjlls,nauseaand sudden
with PCT-PLT,
hypoterision
dufingtransfusion
Priorto this,
the patienthad K€ived at least four PCT-PLTtrarsfusions
with no AE.Thf tEnsfusionwasstoppedandtbe patientwas
treatedwith i.v, fluids and iecovered.Four days later, the
patient*periei:ceda !(ond h,?otensiveepisodeaftertans:
fusion,whichwasspontaneously
resolved.Subsequent
to this,
the patientreccivedl9 additionalPCT-PLTtransfusions
withoutanyclini,calsequelae.
patient
This
did not rKeive any
angiotensin-converting
enzyne(AfE) inhibiton.Basedon the
patient'shistoryandtbe lackoftransfusionreactjonwith the
subsequent
tnnsfusions,the investigatorasessedborh of
thes€eventsasppbably unrelatedto PCT-PLT
transfusion,
PatientJOl-516 wasadmittedfor ishaemiccardiomyopathy
and underuentdoublevesselcorcnary artery bypassgraft
(CABO).Thepatiot's
postopentiverecoverywascomplicated
by a significantdsreasein bloodpre$ure,which occured lO
min afterstanoftnnsfusion of PCT-PLIDespltevasopressor
suppoltanda 6-minpedodofcirculatoryarest,thepatient's
conditiorcoDtinued
to deterionteaId hr died,Causeofdeath
wasattibutedto an aorticdissection
with majordisseminated
intravascularcoagulopathyand mesenteicjnfalct and was
assessed
by the investigatoras unrelatedto the PCT-PLT
lransfusion.
PatientJ0l-780experienced
a hypotensive
episode,
cyanosis,
oxygendesatumtionandrauseaapprcximately30 nin after
receiptof PCT-PLT,
The patient receivedoxygenthempyto
treat the eventand rccovered,The patienthad receivedtwo
unitsofPCT-PLTbefore
and oneunit afterthis eventwith no
adverseRactions.The patient had a history of hypotensive
episodes.which occured in the absenceof tnnsfusions.
Basedon tht patient'shistory the eventwasassessed
by the
jnvestjgatorsprobablyunriated to thePCT'PLrtraDfusjon.
Risk factors associated with adverse event
The risk for AE wasnot srelated with the patienrgender,
age,or antigen-matching,
The risk for AE for patientswho
alreadyhad bren transfusedbeforethe fi6t PCT-PLTtnnstusion appearedtrendinghighei comparedto patientswho
did not haveanytransfusionhistory;howevecthedifference
did not reachstatisticalsignifrcance(P = 0.0675;oddsntio:
1 875; 950/0
platelets
CI: 0956-3 548).Bufry:coaGderived
wercasociatedwith a lowerrisk for A! compaEdto apheresis
prcducts(P= 0.0305ioddsEtio:0.473;950,h
CI:0.240-0.932),
were ofsimilar risk for A-Ecomparedto
Iradiated PCT-PLTS
(P = 0.0848;oddsratio;6.344;950/o
non-iryadiated
PCT-PLTS
Cl; 0.775-51.862).
No trendingcanbe concludedbecause,
of the total 7437platelettransfusions,
only 80 PCT-PLT
components
werey-irradiatedin EFs-Bretagne
and EFSAuvergne-Loire,Haematolory-oncology patients rrcated
with conventionalchemotherapywerf at a higherdsk forAE
compared
to theotherpalients(P<o.O0o1;
oddsErio: 7.660;
950/o
CI:3.014- I 9.457).
Number of trmsfusions prior to the. nrst
adverse event
Among the 45 parientswho experienced
at leasrone AE,
repeated
exposurcto PCT-PLTdid not appearto increasethe
likelihoodof a transtusionreactionffable 3). By using the
non-suryivaiatralysismethod(a subsetanalysisfor patients
with any AI only), the meannumberof transfusiorisbefon
fi6t AEoccurencewas8'8 1,10 1 (median= 4, minimum= 0
andmaximum= 37).
［∞
On a per-patietrtbasis,45 patients{3.20i0
of 1400patientsl
who receivedat leastonetnnsfusion ofPCT-PLTexperienced
the 68 AEs followiDgPCT-PLIlransfusions(Table2). 0nly
the 55 ATRS
39 patients(2.8%of l40Opatients)experienced
attributedto thc PCT-PITtransfusion.Foui patjentsexpedencedseriousAEsfollowing transfusion:however,no causal
rclationshipto PCT-PLTtrarsfusion could be establjsbed.
All AEs regardlessof rhe relarionshipwith the PCT-PLT
tmnsfusionoccurRdwithir 4 h after the stad ofthe platelet
(meantime:0.f t 0.51h, 0-3.3 h).Themajority
transfusion
in patientswho.weR
ofAEs(64,or94.l% of68 AEsiocc-uned
not premcdicated.
The other four AEs occurredin patients
who were premedicated
with antipyreticor antihistaminic
drugs,or conicosteroids,
320 J C Ossclaereral,
Discussion
In accordance
withtherecommendations
madcby thepanelof
theCanadian
ConsensusConferenc€,
an adive haemovigilanc
pmgrammehas beenimplementedin Europeto document
the occurrenceof AE following transfusionof PCT-PLT{61.
To.date,two reportshave beenprepared.The first repon was
on thetEnsfusionof5l06 PCT-PUIcbnponentsadminist€red
to patientsjn frve Europeancentresfrom october 2003 to
December2005[+].The secondreportasdescribedherewas
on additional
7417transfusions
ofPCT-PLT
admlnistered
to
patieits in sevenEurop,ean
centresbetweenMay 2005 and
January2007,This represents
a total of I 2 541 independenr
transfusions
documented
to date.Theitarcno overlapsofPCTPLTtmnsfusions
prcgnmme.
reportedin thishaemovigilance
Overall,th€ incidencsof.ATRattributedto transfusiotrof
PCT-FLT
in bothofthe haemovigilance
reponingperiods
was
infrequenteither,ona per-transfusion
basis[0.8V0frnt period
0 2 0 0 8 Teわ
oイ
s)
Au■
J o u m J c o m p u a l o nk "od l2 0ヽ
ぐ
P0hu8lЫ
n Bg l aL″%
t d",bレ
i“″
s12008194,315-323
Haemovigilanceof photochemicaltreatedplatelets 321
Tsble3 Numbefof Pc[-PtTtranifusionsper patiantpriorfo thc fi6t
adwr;..venf {AEl
02●●
S The Author(゛
J o u d“ c o m p u a l o n o 2 0 0 3 8ヽ
1h al cn kg w dL It d P" t1 Ы
“
/"aお
r1 2S0a0■
8194315-323
on when adverseevents could be reportedfollowing
transfusion.Basedon the patient p,opulationsupported
with platelettrsnsfusion,
the studywasdesigned
to capture
repeated
tnnsfusionsofPCT-PLTwithin patjentsto detemine
potentialeffectsof repeatedexposureto this new type of
plateletcomponenL
A limitation of the presentstudy is the absenceof a concurrcnt codtml group receiving conventionalplatelet
compon€nts
withwhichro determine
a comparative
baseline
incidenceofATR. Howwer, becausereportingis obljgatory,
the expectedoutcomesof this activehaemovigilascrstudy
are the incrcas€in ciinical expeience with transfusionof
PCT-PLT,the d€tectionof unexp€ctedAE following PCTPLTtransfusjons
in patientpopulations
and for indications
that wtrc nol studiedpreviouslyin a fomal clinical tdal
environmGnt,
and.theestablishment
for
ofa safetydatabase
future referene.
In the cursnt study,which was specif:callydesignedto
captureall gradcsof tnnsfusion reactions,the prevalence
of
ATRpertrarsnslon,wasat the lowerrangeofthoserepotled
in studieswith conventionalcomponents,Prior exposureto
PCT-PLTtrensfusiods
did notincEasethelilelihoodofanATR.
TheoverallincldenceofATR wasIowerthan that previously
reportedeitheron a per-tnnsfusionor on a per-patientbasis.
platelet
Basedon cxperience
in a broadpatientpopulation,
prepard with amotosalenphotocheniicai
components
treatin routineclinicalpracrice.
nent werew€ll-tolcrated
Acknowledgements
Thi authonwouldtiketo thankthe followingindividuals
of
Fenwal,formerlyBaxterR€tDEurope,who assistedin the
jmplementation
ofthe INTERCEPT
BloodSystemat theblood
centres,prcvidedcritital itrput into the scopeand designof
the haemovigllanepmgnmme,andtnining ofsite pe6onnel
on dataentedng:Joielynf ElameDt,Jean-MarcPaynt, Nitk
Moerman,ValentineFEnck, and VeroniqueMayaudon.
and statistics
service
Quintilesprcvideddatamanagement
prcgramme.
for thjs haemovigilance
Thisstudywassupported
in part by CerusCorporation.
Threeauthors(D,Sundin;L.
Lin andL, Corash)
wereaffrliatedwith andheldstockor stock
optionsofCerusColpontion
during$e conductofthissrudy.
ThreeauthosU. C.0sselaer,
J. P Cazenave
and0. Garraud)
servedon C€rus'sEurcpeanScientifrcAdvisoryBoard.
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DJ,Gulliksson
il, C.".n.u. J?, Panphilon
D,
LjungnarP,KlUte(H,
VemeijH, Kappe6-K1une
M,deGreefG,
LaloretM,
Uow B,DavisK, MarblieS,Mayaudon
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Conlan
M,LinL,MeE€lF,BuchholzD,
ConshL:Transfusion
of
pooledbuiff coit plat€l€rcomponenbpreparcd
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inactivauon
trcatnent:tle eurosPRmtrial,
Blood2003;l0l:2425-2433
2 Mccullough J, VesoleDH, Benjanin RJ, Slichter SJ, PinedaA,
Snyder E. Stadhaucr E, Lopez-?lazaI, Coutre S, St€u$ RG,
CoodnoughLT, Fridey JL, RaifeT, CableR, Murphy S, Howard F,
Davis K, Lin J'S. Metzel P, Coresh L, (outsoukos A, Lin L,
Buchholz D, Conlan M: Therapeuticeftrca.y and saftty of
plateles treated with a photochenical process for pathogen
inacrivetion:the SPRINTli,al. Blood 2OO4i104:l 534- I 541
3 JanetzkoK, CazenaveJP, Kluter H, Kientz D, Michel M,
Beris P, Ljoure B, Hastka J, Marblie s, Mayaudon V, Lin L,
Lin J-S, Con)an MG, Flament J: Therapeuticeffrcacy and
safety of photochemicallyrrearedapheresisplalels proce$ed
with sD optimlzed inte8Eted sd, TtunsJvsloi 2005: 4t:)443t452
4 OsselaerJ, Mse N, HeNig T, Bueno JL, Cas1rcE, EspinossA,
LaconeA JungeK JacquerM, FlamotJ, Consh L: A prospmivc
. obsewatiotralcohort safety study of 5106plalelct iransfusions
prepared with photochenical treatn€nt, Irarulfusior 2OO8l
doir io.i I l l/j.153?-2995.2008.0t643.x
5 GaFaud 0, Fabdgli P, Tardivei R, Goueec H, Waller C,Merdel 1,
: Raidot JP, Kardel C, Isola H, CazenavcJPr Hemovigilancefor
tmnsfusion of INTERCEPTTMplatflets in routire thenpeutic
use: expedenc in Etablissenrnt FEncais du Sang (EFS)blood
.€nt€r$ Yd S4r9 2007; 93{S I )r32
6 Kcin HG, AndersonD, Berlardi MJ, CableR, CareyW, Hoch JS,
RobitailleN, Sivllofti MLA, Smaill F: Pathogeninactjvation:
naklng decisionsabout new technologies,Repot 6fa consensuS
'conference.
Trd{'tusion 2OO7
: 47 :2338 -2347
7 Andrcu G, Morel P, Forestier F, Debeir J, RebiboD, Janvier G,
Hen€ P: Hemovigilance neMork in Francei organizatjon and
anal)6is ofimmediate transfi$ion incident repofrs fron 19941998.Tn6Ju sion 2OO2t42tt 356- J36.
8 FaberJC: Haemovigllance
In Eurcpe:now and tonotrow; In
Rouger P, HossenloppC (eds): Blood Ttgns.fusionin Euope,
Paris,ElsevierS,AS,200512I 3 -232
銀∞
datawerereponedfortlansfusionr€actions,
with an incidence
of four eventsper 1OO0plateletcomponents[0.4%),during
2 yeaF in which thr reporlingsystemwasfiFt implemented.
ilunblr ot PCI-PLTtraniflsiotri
Full analyrkpogulqtiod
However,this may be an underestimatesinceeach whole
prr irticnt untli fiEt Gcurrncc of AE
(r = I aOO)
blood plateletconcentratein a pool was tabulatedas an
individualcomponent
transfusion.
Kerkhoffs
Morerecently,
I
11{0 79h1
era,. [l5j compared
the incidence
oftransfusjbnreactions.
5 t0:43ft1
pooledplateletcomponents
for Ieucoreduced
in plasmasnd
3
3 (0.2i oh)
plasmawith additivesolutionir a studyof I 68.patients
and
4
3 (0.2r%l
755 tEnsfusions.They obsewedan inc.idenceof 5.5% of
1 (0.070e)
transfusionswith r€actionsfor plateletsin plasmavs. 2.40,b
I (0 e%l
I-19
of transfusionsfor plateletsin a mixture of plasmaand
6 {0.43%l
>20
6 {o.43ob)
additivesolution,0n a per-patient
basis,.9.5%
of patients
N {non5uruivalan,lyrismathodl
45
transfused
with platelesin plasmaplus additivesolutions
M.en t S0
88Jl0.l
had reactionscomparedto I 5'5% ofpatientssuppodedwith
Mcdian
plateletssuspended
in plasma.Theser€sultsfufther support
Mnimum-meximum
0-37
the role of the platelet additive solution,lntersol, in the
reductionofATR observedin this study.
Duling the conduct of this study,an interim an'alysisof
vs. OTqbsecondperiod)or on d prr-patient basis(4 90/ofirst
2497 PCT-PLT
transfusionsadministeredto 505 patientsin
pcriod s. 2'8olosecondperiod).The slightly higher occurthe thre regionsofFrance(EFS-Alsace,EFS-Auvergne-!oire
renceofATR per pati€ntin the fi6t reponingpedodwasnot
andEFS-BRtagne)
wasperfomed [5j.0fthe 606patients,the
surpdsing,becausethe mean number of transfusionsper
ptedominant recipients of PCT-PLTw€re haematolos/patient(7.8t l5:2)[4]wasgresterthanthoseobserued
in the
oncologypatients{45.2%);39.90,b
treatedwith chemotherapy
secondperiod(5.3t lo.8).All ATRSwercmildin ssqity and
and6 3% treatedwith stemcelltransplantatjon.
TheseproporofGrrde I or lower.No seriousAE from both studypedods
tionswereonlyslightlylowerthanthosein theoverallstudy
weR.atbibutedspmificallyto transfusionof PCT-PLT.
population
patienrs,
yet onlyfourof the606parienB
of ) 4OO
0n a per-tnnsfusibnbasis,the prwalenceof,ATRhasbeen
(0 70,t)reportedan AE; including one seriousAE ofvolune
0/o;
reportedi! the litcratureto nnge.from I I to 3 I b owevet
overloadclassifiedasunrelatedto PCT-PLT
transfusion,This
thesestudieswetr conductedsome years ago with variabte iow rateofAE ob*ryed in the Frenchregionscouldconfibute
methbdsof plaleletpreparation[10- l3]. Moie recentiy,the
to the overalliow incidenceofATR per patientin this study.
incidence0fmodemt€andswereATRhasbeenreportedfrom
Prcm€dication
in patientsdid not play a rcle in the overall
thetdal to Educealloimmunizationto platelets(TRAP)study,
low incidenceofATR reportedin this study.Infomation on
which examined8769{latelet transfusionsin 598 patients premedication
wasonly requestedin caseofAE occurrcnce.
duringindudionthqapy foracuteleukaemiaIt4]. In theTRAP 0f the 68 transfusions
with occurrence.
of at leastone AE,
study,ptateletcomponeitswere prcparcdby four methods: only two antiplretic,two antihistaminic
andoneroticosteroid
unfilteredpooledwhole blood-derivedplateletsin plasma; wen prescribedto patients, For the majoilty (64/68, or
filtered pooledwhole blood-derivedplateletsin plasmai 94 lqo)ofth6etlansfusions,patientswercRotpRmedicated,
unfilteredpooledwholeblood-derivedplateletsin plasma
The activehaemovigilance
programmedescribedhere
trcatedwith ultEviolet B itluminationto reducehuman
is a prospectiv€obsruational study,which was designrdro
lzuc;rytcantigensensitization;
plate- assessthe safetyprofile of PCT-PLTin routineclinical
and frlteredapheresis
letsin plasma.Noneoftbesecomponentswer<prepaRdwith
practic€,Thedatafiom this prognmme represent
tbe largest
additivesolutions.The overallincidenceof ATR was 2.20lo
prospectiveexperienceto date for r(ording potentialAE
of
transfusions,and 22oihof patientsexperiencedat leastone
with platelettransfusions
associated
to priorstudies
compared
Afi. In comparisonto the TRAP trial, the cumnt study in
of retrcspective
designand limitFdin sizeIl0,l5-t81. The
which all gradc ofreactionswrre rcported,both the propordon
presentstudy was designedto b€ consistentwith Europear
with a Raction was tower (0.70lo) ha€movigilance
practices
oftransfusionsassociated
in whichreporting
of all grad6 of
aswell as the proponion of patients{2.8o,t')
expeilencingat
transfusion-associated
reactionshas beer emphasized
least one ATR.The useof 65% lntersol, a plateletadditive
In contrast
to otherhaemovigilance
studies,
obligatory
{7,81.
solution, in the prepaEtionof PCT-PLTmay partially conreportingfor all platelettransfusions
wasrequired
i[espectributeto the reductionin the obsewedinc'denceofATR Il 5].
tive ofwhetheror Iot an AE wasobserved,
Thecurcnt study
Theincidenc€
ofATRin thisstudycanbecompared
to data
focusedon AE that could be Iinkedto PCT-PLT
transfusions
frcm the haenovigtlancenetwork in France[7]. In France, afterstartjngtBnsfusioni
buttherewerenospecificlinitations
322 J C Ossclaer`′ο′
prccestesforinactivationofleukocfesto
9 CorashL,LinL:Novel
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11 Heddlr NM. KelmaL, Singei J, RichardsC, FedakP, WalkerI.
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tGhstusion reactions:N Ergl J M€d 1994t lll1625-628
l2 MahganoMM, ChambersLA Kruslall MSr Linited emcacyof
leukopoor pletelets for pwention of febrile transfuslon reacdo s. An J Ctiil PotholI99l ; 95:733-738
13 Heddle NM, Klama LN, ftiffith L, RobertsR, Shukla G, Kelton
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PLI tansfusions: experienceof the TRAP nulticehter clinical
dal, TruilsIusion2OO3
i 43 : | 545- | 552
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Blood Systen
for pfatelets) in a rcgional blood center. Vo, Sang 2007;
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1
0 2008 ThC Authorsl
J o u r n t t cOonm pot a2●
0 6 0 B l a｀
ch kl wn 1g l L彼
Pt udS Ы
"a ル
“
“
j"1`12003)94,315-323
Haemovigilanceof photochemicsltreatedplatel.ts 323
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'
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solution: a prospective, Fndomized study. Iror.t!fusioa 20OO;
40:398-403
18 Heddle NM, Blajchman lrrlA.tvteyerRM, Lipron JH, Walker IR.
Sher GD, Constantinj LA patteson B, Rob€rtsRS, Thorpe KE
LevineMN; A randolnized controlled trjal conparing the
frequencyof acute rcactjoN to. plasna-removedplateletsand
prestorageWBc-reduced plateleb. Translusiofl.ZOO2:42t556566
ｍ∞
O 2008TheAuthods)
Joumalcompilation
@2008Blackwell
Publishiigl.td.,
Vu Sangfinis
l2oos)94,3t5-j23
PLICAT10NS
Transfusion of platelet components prepared with
photochemical pathogen inactivation treatment during a
Chikungunyavirus epidemic in lle de La Rdunion
Patrice Rasonglbs,
Marie France AngeliniTibert, Phitip Simon, Caroline Currie, Herve Isola,
DanietKientz,Marcstledts,Micrr;,a#T;::::J::;diu
tartine in 2005, m epidemic of CNkunguya
1t-l
virus (CHIKV) in the overseasFrench department
\
oflledeLaRdunion,anislandintheSouthlndiil
. I
l:-f
Ocem, resulted in the inJection of more thm
one-third ofthe 750,000inhabitants by early 2006.rCHIKV
is an enveloped single'strmded alpha virus from the
Togaviridae family transmitted by Aed* mosquitoes. It
genera.llycauses a mild febrile i.llnesscharacterized by
arthralgiaslasting up to l0 days,but th€ recenl epidemic
was associated wi$ myalgras, dematitis, hemorrhage,
meningoencephalitis, respilatory failure, cudiovascular
decompensation, and fulminant hepatitis with persistent
anhralgias in somg patlents.'zSubsequently,more than
700 cases of CHIKV infection were reported in meuo-.
politan France arnong returning travelers,and I infection
ABBREVIATIONS: AE(s) = adverse wetrt(s); ATR(S)= acute
tEnsfusion readion(s); CHIKV = Chikungun)" virus;
CPA(6)= apheresis platelet component(s); CRF(s) = 6esg r.t.rt
fom(6); EFS = f,tablissemeit Frangais du Sag; SAX(s)= severe
adverse event(s); TT = tnnsfusion tresmitted.
From the EFS IIe de La Rdunion Dd CHR Centre Hospitalier
Ddpanemental Felix Guyon, St Denis, Ile de Ia Rdunion,
after needle stick of a health care workerxl Owing to the
high prevalence of CHIKV infection and the potentia.l for
transfusion-transmitted (TT) infection, the Etablissement
Frangais du Satrg (EFS lFrench Nationa] Trusfusion
Servicel)suspendedblood donation on lle de La Rdunjon
to prevent T"l-CHIIqIt To meet the requirem€nts for safe
blood components on IIe de La R€union, red blood ceUs
and plasma componerits (ftesh-frozen plasma) were supplied by EFS from metropolitan Frmce. Becauseof the
limited shelf life (5 days) of platelet (PLT)components,
EFS-La Rdunion' implemented pathogen inactivation
prepilation ofapheresis PLI components (CPAS)to maintain local PtI component supplies.s
Pdor researchstudies had demonstrated that CHIKV
was inactivated by photochemical treauTent with amotosa.lenHCI and UVA light (INTER€EPT Blood Systemfor
platelets, Cerus Euope BV Amelsfoort, The Netherlands).6 In addition, this system had been shom to
inactivate high levels of a broad spectrum of viruses,
bacteria, protozoa, md wNte blood cells (WBC) in PUf
components.T's
The INTERCEPTsystem receivedCE Mark
regisuation as a Class III drug device and as of 2005
received approval ftom the Agence Franqaisede SdcuritC
Sanitair'edes ProduiB de Santd (AFSSAPS,
French Agency
of Medical Safety of Health Products) for use with both
apheresis-and.whole blood-derived PLI components in
France.:
The INTERCEPTBlood System Ms implemented in
routini practice as ofVarch 13, 2006, by EFS-Uede La
Rdunion. To date, approximately 4000 INTERCEPT-CPAS
have been adminlstered to a broad range of patients on
IIe de La Rdunion. After the fust year oi routine use of
pathogen inactivation.to prepare PLI components, we
conduct6d a retrospective analysis of the response to
fiansfusion.of i95b componerits to determine the incidence of acute transfusion reactions iATfu) md serious
adverseevents (SAES)attributed to use ofthis novel component, In addition, we determined the incidence of
TT-CHIKVinfection fdr the nJst yeil after ifi plementation
of pathogen inactivation treatment during the CHIKV
epidemic.
F!an@; CHRGroupe Hospitaller Sud Rduiotr de St Piere, Ile
de b Rdunion, FBnce; CeiusCorporation, Concord, California;
MATERIALS
AND METHODS
EFSAlsace, Strasboug, Frilce; Cerus Euope BV Ame6foon,
The Netherlands; the Universlty ofCalifornia School ofMed!
Colleclion of PLT.components
cine, Sil Francisco, California; INSERM U.3l I and UniveGitd
BeforeinEoduction ofthe INTERCEPTsystgm, CPAswere
the sole tlpe of PtI component provided by FFS-La
Rdunion. All CPAswqre couected in donor plsma with
integral fi.luation leukoreduction (Haemonetics, Brainuee, MA). After introduction of TNTERCEPI,PLIS were
collected in approiimately 407o donor plasma.and 60%
PLI additive soluuon (Intersol, Fenwal, La Chaue, France)
ftom donors with PII counts of 250 x 10'g/Lor morc using
a blood component collection system (Haemonetlcs
McS+ system\r;th the GSDPsoftware) to allow automatic
Louis Pasteur, Strasbourg, Froce.
Mdr6s reprint requesls loi Lauence Cordh, MD, Cerus
Corporation, 241 I Stuwell
Drive, Concord, CA 94520; €-mail:
Icorash@cerus.com.
Thi6 studyw€ supponed in pilt by Cerus Corporation.
Receiwd for publiBtion luly 28, 2008; rcvision received
Decehber 12,2008, and accepted December 12,2008,
dol l0.l ll l/J.1537-2995.2009.0211
l.x
TRANSFUSION 2009;49:l0B3-1091.
Vo ume 49.」une 2000 TRANSFuS:ON 1003
1084 TRANSFUSION
Volume
49, Juns2009
addition of Intersol. The tilgeted PUf dose per collection
was 4.0 x l0rr or greater.WBC contamination was reduced
by fi.ltration with an integra.l WBC filter (Haemonetics).
In addition to stmdad viral screening tests, donors
were tested for CHIKV.infectiOn by an investigational
reve$e.transcriptse polymerase chain reaction assay
(RT-PCR).lro
Psthogen Inactivation treatment of PLT
components
CPAScontaining 2.5x tor! to 6.0x l0rl PI-TSin 300 to
390 mL of approximhtely 40% plasma and 60% Intersol
were prepared with pathogen inacti%tion using the
INTERCEPI prccessing system (INT2202, Cerus Europe
BV) acpordihg to malufacturer's instructions for use.
Briefly,a unit of CPAwas mixed with amotosalen (nominal
final concentration of 150 pmol/L) and illumlnated with
long-wavelength ultraviolet IIVA (320.400m) light for a
3 J/cm?oeatment. The illuminated PLjI mixtue was incubated in a compound adsorpiiondevicein a temperature
controlled PLT shaker/incubatot (22!2'C\ for 6 to 16
hous before $ansferring to the final slorage container
Tleated CPASwere stored for up to 5 days under standard
blood bank conditions before issue for transfusion.
Hemovigilance surveillanca
General study design
Thls was a reEospbctive anglysis of data recorded prospectively in plimary care mefuca.lrecords and ai part
of the AFSSAIS active hemovigilance surveillance program-rr There were no patlent inclusion or exclusion cr!
teda other than the requirement for PLT transfusion. All
patients who received PLI transfusion support during the
dehned-study period were included in the analysis. Case
report forms (CRFS)were used to collect patient datar2on
each transfusion of INTERCEPT-CPAsbetween March
13, 2006, and March 13, 2007, regardlessof whether a
adverseevent (AE) was reported
The prindry endpoint of the study was the propor.
tion of transfusidns with AIR after administration of PLI
components. ATRSwere defined as AEs possibly related,
probably related, or related to a PUI $msfusion. SAES
were defined as AEs that were fatal, life-threatening, or
disabling; resulted in or prolonged hospitalization or
morbidity; or were incapacitating. Secondary endpoints
included evidence of acute TT-CHIKV infecdon (basedon
nucleic acid mplification of viral sequences).All transfused patients were monitored for 7 days after each trans.
fusion for potential TT-CHIKV infection using standard
EFS operating procedures,roData also were collected on
use of INTERCEPT-CPAS
by patient priniary diagnosiscategory md clinical indi€tion fo! tlansfusion.
ヾ∞
BACKGROUND:Duringthe Chikungunyavirus
(CHIKV)epidemlcon ll€ de La R6union,France,more
than 30o/oof 750,000inhabitantsw6r6 Inlected.Local
blood donallonwas suspendedlo prevenl lransfusiontransmittedInf@tion(fT.CH|KV). To suglalnlhe avail
abitdyol plat€tEt(PLT)components,the Elabli$emenl
FEngdis du Sang implsmentedunlversalpathogen
inactivalion(INTERCEPT,Cerus Europ€ BV) ol PLT
components(CPAs).The study ass€ssedthe Eafetyot
PLT componenlstrealedwlth pathogen inactivation
transtussdIn rcutln€cllnlcalpractlce.
STUDY DESIGNAND METHODS:This was a retrospectiveobssrvallonalstudy using palient medical
recordsand th€ AFSSAPShemovigilancedatabase
(€FlT) to ldenllfyTT-CHIKVand advers€ evenis (AEs)
dlasifigd as adte tansfsion raactians(ATRS)to PLT
componenlspreparedwlih pathogen Inaclivation.
RESULTSi Durlng1 year, l95O INTERCEPT-CPAS
wore lEnsfusEdto 335 adutt, 51 pediatric,and 41 intanl
patlenls.Ninets€nAEs were obserued in 15 patienls
and l0 weF.classitiedas ATRS.Eight.ATRs@ured in
palients.No ATRS
6 p€dlatdchematology'oncology
were obsgruedin infants,Ths most frequentlyreported
slgns and symptomsw6re Gmde 1 urticaria,itching,
chllls,tgver, and anxlely.No cas€s of transtusion"
relal€d acute lung InJuryfi-s€psis, or TT-CHIKVw6ra
d€lectod.
were well tolerCONCLUSIONS;INTERCEPT-CPAs
al6d in a broad rangeof patients,IncludingInfants.ATR
Incldenc€was low and when presontATRSwero of mild
s€v6rity.
LiIy Lin, Laurence
corash;and
RASONCLES ET AL.
PATHOGEN:NACTIVAT:ON AND CHIKUNGUNVA ViRuS
same criteria as used by the AFSSAPS.hemovigilance
system.ll
The standardized CRFshad been validated in a prior
hemovigilance study.-hData from the CRF were entered
into an independent electronic database used for
postmarketing hemovigilance prdgransrz rl and reviewed
by the principal investigator for incomplete data. At the
conclusion otthe study,AEsclassifiedas transfusion leactions based on review ofthe primary cae medica.lrecords
were compared againstAEsprevioNly repotted under the
AFSSAPShemovigilarce progmm recorded in the eFIT
databasetrtodeterminerhe rotal incidenceofAls attributed to PLT tnnsfusion, These data were then ana.llzed to
determine the incidenceof ATRs.
Statistioal analyses
A statistica.l analysis plan for the study was prepared
and approved before analysis. All statistical malyses,
summary tables, and data listings were generated using
computer software (SAS,Version 8.2, SASInsritute, Cary
NC). The primary assessment was the incidence of
transfusion reactions.The number and proportion (%) of
transfusions ed the proponion of patients with one or
more transfusion reacdons were summaized overall,.by
seriousnessmd by relationship to PIT transfusion. Corre-r
sponding 95% confidence interuals (CIs) for the binonial
proportion were calculated uiing the F distributidn
method. The 957oCI were based bn number of Datients
with my A-E/ATRand the number of tansfusions aisociated with ilyAE/ATR. In addition, the patient population
profi.le,the charaderisticsof the PLI components,and the
chamcteristics of the AEs after PLT transfusion were analyzed. Analysesto identii/ risk factors potentially associated with tansfusion reactions were conducted using
multivariate.logistic regressionanalysis md by assessing
association at a 10%significancelevel. Data were malyzed
on a per-transfuslon and a per-patient basis.NI.INTEhCEPTPLTcomponents administered to patients wele part
of the full analysispopuJationandwere mallzed, whether_
or not an A.Ewas observed.All ana.lyseswere conducted
using this firlt malysis population.
PLTcomponent
characteristlcs
Each CPA was teated with pathogen inactivation using
the INTERCEPTBlood System on either Day 0 or Day 1
after Pijf collection and stored for up to S days before
release for uansfusiofu PLT components were released
after completion ofserologic and NAL PathoganinactivaUon treatment was used without bacteria detection
other dran routine quality control (QC) assays.pathogen
inactivation treatment replaced cytomefaloyirus (CIvfV)
Vol●
m● 49,」une 2009 TRANSFuS:ON 1085
uansplantation, Among the pediatric datient group, the
proportion of hematology-oncology patjents (66.7%)was
significmtly higher 1p=9,9911 than among the adult
patient group (26.3%).
Approximatelyhalf of rhe patient population (5l.5yo)
rec€ived [ansfusions in intensive carc units and the other
half (48.sqo)weretmnsfused on non-intensive care hospital services (Table l), There were no outpatient transfusions in the current sweiuance program. Subgroup
analyris showed that, while most ofthe pediatrjc patients
(78.4%) were transfused in non-jntensive care.hospital
wards, the majority ofinfanb (9O.2qo)
wele transfused on
intensive care units.
Patient demographlcs
PLT transtusion exposure
Alproximately 53% of patients had a prior history of
transfusion exposure to some blood componenl The
median number of PLI transfusions per patient was 2.0
(range, l-66; Table2). Of 1950 PLT uansfusions, 1372
uilsfusions were administered to adult patients while
487 and 9l tnnsfusions were administered to pediatric
patients ild infants, respecrively.Based on the respective patient population, 36 to 47Voof patients received
two or more PLT transfusions. The number of tnnsfusions per pedjatric patjent (9.51 14.7)was significantly
higher (p < 0.001)comparedto those ln the adutt popu-f
lation (4.1 a 6.2) while rhe opposite was true for infantsw
(2.2t2.4, p <0.002). Based on primary diagnosis category, hematology.oncology patients in all age groups
received a higher proportion of PLI. tramfusions
per patient than drose in other diagnosis gloups
(Table2).
Between March 13, 2006, and March 13, 2007, a total of
1950 INTERCEPT-CPAS
were Emsfused to 427 patibnts
(TableI). Each patient received at least one INTEnCEPTCPA. The patient population consisted of 335 adult
patients (>18 years), 5l pediatric padents (>l to <18
yeats), and 4l infants (<l yea). There were more nale
patients in each age group (Table l).
Hematology-oncologydisorders treated with chemtherapy and stem c€ll transplantation constituted 29.0%
of the primary diagnoses among the trilsfused patient
population and these paUents received 6l% of the pllf
components (lhbles I and 2). The largest patient group
supported with PLI components w6 rhe generalmedical
population (58.5%),but they receivedonly 30% of the pLT
components. A number of patients receiving pLI uansfusions (12.2%) underwent major surgiial procedues including cadiovascular surgery or solid organ
l
TABLE l:pem。9[lphi●
S 。[2,tients trantfus,d with:NTERCIPT・
cPA3'
Podl●lc(￨・
50
_`duに (n.335)
Mal€
Female
Aga (y€ars)
M6an i SD
Median
Flange
Car€ location
lnlgnsivo
Nonintensiv6
Homatology-oncology
primary th6rapy
Convontionalqhemotherapy
Slen c€ll transplant
Surgery
Cardiovasculaf
Solid ofgao trangplat
Gen€rsl m€di€l
262(614)
165(386)
460
(l to 87
220(515)
207(485)
124キ(290)
107(822)
14(113)
52(122)
49(942)
3(58)
250(585)
2021603)
133(397)
9 4 ±5 3
>181087
172(5'3)
16314871
87(2Q3)
69(793)
10(115)
48(143)
45(038)
3(62)
199(5941
1(0.3)
The number of pEtignts(n) and th€ proportjon(%) within each €tego.y
pe"nfeo.
"rJ
i Ag€ for infantsWasonly .@rded Es <1 y6ar NA = not applicablg.
t Eight aduh paltafs had no activs thorepy sp@ingd at ting ot transiugion,
1036 TRANSFuS10N Volum●
40.」Ⅲ 02009
o5(686)
16(31.4)
l t0 18
４。４３３０４０
１ “ ３３
︲
RESULTS
serology for patlents who required CMV-safe PLTSand
replacedgamma irradiation for prevendon oftrilsfusionassociatedgraft versus hos( disease,
The INTERCEPTprocess resulted in a mean PLI loss
of 7.8%dUeto volume loss duing container trmsfers. The
mean PLI yield of INTERCEPT-CPAS
was 4.Zxt1tt !
0.7 x l0rr Plfs per component. The residual WBC count
met the national .QC requiremeni (<0.5x 106/unit).
Approximately i5% ofPLT components were divided into
2 units befote tiansfusion to fulfill clinical demand. The
proponion of split PLI components was similar to that
in the period before inplementation of pathogen
inactivation.
的
問
回
ｍ
囲
田
ｍ
に
Ｏ
Data collection methads
All patients transfused with PLfs prepared by EFS.La
RCunion ftom March 13, 2006, through March t3, 2007,
were identi.ned from the EFS-k iidunion electronic database for the collection, production, and issuance ofblood
components. Each patient was identified with a unique
study number to preserve anonlrnity The following data
were collected; PLT product code; patient unique identifi,
cation number associated with the component, patient
'demographics
(age, sex), and primary diagnosis based
on clinical care area; primary therapy (chemotherapy,
hematopoietic stem cell transplant); surgery (cardiovascular or organ trmsplant); or other (general medjcal or
multisystem organ failure).
Primary cile medical records of each patient were
reviewed for the 24 hour period before each uansfusion to
establish a baseline profi.le of the patient's clinical cond!
tion, for 7 days after each PLT trmsfusion to idenrify new
AEs arising after transfusion, and to record the relationship of AEs to PUf tnnsfusion in the prirnary medical
record as assessedby primary care ph,Ticims. This review
was conducted by an observer without knowledge ofAIs
reponed in the AISSAPS hemovigilance system (eFIT).rr
For the 24 hours before and for the 7 days after each PLI
transfusion, medical records were specifically reviewed
for widence ofclinical conditions that couldbe attributed
to transfusion-related reactions, including fever (increase
in temperature of2 or l'C with chius), chills, nausea,skin
rash, urticaria, dyspnea, bronchospasm, tachycadia or
bndycardia (change in heart rate by >25 bpm), h!?otensiod or hypertension (decrece or increase in systolic or
diastolic blood pressure >30 mm Hg, respectively),hemoglobinuria, hemolysis, and change in general well-being.
Specific criteria were prwided. for the diagnosis of
transfusion-associated acute lung injury (TMLI).!3 Clin!
cal microbiblogy laboratory records were rerliewed for
documentation of trmsfusion-csociated sepsis, The
diagnosisof uansfusion.associatedsepsls required.the
isolation ofthesarnebacteria speciesfrom the patien! and
the implicated PLT component.
Tlansfusion CRFswere completed for each PLf ransfusion regcdless ofwheiher or not an AE was noted in the
medical record. In case of the occurrence of an A!, add.itional clinical and biologic information as well as test
resu.lts for CHIKV infectlon (nucleic acid resting (NATI by
RT-PCR)were collected. These data were used by the
medical record reviewer for assessmentof causa.lityand
swerity based on the medical record. Clinical severity of
AEs was classified according to the following scale: Grade
0=isolated dysfunction without clinica.l or biotogic
manifestation; Grade I = absence of inmediate or longterm life-threatening effects; Grade 2=long-term lifethreatening effects; Grade 3 = immediate life-tfueatening
efrectsiand Grade 4 = death. The relationship ofAEs to the
mos! ploximate PLI transfusion was classified using ihe
RASONGLES ET AL.
1nlants(n=41)
25(610)
16(390)
NAI
NA十
37(902)
4(98)
0(73)
3(1001
0(0)
1(24)
1(100)
0(0)
37(003)
PATHOGEN INACTiVAT:ON AND CH:KUNGUNVA V:Rus
TiBLE 2, Trsnstusion sxposur3 among pa$ent populsilons
A‖
All palients
Transfusions(n)
Mean i SD
M€dian
Rangg
H€malology€ncology
Transtusions(n)
Mean l SD
lredian
Rang€
Surgi€l
Translusions (n)
M6an a SO
Median
Range
General medical
Transtusions (n)
M6an : SD
Medlan
Rilg€
Mlssing diagno$s
Translugions(n)
Mea : SD
M€dlan
Range
patonts(n=427)
６
。
６
帥
け
．
２
︲
Popuatbn
6nts(n=335)
Adun pa‖
Pediatrc lathnts(n=51)
h●nt pa‖
ono(n・41)
60
０
︲
６
¨
“
“
︺
ｏ
・
フ
︲
︲
135
28■37
20
24=28
３は﹁︲
３
︲
３
３
︲﹂御︲
4(09)
5(12)
5(121
S(121
1(02)
4(09)
1(02)
2 (05)
4(09)
4(0.9)
2(06)
4(12)
1(03)
1(03)
1(03)
2(06)
9076)
13(27)
0(113)
8(16)
l103)
210、
6)
0
2(39)
1(20)
4(78)
4(78)
0
4(78)
4(78)
Anメlety
2(39)
Othe1
6●
41
2105)
1′
2(39)
103,
0
5(98'
' Oata
are roporled as number (%). No AEs w€r€ reported for infant pationts;lhus, these palients and transfugionsare not includ€din this
t8ble.
t Numb€r ol signs/symploms can qcegd numbgr ot AEs du€ to mulllpl€obs€ruedsigns/symptgmgper AE.
relationshiplhat an AE was possibly r€lated,probably relaled, or relalgd lo INTERCEPT-CPAlEnslusion.
ATR = EHI
AE6 and ATR8 atter PLT transfuslon
The incidences ofAEs and ATRSwere evaluated on a pertransfusion m well as per-patient basis fTable 3). On a
per-transfusion basis, 19 transfusions (9570 CI, 1.0%.
1.5%) were associated with m AE. Of these AEs, l0 (95%
Cl:0.580-0,9%)were clasified as ATRSpossibly, probably,
or related to INTERCEPT.CPA$ansfusion. No SAEs,no
1;P」
侶ぽ
η
tered
hematology-oncology
teated
potentially immune-suppressive therapy, There were ho
cass of TICHIKV reported in thjs suruey based on the
test results using an invstigatlonal a$ay for vhal hucleic
acid or posttransfusion clinical obsermtion. for signs aird
slmptdms of CHIKV infectjDn.
casesofTT-sepsis, no casesofTRAII, and no deaths due
to INTERCEPT-CPAtransfusions. were reponed. On a
per-padenrbasis, 15 patibnts (95% CI, 3.5%-5.7%)wio
leceived at least one trarsfusion of INTERCEPT-CPAs
experienced an AE after PLI transfusions (Table3)i
Only 8 patients (957o CI,1.9%-3.6%) experienced
an ATR attributed to INTERCEPT-CPA trusfusion
(Table3).
Vol●n●49,」une 2009 TRANSFuSЮ
N lo87
'嵐
′
蜜
鑑聴謝譜 ∬出雷
躍
1島
patent basls Most of ATRs we,described as Grade l
itthmg(00%),品 carla lo,9%),ald Ch」
Is(o5%)● dl all
bhe■ ObServedat a rate Of0 2%orleSs per patient.
fA「
s an,AT,6TP'製
itri:
:li:11°
161'S°
.
DtscusstoN
CHIKV resu.ltedin an epidemic on La Rdunion Island iri
which appro:timately4l% of the population was infecied.
Serologic and epidemio)ogjc suryeillance studies estiPё
d●tiC'atlents expenenced a hlghOr mtidencl of AEs
mated the preva.lenceofasymptotnatic infectibn at t5% of
total CHIKV infections.' Efforts to identiry infected blood
甘耀じ謬器鞘 11踏 :1織糊 :』:凛
dono$ ltith either serologic assays or CHIKV specnc
patents compared to l AEs 10 4%)an1 2 ATRs(0:1%)1,
nucleic acid amplification assayshave sholvn consideradut pauen“
c
Patien“
onaper_patientbasis,9 pedia●
able variability and suboptimal sensitivity.r5Themean,risk
0767)exP,nOncod at least ompared
l AEし to 6 adut ofcontamination ofa blood donationthroughoutthe epipatents o 8701 Smlarly 6 pediatlc nts(110%)
Patё
demic was estiinatedat 132per l00,000.donations,
md at
e,periehced leaSt
a、 l ATR,omp●
ed t0 2 addt,atelts the peak of the epidemic, the
risk was estiinated at l,500
(06%)
per lO0,OOO
donations.r At the time of the current study,
For aE.AES repb=“ d in pediatrit patents, the
optimal methods to detect infected donors with low.viral
Sッ
mptOpsysigns were prё
dbminandy Grade l m sever,
titer6.werenot available, and a NAT with sensitivities of 40
conSsl●g offeve■
chls,itclung,ur"ana,aぃ。e,tachI
to 350 copies/mLwas only developedlater.roIn.the period
cardla,and●lala.slhg‐Cable p)For pediatric PaJβ
nお
of this study, collection of CHlKV-contaminated PLTS
expert,chgダ Rs● 9 spOptOms/dglヽ hduded ichm3
ftom asymptomatic donors was plausible. Driringthe epiurticaria,tachycardla,and facial nushhgi none of which
demic before w€ of pathogen inactivation, two casesot
were r■o●ё
d h admt patients NO AEs wett associated
TT-CHIKVwere suspected,but neither casecould be conwiththe 91 NTERCEPT‐CPA transmsions admmstered to
clusivelyproven.'0At leastone blood-borneuansmission
41■nfants who requlred PLT su,pOrt
due to a needle-stick has been documented.i
This study accomplished muJtiple objectives. ForeCh●ractOFlstics Of AEs and ATR3 aSSOCiated unth most, it provided hemovigilance data to evaluate the
transfusion of 3p‖
t cOmponents
efectiveness of the INTERCEPTBlood System to prevent
Of the 1950 tran,Fusions,540 1NTERCEPr CDヽs、vere
PLT TI-CHIKV durin! an epidemic. These data are espeobtal,edfrOmlspl■PLTcomp6nent The ratoS OfttESand
cially relevant given the specificassociationofCHlKVwith
1000 TRANSFuS'ON V● l響
uno 2009
"。49,」
０∞
1 ( ●1 )
2(01)
￨(0:2)
0(03)
0
0
2(01)
Pedjavic pati€nts(n = 51)
Transtu$ions{n = 487)
０００
5(03)
7104)
5(03)
7(04)
1(く01)
4(02)
0(03)
ωｍｕｏ
10(05)
∼口t patlens(n_335)
Trans,siOnS(n=1072)
問ｍｍｍｕ鰤ｕｍ団
TranEfusionswllh I or >AE
Sign€/symptomspgr tBNlusiont
FeVer
Chill●
Itching
urtlcana
Dyspnea
Anxl●ν
Olいo「
Signs/symptoms per pa“entt
Fover
Ch‖ls
ltching
Uttcatta
1 5 ●5 )
19(101
fl:
品
l棚n=鶏
鶏器
蹴覇轟』
:場
首
ツ輩:踏 d
a l s y m p t o m s h t h e octahteerg"olrnyd iodfe“
^ d d iO ●
TABLE 3, Cllnlcal char.cterlstlcs of AEs and ATRSamonO pailenl populations.
wi崎 lo子 1繁 E
OVera‖patlent po,u:atiOn:
BL二
l comp♀
°n l h e f r e q u T , y o f , E s a l d
CharaCter:st:OS of c:lnica:sign3
1.EIect olザ
摯
躍ぽ
6iat,d With
and sympto“s ass●
PLT transfusicn
Of au AEs, 9■ l perrtran,fuSOn
basls,the host iOquently Observed TOla
1950
19 0 0)
10(05)
Dala ar€ rcpgrledas number (%),
ツnptoms/signs,3%104%of 19,Q
tanSヽSiOns)were fevOL Is,itchingi
ch」
and urticaria(Table強3).を
ety(o2%)
w a s t h e s , c o n d m o s t f r e l u e n t l y r e p osrllgend s yAIRS
l n pon
t oamper-transfusion
′
basisfor split components were
l y o n e m c iO df e ■
O■
d y s p n e a w a s r e , o r t e d : 0.4
A d dmd
i t090,
i o nrespectively,
al
compiled to I:2 and 0.790for
symptomsin■e category otherlincluded
taChycardla,whole cdmponents. Of the 19 AEs reponed, only 2 AEs
of“
hciai nushm3 b9dy Pain,ahd COЧ
gh,lbⅢwith lh ind「 (one in a 77.year-old male patient and one in a l6:ye81%Or less of transfugons Most of old male patient) were associatedwith tmnsfusion of a
■dual mollente。
10・
(Table4).
the ATRs were described prhcipally as Grade l wtcaria
split INTERCEPT-CPAS
di(Clulg(177)●
th」i。
(her sylnp19mS/S`rS
(03%)a■
observed at a rate of O l%o,less Of transhsions
on a per‐
ed obseⅣ
patent basis.the most frequcntly
Incldence of TT-CHIKV
symptO●s/signs(1.2700f427 en“
pa」
)were CHlls,itchln3 A substantia.l proportion of transfusions were adminis直ety lol,%)were tle
,nd uructtia(Table 3).Fever and山
to
parients
with
淵1鵬
瀾諄♀
hs
20
・427)
測l pa1lonts●
RASONGLES
ET AL.
PATHOGEN lNACTiVAT10N AND CH:KUNGUNVA V:RuS
after transfusion of INTERCEPT-CPAS.
This finding may
not be surprising becausetIe proportion ofhematologyoncology patients and the levels of PLT component
exposure were higher mong pediatric patients. On
the other hmd, no AIs or AIRs were observed in
infants who received INTERCEPT-CPA transfusions
largely for nomalignant medical disorders, but this
population was of limited size and less intensively
transfused.
The study also provided expedence with the implementation and operational logistics of the INTERCEPT
system in a remote, small regionil blood center EFS-Ilede
La RCunion performs approximately 100to 150 apheresis
PLf couections per month.a Complete conversion to
pathogeninactivarionofPLTcomponentswasachievedin
2 week. In routine operation, no additional personnel
were required after implementation of the INTERCEPT
sys(em.
This ia $e fust study to demonstrate the utilty of
pathogen inactfuadon as a proactive approach to prevent
a potentially TT infection duirg m epidemic. The technology facilitated the availability ol PLT components
that otherwise were in limited supply. This expedence
is relevant given the obseryation of imported cases of
CHIKV infection . in metropolitan France, Germany,
the United Kingdom, BelSium, Noruay, the Czech
Republic, Canada, and the United States32asand the
aulochtlonous outbreal of CHIK infection in the EmiliaRomagna region of ltaly.26The successof EFS-ln RCunion
in inplementing the INTERCEPTBlood System demon.
suates the utility of pathogen inactivation to support
the availability of labile blood compondnts during an
epidemic.
ACKNOWLEDGMENTS
The authoF alEgratefulfor the supportofCh@talWallerin prq:
viding guidanceed traiDingfor tbe cotrductof the hemovigilance study of pathogen-inactivated
PLI components,Lynerte
Sawyerperiormedcritical studiesto validateinactivationof
CHIKVinPLf andplasmacomponents,
Theauthorstha[k Carole
Ripaudfor assistucein facilitatingcomunicarions betweenthe
inwstigators of EFSL€ Rduion and CerusCorpontion and
Hmoverfor editolialassistance
Wea.lsoacknowledge
Jessica
the
effortsoftunaud Besnddih facilitatingthis study.
CONFLICTOF INTEREST
Threeauthors(DS,[.I. andrc) werea!frliatedwithild heldstock
or stockoptionsin CerusCorporationduringthe cotrductotthis
study.M, wd a @nsultantto CerusCorporation,
md CCreceived
a rsearch glilt &om CerusEuropeBVfor cotrductof this study.
JPCreceivedresesch6upported seryesoo ScientificAdviso.y
Boardsfor Ceru6CrrpoBtion.
Volume 49.」une 2000 TRANSFuS:ON 1039
:
ve obsewa●
A prospec●
Ond cohort saFew study oF5106
ul
1hteやt transFuSons uslng components prelared面
photOchemlⅢ
p a t h O g e n i n a c t l v a t o n t■a
F enaⅢ=
tme、
REFERENCES
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Valk H,Desendos,C,WorkゴOu,″Quan,tative ESthatibn
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KL
The
Amencan_
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EuropOan Consensus ConferёnCe on ARDS:demioons,
"ayaレ:″
donatloFl dWhg。
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mecllankms,relevant out"mOs,and cu1lical trial coordi‐
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Mendd I,Rttdot IP,Kandd C,DeveuteFR,Pablgi
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Bヽcornet L,Diancottt L,Micle1 0,DuquerrOy s,Culgon C,
Frenklel MP,BrChn AC,Cubito N,Despや sP,KunsI F,Rey
FA,Zeuer H,lnSSo S.GenO●e mooe,du● on 6f Chlkun‐
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Iacquct M,Sundin D,Lin L Cor■ h L m aCtive haemovlgl‐
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chemcaltreatment Vox Sang 2008,94:315,23.
3(asunOva E,QuateSOus',TarantOla A lmported cascs of
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060324
detecuon of chlkungunya w輛ュ
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Euro SЧrvein 2007:12 Avauable tom:http:″
wⅧ “
cases of Chlhnguny■
eurosuⅣemanclorg′ew′2007/070913 as夕2
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恥br●
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5 Rasongles P,IS●aH,KientZ D,Cazenave JP,Sa″ γer L
Corash L Rapid Ⅲplementalon oFphOtochemtal patho‐
gen ina■ivatiOn(DITttCEPT)● =preparation of,latelet
COrnP。lentS dWlng an epidemlc of Chikungun黎 ¨ru,
Vox Sang 209o,916upp13):32
6 SavwerL S,mp"n.JOlanneS A,Dubens●
T,KhscyJ,
Tsetsar01 K Vmandlngham DI早
iggS S Inactlva●
o,of
16 Lawent P,Lc Roux K,Cr市
ard P,Berttt G,Naze F,Picard M,
stattsky F,3arau C,SchttneckeFI,Mthau■
^DO“ 1・
opment 9fa sCnsitlve real.tⅢ
O臀 VerSe transclptase PCR
assay●
t h a n i n l e r n d lCtOon tlゃe t e c t a n d q u a n t i ″
chikungunya ntus Clln Chem 2007:53:1408‐14
1 7 C h e r n e s k y LMa、
rke RP Contras,ng ereOs oFlabblt
huⅢ
a n p l a t d chtksu nOgIu nCy・
nal宙
sふ
fectM,c贔
,
ヽlicrob'ol 1977,23:1237‐
44
c h i t t n n" -n 3ッ1 n p l●薇
e t s " d P l a s m a u s n g t h lS
e
I卜
町ERCEPT 31ood Systemtt Sang
170支200793(suppl
l):170
7 11n L,Dlkeman R,Moll● lB,Lukehart sA,Lane R,Dupuヽ
K,Mc● el P,Corash L Photochemlcal treltment of platelet
concentrates●th amotosden and Wヽ hactivates a b=oad
卜∞
Pl;fs,rzrowhich could lead to low detection sensitivity for
serum-based tests,In addition to evaluatingthe efficacyto
prevent TT-CHIKV this study provided an opportunity to
entend the safety profile of INTERCEPTPLIS tmnsfused
to a broad patient population. Finally, this study permitted an evaluation of the operational logistics of the
INTERCEPT PLI System implemented under emergency
conditions.
Data provided by EFS-[.aRCunion for the yeus 2dO4
md 2005 with conventional PLI components suspended
in 100% plasma indicated m'AlR incidence of 2.2 and
5.4% of PLT transfusions among heavily transfuied
pediatdc oncology-hematology patients, respectively.reIn
comparison, this study demonstrated a lower incidence
(1.6%)ofATBs per PUI fansfusion. These results are consistent with reported ATR frequencies reported for
INTERCEPTPUI components in routine use from multiple
European centers,rar' but lower thm the frequencies
reported for treated PUI components in the Ewosprite
(6%) and the SPRINT clinical trials (3%).20"The higher
incidence ofAIRs observed in the clinical trials may have
been due to differ€nces in padent popula$ons, which in
the clinical trials consisted largely of heavily transfused
hematology' oncology patients undergoing hematopoiedc
stem cell transplantation. Similar to previous studies, all
of the ATRs observed in the curent survey were of mild
severity, and none wer€ indicative of clinical CHIKV It is
relevmt to note that the size ofthis studywas insutficient
to characterize the incidence of septic trmsfusion reactions, although none were reported.
The clinical symptoms of CHIKV infection include
fever, swere polyanhalgia, myalgia, dermatitis, hemorrhage, meningoeniephalitis, respimtory failure, cardiovascu.lu decompensation, and fulminant hepatids with a
monality ratb of one in 1000 during the La R€union epidemic.22Thus, review of pdmary medical records should
have been suhciendy sensitive ro detect TT-CHIKV No
TT-CHIKV caseswere detected in the patient population
monitored in this study after implementation of the
INTERCEPTBlood System for PLIs.
The retrospective suveillance described in this
repon provided an opponunity to evalua(ethe sensitiviry
of the AFSSAPSactive hemovigilmce systemrr to d€tect
trmfusion-relatad AEs.We did nol detect any additional
uansfusion-related AEs in our independent review of
primary medical records compared to the AFSSAPS/eFIT
database for transfusion-related incidents. This limited
experience is @nsistent with the sensitivity of the
AISSAPShemovigi.lancesystem in detecting transfusionrelated AEs.
This study included a substantia.lnumber of pediatric patients, some of whom were inJmu. None of the
prior studies with INTERCEPTPLT components included
a substantial infant patient population. Interestingly,
pediatric patients had the highGt raie of AEs and AlRs
RASONCLES ET AL.
Larke v,hthedoⅢ
EF StabnレanOn oFchikungunya宙 rus
i,Fec●
●ty by human bloOd platelets I Infect Dls 1970,1221
523‐
31
19 Angelinl‐Tibert MF,Rasongles P Into■
ra,Ce des CPA
traltes p●
INTERcEPr― Amotosalen e,o■ co pediatrie
paris;Etab:issement Francais du Sang;2007
spectrum ofpa■
ogenc bactoHa TransFu`lon ;20041“ 20 van Rhenen D J,Cu:llkSsbn H,Cazenave IP′ Pamphuo,D,
1496‐
504
LlungFan P,Kluter H,Ⅵ rme,H,Kappers_Klume M,do
Creef GI LaFore,M,Lioure B,Da■sK,Marbhe S,Mayau‐
8 Ll,L,Hanson CV Alter HL Jau、哺 V Bcrnard KA,Mwthv
KKI Metzel P,cOrasl llnaltiVa●
o,of、Ⅲvses in platdet
don v FI徊 lentI,conla,M,Lin L,Metlel P,buChh91z D,
concentrateo by phot9chemtaltrealment“ ぬ ¨001os」en
Corash Li euroSPRITE t●
ali nanshslon oF pooled bu町
aFld 10,g‐
Wavel"gth u●
。
let hght■
SOn 2005■
coat platelcl,o,pOnents prepared witt phOtOchemical
a“
anS｀
,
58000
ent the ewOSP路 ■ trial
patl10gcn hactivation treatお
9 Castro E,Ctrcnes N,Bueno JLi CarJOn,,L●
Blood 2003i101:2426‐
L,Fresno M
33
T h e c m c a c y o f l b o t O C h et,elaCt」
r n e n t t t t h a meOnt o s 」 21 McC口 lough,,%sole DH,Beniamin RI,SlichteF S',PIneda
HQ ahav、ぃ●。let A Nα
「ERCEPT)お r lnactivation oF rry・
A,Snyder E,Stadtmauer EA,Lopez‐3aza I,Coutre s,
‐
″`σ烈7'mp● 。led bu″ oOat platelets Transhsioh
S t F a u S S R C , C o o d n b u g h L T , F r i d e y JeL ,lR,a l i e t C a Ы
′αえὸο
Murphy S,H… ard F 4th,Davis K,Lul JS,MOtzel P,C●
2 0 0 7 , 4 7 :4413 4 ・
rash
1 0 ハi g e u r u M F , F _ y P , R a s o n J e S P E p i d ` m ig cu ・d e c h i Li
k u Koutsoukos
■
A:Lm L,Blchholz DH,Conlan MG TheFa‐
nya l hvmoh
Rё et rans,s10n Sanguhe■
■
e Buuetln de
th a photo‐
peuac ofFlcacy and saFeυ
oF platelets treated哺
r■￨口
。
0●
139・
Chenuc」 prOcess for p。
10
ふogen“ aCtiVation:the SPRINT
●gi攣"dしl AFssaps却
1l Anl"uG,MoraR Ⅲ
oIF,RObbO D′ ´h宙er C,Hl¨
1lal,100d200,,104:153441.(
ⅢⅢ
P,Hemttigtance ne■ voェ
22 Renaut P,sOlet,L SISSOkb D A maloF epidemiじ oFchinⅢ
ト“ nanc。。18管i“■OFl and
anal"lsoFhmeⅢ
te tansh`:on incide,treports iOm
mya vLuslnfeclon on Reun10,Island,France,2005,
1994‐
1998 hnsmslon 2002:42:1356‐64=
2006仲 J nop Med Hyg2007,77:727・
31
12 0,selaer IC,Mess9 N,HerVlg T,Bueio J,caStro E,Espl‐
23. AngeuⅢ ・
Tllert ME Currie CI Slaelts M,C●
rasl LM,
nosa A,AccprsI P,Junge K,,acquet M.FlamentJ,cOraぬ
L
1090 TRANSFus:ON Voluho 49,」
une 2∞9
RasOndeS P SattyOfplatdet cOmpOnents prepared“
th
and
PATHOGEN:NACTiVAT:ON ANO CH:KONGUNVA VIRuS
:ξ
胤iよ
よ
T忠lLp眈憮
棚鮮I淵
ばli罵
鍵l搬席協織
T編]熾1闇
4322A
MOrtalヽ
Vtty Rep 200●
5511040‐
2
‐
2 4 D e p O O r e r ce o■u l o m b i e F Du nCgh“
yよa r i s k a s s e 2s 6s ‐R e z z a C , N I c o l e t t i L , A n g e l i n i R , R o m i R , F i n a r e n l A C ,
:話
『
器=籍‰
1器よ
調現
T脳」
酪譜茫 ,ll鷹
ぶ「
1ビ'
議縁
凝鷺瑞
eurosu晋 1lanCe oFg′
eW′200,′
2
cassonO A CHlKV stud,group lnた
c●On輛 th chょun証 ‐
"051l asp″
er E,Carcね・
Di″ J,B」samO G,Shranatan S,3erg_
nya urus in ltaly:a16utbrak ln a temperatよ
e」。i
15.Lr●
Blauwet t,sohan M,Baddoじ L,Reed C,Baggett
Lancet
200■
3701840‐6ロ
,annへ
H′Campbeu cr smith■ Powersん Hayes N,Noga A′
∞∞
Volurne 49,」
une 2009 TRANSFuS:ON、
lo91
後調査及び観察研究の
TRANSFUS10N PRAOT10E
ROUTINE uSE OF PATHOCEN INACTIVATED PLT COMPONENTS
Univers4 adopuon ofpathogen inactivadonOfplate19t
components:impact on PIatelet and red b109d Cdl
compoコ vent use
‐
: メ %れ Craンル Ose″ σ
ち働 αη協,Doya力 ,■α“″れ“ Dafoれ ,Caci7σDabび ■4″″ 呻
翡,
力 Oydο
れ為ルグ″ B οζ
L れ αれ′こあ“んれぁ c a 法ん
磁 Йα″9 昨 s s ' M α“ σ1 / a 助
ヶルゅ昭 J η, L J ″
uring the past four decadesmultiple new procedures and practices have been introduced
to improve the safety and emcacy of platelet
plateletpheresis, preparation of whole blood-derived
buffy coat PL[s, additive solutions (ASs),process and filtration leukoreduction, initial blood draw diversion, and
gamma irradiarion.'Addidonalinnovationsto detectbac.
terial contamination,, change the PLI transfusion threshold,3 reduce thq incidence of alloimmmization,. and
change the PLI trmsfusion dose5have been evaluated in
clinical uials of varying size od scope,and mily of these
innovations have been introduced into roudne clinical
practice.6T
In 2003 pathogeninactivationpreparationof
PULcomponen$ was introduced into clinical practice in
Europe.as
Theseinnovativetechnologieshave been evaldatedin
clinica.l trials; however, additional information regarding
the impact of new technologyon blood center operarions
and patient outcomes cm be obtained from the experi:
ence in routine use. A recent international consensus
conference on pathogen jnactivation technology recom.
mended that data be collected during routine use to
'were
monitor impact as these novel technologies
ABBREVATIONS:
BTC= BloodTransfusion
Centec
CUMG. Cliniqu6 Univercitaires
Mont Godinne;
PC(s)= plateletcomponent(s).
F r 6 , t h e T r a n s F u s i o n C e n t e r a n d t h e H e m a tc oe l, oC "l S" e‐■
:qυ
es unirrSItalres de Mont CollnPe U"●ersi"CathOliq●e de
Louvaヽ YvoL Belびumi and cerus cOrporation,Concord,
Californla
ス″ `s″ ′ヴ″ぉた夕‐S●`ο
:Laurehce Corash,MD,Cerus
COrpOration,241l Stanweu D●ve,Concord,CA 94520,o‐ma■
icorash@cerus com
RecelVed● pubHCa,on May15,200■
re■
●
dO,recdveo
January 14.200,and a,cepted,lwary19,2099
do::10.1111/1.1537・
2995200992151x
TRANSFuS10N 2009:49:1412・
1422
1412 TRANSFuS!ON Vollm●
491」uly 2009
MATERIALS
AND METHODS
Overallstudydeslgn
The BTC Mont Godime collects md supplies all blood
componentsfor a 400:bedceachinghospital of cheUniversitd Catholique de Louvain (Mont Godinne, Yvoit
Belgium).The trIe pedorins approximately 20b0plateler.
pheresis and 7000 whole-blood mUections per year to
suppon a diversep:tient popu.lationwith major subpopulations cared for by hematology-oncologyand cardiovascular surgely specialists.The BTC issues all labile blood
components for transfusion and maintains an electronic
darabaseto record the transfusion or destruction of all
issued blood components. Longitudinal trmsfusion
recolds are maintained for all recipients of these componenls either in hospital or in outpatient Oeatment clinics.
Data for this study on utilization of blood components
were obtained from electonic blood bmk recordb and
clinical laboratory records. The period from october l,
2000,to September30,2003,constituted the contrcl pedod
when a.llPLI components wer'eprepared without pathogeninactivation treatrnent,and the period from Noyember
1, 2003, tbrough October 30, 2006, consrituted the test
period'when all PI-II comporientswere prepared with
parhogen inactivation. One of the authors 0CO) has been
the medical director of the BTC during the entire period
covered by this study and supenised the hemovigilance'
progiam. Individual patient infomed consent was not
required to obtaln the data couected as this study was
conducted uder the existing hemovigi.lanceprogram for
the BTC in compliance with Belgiari Law to monitor the
impaat of nil technologies on blood transfusion practice.Ia Patient privacy was protected undtir the hemovigi.lmce progrm.
Collectlon and preparatlon ot PLT components
Contrcl peiod
Duing this 3-year period 85% of PLX components were
collected on a cell separator (Amicus, Fenwal, Inc., Round
Lale, IL) and 15% on another ceu separator (Spectra,
Gainbro BCT, Boulder, CO) with process leukoreduction,
For components collected on the Amicus device,T-Sol PLI
AS (Fenwal,lnc., La Chatre, France) was used in a rauo of
approximately 35% plasma and'659o T-sol. For components collected on the Spectra device, PLls were sus.
pendedin 10070
plasma.For borh platfoms, components
were prepued as conventlonal PLf components in compliance with national regulatory requirements. A.ftercomponent preparation the PlI concentlations (l0e/L) and.
the volumes (mL), baied on weight, of each component
were measuredand the tota.lPLIdoEe per component waq
calculated (10!t P[fs). PLI components were treated with
gamma irndiatjon as required for patient Specific indicadons, and tested for c)'tomegalovirus (Clvfv) utibodies
as required for patient specific indicatiohs. During this
period, PUTcomponents were stored for up to 5 days.
Test period
Duting this 3.year pedod all PLI components were collected on t}le Amicus cell sepeator (Fenwaj, Inc.) with
procesg leukoreduction and with the Intersol PLI AS
(CerusEurope BV) in a ratio ofapproximately35% plasma
and 6590Intersol. After collection, the PLI concenrmtions
(1o'g/L)
and volumes(mL),basedon weight, ofeach component werc measured and the tOta.lPLf dose was calculated (10'r PLTS).These components were prepared with
pathogeninacdvarionunder the CE Mark regisEatlonand
in accordance with national regr:Jatory requtements.
Within the nret 24 hours after collection, all PLT components were treated with pathogen inactivation
(150 [mol/L amotosalen HCI and 3 j/cm, UVA ligh!,920400 nm) accordingtothenanufacturer'sdirectionsfsruse
(INTERCEPT,
CerusEuropeBV). For quality conrrol (QC),
the final volumeofueatedPLTcomponentswas measured
on approxinately 30% of components and used to estimate the final PLI content of each component based on
volume loss.Patlogen inactiwtion treatment was used in
place of gamma irradiation and CMV serologyresdng to
meet specific patient indication requirements, and it was
used instead ofbacreria detection to meet national regula.
tory requirements.With pathctgeninacuvation ueatment,
PIX componentswere.stoledfor either 5 or 7 days in accordmce with nadonal regu.latoryrequirements.
Duing both study periods, blood qenter opEmtional
logisticspermitted issumce of PLTcomponents within the
Vdum●491」
uly 2009 TRANSFuSiON 1413
い∞
BACKGROUND: Palhogeninactivationof platelel(PLT)
components(INTERCEPTBlood System,Cerus
Eurcpe)was lmplementedlnto rcutinepracticeal a
blood center supporllnga leniary iars hospital.Uillizs. lion ot plalel€l components(PCs) and red bloodcell
(RBC) componsntswas analyzedlor 3 y€a6 betor€
and 3 years att€r introduciionof pathogeninactivation
lo assesslhe lmpactol palhogeninactivationon comDongnluse,
STUDY DES,GNAND METHODS;This was a retfosp6ctiv6 analysisot prosp€clivelycollecteddata.An
eleclronicdalabass used In roulin€ bloodbank hemovlgilanceto monltorproductionand use ol bloodcomponentswas analyzedto asse$ clinicaloulcomes.
RESULTS:TEnsluslon recofdswere analyzedtor 688
pati€nts supporledwith conventlonalPCs and 795
patlsnts supportedwlth pathogeninactivationPCs.
Additionalanalysgswors cdnduct€dlor intensively
transfusedhematologypallenls.Patienldemographlcs
(age €tegory sex, and diagnosticcategory)were not
dltfsrent in the two obsarvatlonpedods.Fof alJpatienls,
mean numbers of PC per pallenl were not ditlersntfor
convBntionalPCs and pathogeninactlvationPCs
(9.9 l 19.5vs. 10.1t 20.9,p = 0.88).Datafor h6malology patients(272 @nventionalPCs and 276 patho.
g6n inactivalionPCs) confirmedthal days of PLT
supporl were nol ditfsront(31.6 a 42.6 vs. 33.'11 47.9,
p = 0.70) nor was total PLT dose ('lo') per patient
( 8 7 . 3t 1 1 5 . 4v s . 8 8 . 1I 1 1 1 . 6p, = 0 . 9 3 ) .R B Cu s e ,f o r
all patientsand hsmalologypatienF, was nol dill€rent
in th€ two obseNatlonpeiods, Bitherduringperlodsof
PLT supportor outsids periodsof PLT tEnsfusion
suppon.
CONCLUSIONTPathogeninaclivatlonof PCs had no
adveBe impact on compon€nlus€ durjnga 3-year
obseruallonperiodol routin€practice.
adopted.roIn 2003 the Blood Transfusion Center (BTC),
Cliniques UniversitairesMont Godinne (CUMG), initiated
unjversal routine uie of PLf components prepared with
photochemica.lpathogen inactivation treatment (INTER.
CEPT Platelet System,Cerus Euope BV Amersfoort, The
Netherlands) for transfusion support of patients with
thrombocytopenia. Three randomized conuolled clinical
trials ivere cdnducted wjlh this pathogen inactivation
technology in support of CE Mark registration,tr'rr but
data on component-utilization were collected only for
conduct of clinical trials in which the experimenta.lcomponents were produced in limited qumtities rather than
in rcudne production.
The BTC MontGodinne is the sole source ofPLI components and thC principal source of red blood ceU (RBC)
concentrates.fora teniary care mbdical center.The blood
center collects data on the use of blood components
under the auspices of a lemovigilance progam. We
conducted a analysis of the utilization of PLT and RBC
components for 3 years before the adoption of pathogen
inactivation technolog!' for PLTSand-for 3 years after the
adoption of this t€chnology to evaluatethe impact of this
new technologyon component utilizationunder routine
clinical pmctice conditions.
ROuT:NE uSE OF PATH09EN:NACTiVATED PLT COMPONENTS
OSSELAER ET AL.
一
叩
匝DI輛￨
:1熱￨￨
1414 TRANSFUSTONVolume49, July2oog
RESULTS
yielde,andprocessing
PLTcollectlons,
losses
Dwing the coirtrol period, 5576 collectiom were performed with a mean yield of 6.28x l0!r PLIS. The 95%
TABLE L Oemographlcsot all patlents recelvlng
PLT comDomnts In lhe two obaeryatlon Derloda
Study periOd
Pa‖ents(n)
Moan ago,year9
s16(%)
17・
64(%)
control
Test
p Vauo
795
60 8
62 9
0 01
09
10
497
45.3
688
≧6o(・
/.) .
494
537
02'
Maレ(%)
62o
623
087
Plmary diagnOsに
(%)十
日omat91。
9y
305
347
0nco ogソ
65
88
′
CV Surgery
31 7
34 7
0`he■
222
218
012・
・Represonls p Va ue forlhe diSllbuton
i
od by plmary gnosに
dほ based on th●
l Panent,were dasu“
■di,O
d
bl∞
:dllCal service
pr●mediCal care and ordOlng
ord medca
‡The de●
gnalbn ol other rolett lo pabnt
on geぃ
。
SerVり
S and sur91ca
●
s●
●●
lぃ
0「
vascuL子
( 9V)
γl●
lan cardl●
摯]tiЪ
計器寵路器棚ξ
計
稲喘'9
Patients (n)
Mom age, years ('/d
< r 6 (o/.)
17-64 (%)
>6s {%)
Male (%)
Primary diagnosis(%)1
369
Homalology
on@logy
CV surgery
193
1 019・
Olh€r+
' Bepregentsp value fd the dlslributon.
i Patientsivere classifigdby prima.i dlagnogisbsed on the
. clini€l serylce providingmedical car€ ancl orde.ing blood
compon€nt9,
+ Th6 dosignationol oihor rofe€ lo pationls on g€neral medical
servicesand surgical s€Mces olher lhan cardiova€cular(CV)
surgory
|
2
.3
4
5
6
7.10 r10
FlB. 2. The dtstrtbution ofthe p€rlods ofPLT trusfuslon
oupport for all patients rec€lvlng PLf compon€trts.The ftequency dlstribudon ofthe perlods ofPUT rupport for patlots
during the perlod before INTERCEPT (p;e.tBs, f, D = 688) ud
the perlod after IIIITERCEPT (post'IBS, r.|; n = 795) wai detor
mlncd,Th€ proportlon of patients lseryEsscd on the ordlnale md th€ nmbs
thiabrclcoa.Therc
of perlods of PUI transfu6lon rupport on
wd no itstlstlcrl
budon of suppon cycls betwn
dlf€me
obsemtlon
l,n the dirtrlpertods,
Volumo 49,July 2009 TRANSFuS:ON 1415
〇い
Dudng both study periods, primary care physicians
ordered all blood components per standard ofcare. A proportion of patients had multiple PLT transfusions and
multiple periods of PLf support during the 6"yea observation period. A peliod of PLT support was defined as the
interval between the fir6t PLif transfusion and all subsequent PIjf transfusions with lessthan 5 days between PLI
transfusions. If an interval of more than 5 days occurred
between PLf transfusions, then a new period of PLT
support was considered initiated. The total duration of
PL:I suppon foreach patientwas defined as the nmberof
days between the first and the last PLTtransfusion within
the same period of PLf support. The days of PLI support
for mu.ltiple periods were summed to obtain a total dwa.
Data ftom the BTC were extractedinto a computer d'ata.
broe (SAS,SAS,Inc., Cary NC). Valuesfor all continuous
vadables were summuized as mean md stmdard, deviation (SD), median, and rmge. Differencesin mean values
between the two observation periods were compared by
two-sample t-test for continuous data and Fisher's exact
test fbr categorica] data. Diferences in median values
between the two obseryarion periods were compiled by
the two-smpleWilcoxon test. A.llp values.reportedwere
two-sided, dnd statistical sigiincmce was decltred at a p
va.lueof less than 0.05.
For the complete patient populdtion receiving one or
more PLI components in either period, the mem number
ofPLI transfusionsupportperiodsand the distribution of
support perjods werc not statistically different (Fig.2,
Table 3). The mean duration of PII support, the mean
number of PLT trmsfusions, the total PLI dose, and the
● ２
ot PLT and RBC comDonents snd data
Utilizatlon ol PLT and RBC componenls
︲
０５ ” ︲
２餃
６
４
Oata analysls and statistical methods
Transfuslon
coll€ction
Patlent populatlohs and demographics
Duing the control period, 688 patients received one or
more PLT componentscomparedto 795 patientsdudng
the test period (Table l). The incrcased number of
patjents in the test pedod reflected increased clinica.l
activity as qew cltrical programs were implemented at the
CUMG. Patient demographics with respect to age distibution, sex, and priinarydiagnostic categorydid not differ
significmtly in the two t{eatment periods (Table 1).
Duing the tvvo study periods apprcxiinately.90% of the
population receiving PLI support ajso required one or
more RBC concenEates,md.the demographics for'these
patients did not change significantly during the two
periods (Table2).
８“けｍｍ囲
一
加
８
“¨“４
1珈￨
鮒
職
■
珊
m l
cenual interual for the distribution of transfused dosesin
the control period ranged from 2.1 x lot ' to 6.3 x l0r I PLTS.
Duing the test period, 5997couectionswere performed
with a mean yieldof 6.82x 10'r PLIS.After roudne implementation ofthe TNTERCEPT
technology, 12,002products
were treated with pathogen inacdvation. Approximately
50% of collections were targeted as double.dose collections and were divided into two rhempeutic PLI dDs6.
The 95% central intenal for the distribution oftransfused
doses ranged from 1.9 to 5.3 x l0Ir PLTSduring the test
period. Eight pathogen inactivation procedures had technical failures (0.06%),of which 5 were due to operator
eryorand 3 were due to dispojable failues associatedwith
incorrect placement of a clamp dwing storageleading to
plnhole leaks.ASpai't ofthe QC process,4066components
dwing the test period were assayedfor volume loss during
pathogen inactlvatlon processing. Mem volume loss
without accouting for addition of motosalen (15 mL)
was 8.2 : 2.2% md the distdbution of volume losses
exhibited a 2stl pe&entile gf7.o% and a.75thpercentile of
9.4%.Volume loss correlatedwith PLIloss. With consideraUon of the dilution due to additiori of.motosalen (4.4%),
tle-mean prgcessing loss was 12.6%.
幅一
秘叫叫″螂秘協叫
tion of support for each patient dudng
each observation period. These deflnitions were based on tie assumption
that ifno PLI tmnsfusionswere required
after a s.day interval then trusfusionDeyi
dependent thrombocytopenia was no
longer present. These definitions have
previously been used in randomized
clinical trials to eva.luatePLI tEnsfusion
therapeutic efficaryrLrs
The BTC Mont Godinne entered all
blood components into an elecuonic
databaseat time ofcollection and labeling (Blood Bank Management System,
45 In-formation Systems, Minthorne,
UK; or CTS Serueur,INLOG, Limonest,
France).When components were issued
for trmsfusion a standard form accompanied each component and was
returned to the blood center after transfusion or with uused compon€nts. No
patients were excluded from this analysis, The BTC maintained a longitudinal
Flg. l. Oparadonal loglstlG fo! productlon ud r€leNe ofPLT oniponents uslng
- conwDtlonal
uansfusion tecord for each patient supthre methodc. BefoDcultud
tating wlthout bacterlal {ltuei
bqcponed with blood components includteilrl cultwe o @nwntlonrl
tqtlng b'l$ bactorlsl cultw;
6d INTERCEPT patho.
tng unique patient identification data,
g€n lnacllwdon
wlth conrentlon.l t6tlng,
clinical seruicelocation for trdnsfusion,
unique blood component identification
same time frame after couection, testing, aDd pathogen
number, date of tmnsfusion, dose of PLI component
(Fig.
inactivation tfe4tment
t). The preparation of RBC
transfused, and age of PII component transfused. The
concentrates did not chilge in my substantial mamer
BTC obtained patient clinical laboratory data from elecduing the 6-year study observation period, ild all RBC
tronic laboratory records linked to unique patient identiconcentrates were leukoreduced by flltration during bot}!
fication recordswith protection of patient confidentiality
periods. RBC concentlates were treated with gmma kraunder the hemovigilance program. Usihg these electronic
diation and tested for CMV antibody per specific patient
data capture systems, greater than 9970of issued blood
requirements using the sarne methods in both study
components were traceable within the system.
periods.
ROur:NE uSE OF PATHOGEN:NAC■ VATEp PLT COMPONENTS
OSSELAER ET AL
mean dose of PLTSper day of transfuTABLE 3, PLT lransfuslon support tor all palienls betor€ and after
sion supportwere not difierent between
adoolion ot oathoqan lnactlvallon lr€atment ot PLT comoonenls
the two ireatment periods (Table3). For
Parmeler
P Va|!e
patients receiving both PLT md RBC
Numbor of palients (n)
688
795.
0.01
components (control, 629;test, 721),the
Periods of PLT supporl (n)
2.2 \3.2)
2.2.14.4\
0.86
mean numbers of RBC concentrates
Days of PLT suppod (days)
14.2 (30.5)
13.1 (32.0)
0.49
(n)
(20.9)
Transfusions,/patienl
10.1
9.9
0.88
(Table
09.5)
per
patient
transfused
4) were
Transfusion€i/dayof suppori (n)
1.0 (0.5)
<0.01
1.1 (0.6)
not different in the two obsewation
Total dose/pEtienl(1011)
41.5 (82.8)
36.7 {76.5)
0.24
periods (control 16.5t 20.9 vs. test
4.2 (2.1)
Dose per day oI suppod (10rr)
4.0 (2.3)
0.20
16.5+21.5,p=0.98).
' Dala presentgd as Deu (SO).
Because RBC concentrates may be
transfused to correct anemia due to
blood loss or malrow hypoproduction
arising from many different causes,we
IAELE 4. RBC use bi all patlenb during the ob8erustlon periods,
also examined the use of RBC concendurlng p8rlods of PLT support, and oulslde perlods ot PLT suppgrt
trates during periods of PLI transfusion
betore and atler adoptlon ot pathogen Inaollvation trsalmenl ot
support and outside pedods of-PL[
.
PLT comDonents
uansfu sion support to determine if there
Paramel€t
were difierences duing transfusion.
ABC υ se dua,g the θ
ηr17o oお
θ′
var"ρ θ″οd
Patlonts(n)十
dependent thrombocytopenia ild out
1511(205)
RBC un“s′
150(2'p)
palent(n)
side.periods of trmsfusion-dependent
FBC use during lhe entire obseNation peiod
thrombocytopenia. No significilt difPalents(n)ll
RBC unlsfpalont(n)
165(200)
16S(215)
fer-enceswere obsewed between study
月80υ●
●“rl●
er10dS O/PLア
9uppO″
9 ρ
periods in the use of RBC components
Palonts(n)§
545
duing suppon of thrombocltopenia
RBC un19,alont(n)
104(144)
107(162)
071
and outside periods of PLI component
tmrsfusion support 0able 4).
RBC un19ゆ
9,4{145)
a‖
ent(n)
The broad patieni population sup' All valuos exprs$ed as mean (SD).
:
ported with PLT and RBC components
with
Patienls
transfused
PLI
componenls
during th6 obsoretion period,
i
was heterogeneous with respect to
t Palients tnnsfused with RBC @mpon€ntsand PLT @mponentr during tho entir€
obsetoalion p€iod.
primary diagnoses and the level of PLI
S Pali€nts transfusedwilh RBC componenls duilng perjods of PLT kanslusion support.
support required; To mole specifica.lly
ll Palionts transfusgdwilh FiBC componsntgoutsido periods of PLT transflsion support
4enne the impact of pathogen inactivation on PLT component therapy, the
subset of hematology patients.was analyzed separately
included patiens who received Ptirs without RBC EsnsThis population required more intensive trasfusion
fusion duringPLTsuppon and patients who rceived both
support with less acute blood loss due 10 surgica.l interPLI md RBC suppon. We obserued no significant difier.
vention and, thus, was a more homogeneous tropulation
ences il use of RBC components by hembtology patients
in which to evaluate both PC and RBC use. The majodty
during the entire obseNation period during periods ofPLT
(more than 60%) of hemamlogy patients had more than
support and outside periods of PIJI srippon (Table6).
one period of PLt transfusioil support (Fig. 3). The disuiS'irnililly, data were ana.lyzed fo! a population of
butions of the periods of support wele not statistically
oncology padents fotlowed dwing the 6-year obseryauon
difereni between the two obsewation periods (Fig. 3).
period. These patients were less intensively transfused
with PLI components thm the hematology patients, but
Hematology patien$ were more intensively transfused with PLf components, had more pedods of PLf
did have multiple pertods of PLI supporti however, the
suppon, and had more days of PLT support than the
distdbution ofperiods of support was not different (Fig. 4,
general patient population (Table5). Comparison of the
Table 7). Significant differencesin favor of INTERCEFTPC
were detected in uilsfusions per patient, tota.l PLI dose,
two obseryation periods demdnstrated no significant differences in the mean number of PUI transfusion support
and the doseper day of suppon.Therewereno signifimt
periods, mean number of days of tEnsfusion support,
differences in RBC concentrate use during the entire
number ofPLI tnnsfusions, the dose ofPLTs, nor the PLT
obseruationperiod for patients receiving PLI transfusions
dose per day of PIJI support (Iable 5). We examined the
and for patients receiving PLT and RBC components
(Table8).
use of RBC components for hematology pauents during
thd entire tnnsfusion period as well as during md outside
To examine the impact of trusfusion practice and
periods of PLI support (Table6). ln this malysis we
clinical responsesto PLTud RBC transfusions, the mean
脇ρ
θ ″Pこ
r:そο
″
:[1:濡
:β
i紺炒
1416 TBANSFUSIONVolume49. Julv2009
and media lowest daily PLf counts were determined on a
per-uansfusion basis fbr the various patient populations
duing both obsenation periods (Table 9). we did not
analyze data for the oncology patients due to the small
o/・
.
“
=ち
number of transfusions; however, we did analyze data
こ2 0/0●
・
separately lor cardiovascularsurgery patients since tliey
receivedPLI uansfusions at higherPLT count levels.There
was avery broad and asymmetric dlsuibution ofthe daily
lowest PLI count for all patient groups, md the median
values werc considerably different fiom the mean va.lues.
The proportion of PLI.transfusions with recorded PLI
|
2
3
.
5
6
ruo rlo..
comts in the medical record on the day of transfusion was
similar in each period for each patient group (Iable 9).
Flg. 3. The di6trlbutlon olrhe perlods ofPtI trestuslon
Whi.le-themean valuesfor the daily lowest PLI count were
support for hematologypatients rcceh'lng PIT componento,
significmtly higher (p < 0.001)in the test period for all
The freguency ailstrlbudotr of the perlods ot PI-;f support fo!
patient groups, the mediil values were not statistically
patlents for th€ perlodbefore INTERCEPT (pre-IBS, *
different (p = 0.23).Exploratory analysesusing ana.lysisof
n = 2?2) ud the perlod qfier TNTERCEPT(poit-I85, ir;
covuiance (ANCOVA) models were perforrhed on the
n = 276) was deientrlred.The propoition of patlents ls
transfused PLI dose with the nadir of PLI: count included
expressed on the ordlnate ud the numberofperiods of PIT
as a covariatein the models.Treaunent group (test vs.
trusfuslon support on the abscts&Thec ws no statlstlcat
conuol) and patient's primary diagnosis (hematology,
dlfferene In ihe dlctilbutton of support cycles beMen obser.
oncology, cardiovascular surgery, and other) were also
Etion ireriodr.
included in the models. Results from
these exploratory analysesshowed that,
within each treatment group, the
adiusted means (after the adjustment
Paranetor
for the nadir of PLI count and/or theFl
Numbef of patients(n)
276
272
primary diagnosis) were nearly the.O\
4.1 (6.9)
Porlods of PLI suppod (n)
3,7 (4.6)
0.40
Duratiorofsuppon(dbys)
31.5(42.6)
33.1 (47.9)
0.70
same as the unadjusted sample mems,
Translusionvpalient(n)
m,S Q7.1J
24.2 {30.5)
0.17
and the obseruation ofsignificant differTranstuslonvdayof supporl (n)
0.8 (0.4)
0.8 (0.3)
0.13
ences for the mbans and the nonsisnifi(101t)
Tolaldose/pailerit
87,3 (115.4)
88.1 (111.6)
0.93
cant difference for the median re-main
3.2 (1.4)
3.0 (1.3)
Dos6 per day of$pport (10r')
0.12
' Data prosented m€an (SD).
unchanged with and without the adjustas
ment for the nadir of PLI count and/or
the primary dibgnosis.
To further,ercmine the impact of
TABLE 6.RBC 180 by hematology pati071tS dψring tぃ
。o160rVatlon
the adoption of pathogen inactivation
periods,dur;lg peFiOd,Of PLT support,and outsid9 periods of PLT
ueatment of PLI components on RBC
use as a surogate measure forbleeding,
we determined the me.ari daily lowest
p Value
Parmgter
Test'
Control'
hemoglobin (Hb) 'level per patient for
. .
Pstienls(n)t
272
276
those pauents receiving both PLI and
RBC unis palent(n)
24‐
5(271)
264(304}
o43
RBC concentmtes (Table l0). No difRBC use dulng the edire obsetuation petbd
ferences in t}le mem lowest daily Hb
Palent ln)‡
257
266
RBC un“ずいal ent(n)
250(272)
274(305)
055
level were detected in any patient
FEC IJsθ
e rl●
●
●0′PLT sψ
″o"
"●ng ρ
groups before and after implementa)§
222
Pa10ntS(い
tion of pathogen inactivation for PLT
176(233)
054
FBC unIS7palent(n)
1 164(191)
RβC υ
sθ●
●tst“perOd●0′PLT suppO″
. c6mponents,
勝 :魔
』肝盟 mf器
1鶏:キ
l電
ま
辮脚謬蹴 mttξ
SIPP°
“bd°
・and al,r♂
・
“
On treamen
:騨
毬:L:1習
躍en haCI∼
PaJonts(n)‖
RBC un‖ypa‖ont(nl
127(188)
12,7(192)
l o0
' Ail vdus express6das ngan (SD).
i Patlgnls tEnsfusd wlth PLT @mponenlsdurlng lh6 obseryalion peiiod,
t Patignts lranslusodwlth RBC @mponentsand PLT components dudng the entir€
ob$Nation dgriod.
$ Palienls lransfusodwlth RBC componentsduring periods ol PLT hansfuslonsuppon.
ll Pqtients kansfu€edwith RgC compon€ntsputside pedods of PLT transfusionsuppofi.
otscusstoN
This study provides an assessment of
the impact of pathogan inactivation
on the utilization of PLI and RBC
components in both broad and
Volume49,July2009 'FANSFUS,ON t4t7
OSSELAER ET AL
ROυT:NE uSE OF PATHOGEN,NACT!VATED PLT COMPONENTS
２７
︲
７︲ ∝ ９
” “
°
nl
器篤斧「
:il案
:ご
:::(1蓼
ざ
０ ● ０ ● ０。
叫叫慨班ｎ
1410 TRANSFuS!ON Volumo 49,July 2009
period after inplementation of pathogen inactivation. This required an additional l0 minutes of donbr couecUon
Pahm€ler
time, but was well rclerated without
tnpact on donor recruitment or reten6812
7994
42(10)
36(09)
く
tion, For the broad padent population,
0001
471(714)
6351953)
゛
001
adoption of pathogen inactivatlon for
MoJah PLT cOunl(1007L).
220
039§
PLI components had no significilt
Cardlo1/ascurarsmpa″ “・
PLT'angOい onS ln)・ :
impac( on utilization of PLI compo534
'
43(10)
38(08)
く 0001
PLT doso/1ransfusbnf
nents as measured by multiple indices
PLT count(10'た
7112(514)
774(451)
009
ll
including mean number of trmsfusions
M o d a n P L Tu ∞
nt“
03/L)
68p
.
0005§
10gy″llerrs
わ
θ
mal●
per patient, mean total dose of PLTSper
4″
Ptt lrans●
Ыon,(￨)▼
patient, or mean PLf dose irer day of
PLT O,se/trnsfu●
42(10)
。
nl
36(09)
support. The only.significant difference
PLT Count(100■
4411723)
60o1973)
lq
Modan PLT count“
017L)
detected was an increase in the mean
lnte nsively t@nslu$od hqlalology paliqls"
number of PLf tran{fusionsper day of
supportfrom 1.0to l. I (p < 0.0l) among
36(09)
. 42(10)
440(7201
605け 7)
the broad patient population, This difModan PLT ooun`lo■
〕
fererice may have arisen due to a small
Th6 tolal numbgr of PLT lranslusionsadminisleredduring each poriod wilh at l€ast
decreasein the mean dumtion of PLT
one PLT count on th€ d€y of transtusion,
support from 14.2to 13.I days (p = 0.49)
The m6an.(SO) tor he PLT dos€ (101r).
after implementationof pathogeninac.
The @n daily lowsl PLT counl {SD) for lranslusionswith a PLI qount availablein
ihe medical rE@rdon dEy of transtusion.Dlring lhe conlrcl and tbst periods there
tivationr The reason fol .the slight
wsre 4690 (68,8%)and 5797 (72.5%) kansfus'one,Gsp€cliv€ly,wilh r€corded PLT
decreasein the rcan duration of PLI
counls.
suPPon ls unclear. Becausethe decrease
Bas€d on two-saml€ Wilcoxon lesl.
(SO)
Tho m*n dajly lqwost PLT count
lor transfusionswilh a PLT count availabl€ in
in duration of PLI support was not sig'
the medi€l .e@rd on day of transflsion. During thp control and tost pedods thers
nificet, we concluded that the increme N
werc 320 (77.1%l and 370 (69.3%) lransfusions,r€spectively,wilh r@orded PLT
in mean number of PLI uansfusions per O
counls,
Th€ nean dally lowgst PLT count lsD)llor transtuslonswith a PLT count availablein
day was likely not clinlcally relevmt.
lhe medical rg@rd on day of transtusion.During th€ cbntrol and test periodglhere
This differencewas not detected among
w.@ 4144 (73,2.h1stld 4914 (73.4%) ranstusiong resp4tiv€ly, with recorded PLT
hematology or oncology patjents.
@unF.
Intensivolytranstusd he;alology patientgw6re detined a! lh6€ patiEnts who
. BecausePLI transfusions are used
recaivedlrc or mgre PLl'tEnstusiore In a trealmgntperiod,
to support patients with either quantitaIt Th€ m€an daily lowosl PLT count (SD) for transfusionswith a PLT count available In
the m€dical re@rdon day of transfusion.During the @nfol and test periodgther6
tive or qualitative PLT deficits with
wer€ 4120 (73.1%)and 4893 (73.4'l.) kanstusions,.espdtivsly, with rg@rded PLT
potential forbleeding, we examined the
counrs.
use of RBC concentrates as an indirect
measure of hemostasls. While RB€
traltsfusions may be administered to
nia. While it is possible that chmges in chemotherapy
conectanemiaduetohypoproduction-aswellasbleeding,
regimens over the 6-year observation period resuJtedin
data on use of RBC support plovide a partial measule of
less intensive manirwsuplression minimizing the impact
the impact of PLT transfusion on prevention of bleeding.
of a change in PLf component use, severalfactors argue
For all patients supponed with PLT componen$ in either
against this effect. Firet; the mem duration of PUf uansperiod, thele was no impact on the requireinent for BBC
fusion support and the number of periods of trmsfusion
Eilsfusion after introduction of pathogen inactivation of
suppon were sinilar ln the two observation periods, ind!
PIT components. This trend wre consiste4t for patients
cating that chuges in prirnary disease treatment had
supported with PLI and RBC components during periods
minimal impact on the marrow suppression md .the
of PLTsuppoil, when patients would be at greatest risk for
extent of transfusion-dependent thrombocytopenia. In
bleeding, and outside periods of PtI suppon when RBC
addition, the similar use of RBC components dudng and
use would be most reflective of transfusion to support
outside periods of PLI support in both obseruation
hypoproductive anemia.
perlods is consistentwith a lack of change in hema@poilhe broad patient populauon included a substantial
etic function secondaryto primary dise'asetherapy.
proportion of cardiovascular surgery patients (approL
Implementationof pathogeninactivationdid result
one-third of the popuJadonin both periods)with shortin mem PUI loses of 12.69o.This was pariially compentem PLI support and obligatory intraoperauve b)ood
sated for by. collection of larger PLT doses durlng the
loss.To examine the impact ofpathogen lnactivation in a
TABLE 9. Dally lowssl PLT count tor pallents transtused before and
after adootion of Dsthooon lnactlvatlon tr€atment bf PLT comoonenlg
仰⑩塞 ⑩田ホ
adoption ofthe newprocess. In additior
to providing inJolmation on the impact
of the inno!"tion, the study provides
Pa€met€r
p Value
information on the utilization of PLT
Numbor of parl€nt8 (n)
45
70
and RBCcomponents in a broad patient
Perlods al PLT support (n)
2.0 (1.5)
1.8 (2.6)
Duratlon of support (days)
popr:Iation and in specific' patient
7.9 (11.2)
5.0 (11.0)
(n)
Transfu6ionsr'patlonl
6.8 (9,1)
3.9 (6. t)
populations s'ith more intense transfuTransfusions/day of Eupport (n)
1.O (0.4)
1.0 (0.4)
sion requirements. Td our knowledge,
Total dose/patienr(10'11
27.5 (A7.71
14.5 (22,5)
this is the first study to examine the
Oc€ p€r day ot support(10r')
4,3 (1.7)
3.7 (1.4).
'
impact of a newlLT preparation techDala presenlgd as m€En (SD),
nology on the routire produciion and
utilization of PLI components for m
obsewation period as long as 6 years.
TABLE 8, FBC usa by oncology pstlsnts durlng
In PhaseI and 2 c.linicaltrials with autologous radiolhs two ob&ruatlon pe.lods, before and aflar
labeled S-day-old PLI components transfused to healthy
adopllon ot pathogsn Inactlvatlon trealment ot
PLT components
subjects, we detected a lSEo to 20Eoreducrion in PIT
c。
嗜ro° ■
p Value
“t'
viability.rsSubsequently,a large Phase3 cllnica.ltrial dem摯 ramaer
Fac υse d●
rla9め●●
りο
Л
′
″ヵ
a9●
a17●
●ρθ/fOd
onstrated increased utiliation of PLf components trcated
45
70
P a u e n t s (:n ) 十
with pathogen inacdvation compared to conventional
RBC unls/pat ent(n)
86(90)
80(77)
073
PCs.t2This observation was due in part to di.fficultieswith
88C u"`″ ″のク"θO″"●●
●9en/ationρ
θr7●
d
Pattents(n)‡ 38
57
production of consistent PLTdosesduringthe clinical trial
RBo unnS/pallent(n)
102(90)
00(7● )
086
and the suingentrequirementto avoid of-protocol uans・ A ‖v a u e s e x p r e " o d a s m e a n ( S p )
fusions.r2Ana.lysis'of patients in both trearment groups
I Palents transfu80d Wnh PLT components durng the observa´
supported with. components consistently containing
“
on P●
‖
od
h RBC cOmpOnents and Pけ oompo・
l Palents transtused w“
more than 3.0 x l0tr PLls, showed no difference in utiliza"
nents dunng th0 0n‖
re observa6on peい
od
tion of PtI components.r6In light of these obseryadons,
we sought to evaluate PLI component utilizadon in the
context of routine practice with production of PLI componeffs over long pericids.
In this study, the patient populations in the two
obseruation periods were compuable with the exception
of a 15% increasein the number of patients receiving PLT
transfusions due to increasedclinica.ldctlvity at the study
c€nte!. In both perlods, approximately 90% of patients
were [ansfused with PLf and RBCcomponents providing
the opponmity to eEmine the impact of the new PLT
technology on use of RBG. There was considerable riuiatlon in the duration ofPLTsupport due to heterogeneityof
the patient populauon, even among specific diagnostic
groups, such as hemarclogy patients. This heterogeneity
H,4.TheìSt■ lutiO■oFthe pe■odo ofPLT taltsfusio●
reflected the diverse popr:Iation ofpatients who received
suppor for oncology pad輌ヽた。d宙 ng'LT comp● hen● .Tlle
PLT suppon in clinical practice and provided a rea.listic
f"quen"dお tHb6●On Orthe peHods OIPLT 3upportFor
measure of the impact of a new technology. In addition,
に、
“tefore
sdoptloll
sfIN「
ERCEPT(pFe‐
lBS,■
■‐45)
p●
the. long time of observation..in which patients experi
and the period aFter:N「ERCEPT(pOSt・ IBS,ハln 870)wa●
enced multiple periods of PLI support duing multipJe
determtned.The proportlon oFpatlen"ls expre8Sed On Ⅲ e
chemothelapy rycles contributed to the heterogeneity,
crdlnate and th,■●mberofperlod9 9fPLT● ans籠siO■
but provided a comprehensive assessmentof the impact
■
cissa.There
was
no
statis●
●
“pp● ●n the ab●
cal difFerence lロ
ofthe new technology on component use.
the dls●:butlon oFsuppOrt cycles bemeen observation
A substantial number of more intensively tiansfused
pel:“9・
hematology patients were available in both periods to
al]ow assessmentof the impact of pathogen inactivadon
specialized patent popda10ns This study,s unusualii
on PLT md RBC utilization among repeatedly rransfused
its scOpe,h that it tovers a relatVely long penod duringpatients. During both observation periods, hematology
ce,
patients received the majodty of PLI components due to
VVhiCh thC new techno:ogy was used in routine prac●
and“ provldOs lata frOm a c6mpaat市e pe●od beb“
longer periods of transfusion-dependent thrombocl'topeTAALE 7. PLT lranstuslon suppon tor oncology patients before and
aftgr adopllon of pathoEen Inactivatlon treatment of PLT comoonenls
Volume 49,」uty 2009 TRANSFuStON 1419
OssELAER ET AL:
ROUT:NE uSE OF PATHOcEN INACT:VATED PLT COMPONENTS
TAALE 10. Dally low€st Hb level tor patlonts
trsnsfused before and sfler adoptlon ol
palhogen Inacllvsllon treaLmeniot PLT
Paameter
ス″ρarr●
●r9
Pat enls(nソ
O Valu€
626
Hb(g/dL)2
85(11)
Median Hb (g/dL)
8.6
Cdrdiovascular suqery patients
Pa‖
ents(n)・
Hb(9/dl)十
83(10)
Median Hb(g/dL1
82
ηa'α
ス″わθ′
Ogy pa"●●
Paleno(nl・
257
85(10)
82(10)
811
Hb (s/dL)t
e.0(0.7)
8.9(0.7)
MedianHb (g/dL)
9.0
8.9
paliqls+
lntensivelyltanslusedhwtdry
Pallent(n)・
Hb(g/dL)十
Modian Hb(g“
L)
89(06)
90
89(06)
' The numbor ot pallon|€transtusod wilh both PLT
and RBC
corc€ntrates Bnd a Hb levEl reord€d in the medlcal Gcord
on tho day ot PLT ranslusion.
I The m6& (SD) daily lowst Hb levol (g/dL)per patient for
gach palienl group.
t tntensivelytransfusedhematologypatienls were defrned a6
thgao palionts who r6@ived two or more PLT t€nsfusions in
a troalment mrlod,
more stable md intensively transfused population, we
sbecjfically analyzed data for hematology patients. This
subpopulation comprised slightly more thm one-third of
the broad patient population in both obseruation periods,
md the hematologypatients had more periods of PIJI
suppon md a longer cumulative duadon of PLI support
(mean, 32-33 days) compared to that ofthe general popu.
lation (mean, 13-14 days). The multiple periods of PLT
suppon (approx. four as the average) hcluded mmy
patients repeatedly transfused during each 3-year observation period. Multiple indices of PLI component utiliza.
tion including mean transfusions per patient, mean
transfusions per day of PLT suppon, mean total PLI dose
per patient, and mean dose per day of suppon were not
statistically different between the obseruation periods.
Among hematology patients, we obseryed a significantly
lower PLI dose per day of PLI support (3.0x lott vs.
3.2x10'r PUts per day, p=0.05) after intoduction of
pathogen inactivatiori. However, tie data for this intensively transfused population supponed during mujtiple
periOds of PLI tnnsfusion over a 3-year observation
period did not indicate any tnpact on PLI utilization after
inuoduction of pathogen inactivation for PLI componbnts (Table 5).
The hematology patient subpopulation provided a
patient population in which to evalu?itethe impact of a
chmge in PLI component prepilation on the use of
RBCs both during and outside peilods of PII support.
This population was not substantially impacted by maior
t42O TRANSFUSTONVolude49, July2OO9
_i
surgical interuentions, thus prcviding a more reliable
estlmate of the impact of a change in PLI component on
both hemostmis, as measured by RBC transfusion
requirements during pbriods oi PLT support, and the
impact on RB€ production, as measured by RBC transfusion outside pedods of PLf support, No significmt differences in RBC uie were detected after introduction of
pathogen inactivation for PLT components. We interpret
these obseryations to indicate that hemostasis and RBC
production were not affectgd by a change in PLI compo,
nent Preparation.
We a.lsoexamined the impact of pathogen inactivation on PLI use by oncolo$/ patients. However,this was a
small patient population; md rhe data were limited. Consistent with the obseilations for hematology patients,we
did not detect any highly signifcant impact on PC or RBC
use due to the change in PLT component; however,these
observationsrequjrc con-firmation in a larger population.
As an added mears to examine the impact of a chmge
in PLI component on transfusion practice and clinical
outcome, we exmihed data on the daily lowest PLI count
and dailylowest Hb level on days of PLI and RBCtrmsfusions.We hypothesizedthat the lowest PtI count and the
lowest Hb within I day on days of PLI and RBC trmsfusion, respectively,would provide a compuative indicator
ofthe level ofthrombocytopenia and anemia on the day of
transfusion in the two observation periods. These data
were analyzedon a per-trmsfusion basis as the laboratory
indices were related to specific transfuiion events. We
ana.lyzedthese data for all patien$ as well as for specific
subsetsincluding cardiovascularsugery patients, hematoloty patients, and intensively uansfusdd hematology
patients (those with two or more periods of PLT trusfusion support). Duing the 6-yeil period of this study at
CUMG, the broadly accepted clinical threshold for PLI
transfusion was a PLI count of l0 x loe to 20 x 10'g/Lmd
for RBC transfusion a Hb level of 9 to l0 i/dL The BTC
Mont Godinne does not require a specific pietransfusion
PLf count or Hb level to issue a blood component.
Primarycare physicims ordered blood components based
on indivilu,al patient assessmentsand their independent
clinica.ljudgment.'
We used the Ptl count data in two ways. First, the
dailylowest PtI countseryed as a comparison ofpotential
changesin degreeofthrombocytopenia between the two
observation periods. For all the patient grcups ilallzed,
t}Ie mean lowest daily PLI count was associatedwith a
large SD, and the diference in the mean md median
values was a rcsult of rhe heterogeneous distdbution of
PII levels ih the lilge patient population. b(ept for cardiovascu.larsurgery patients, the median values were
not signncandy different between the groups md were
2l x l0s to 23 x l0e/1. reasonably close to expectedtrans,
fusion threshold va.luesfor patients withlhypoproliferative
thrombocytopenia. This trend wro similat fo! more inten-
sively uansfused hematology and oncology patients as
well. Cumulatively, these data suggest that after imple.
mentation of pathogen inactivation, patients did not
experiencea lower PLI count nadir during PLI support.
We postulated that the mem lowesr daily Hb level
conld serve as a surrogate measure for hemostasis provided that therev!'asno indication for differential suppres.
sion of erytbopoiesis by the new PLI component. We
ioncluded that the simiia we of RBC components
outside periods ofPLT support, especiallyfor hematology
patients,supported this hypothesis.The lack ofdifference
in the lowest daily mean Hb levelson days ofPLI transfusion is consistent with the conclusion that the new PLI
compbnents provided adequatehemostasis.
Recently, two multicenter hemovigililce studies
monitoring the safet)t of 12,543PLT components transfused to 2O5l patibhts have shom that PLf components
prepaed with pathogen inactivation were well tolerated
when used in routlne practice.tT'r8In conjuction with
theseobservadons,the current srudy utilizing longitudinal
data collectedaspdt ofa hemovig0anceprogrm demonstates that PLTcomponents preparedwith pathogen inac.
tivation.canbe implemented into routine practice withoui
substantially
impactihgPLTor RBCcomprinenruti.lizarion
over a substantia.lpedod oftrmsfusion support.
CONFLICT
OF INTEREST
receivedresearchsupponfor conducrof this6rudy
).C.Osselaer
andseryeson a speakprboardfor CerusCorporation.LS.Lin is a
consultant
to CerusCoiporation.
L. LinandLCorashareemployeesof CerusCorporation.
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Volumo 49,July 2009 TRANSFuS10N 1421
OSSELAER ET AL
n瞥
∬
i撃
:1ま
:鷲
T錦北l° 1露橘
ぶ器:∫
∬
隠温li:鰤よ
i意
よ
1鑑癬'7
::書
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th
Mendell,Rald。 ,P.Kandel C,De M9uter R,Pab● g‖P,
Delenau D,AFrOyO IL,Padr6n F,Couezec H,Corrd M,
' phOtochemcal pathogen inaclvation treatme,Trensh_
son 200■
401061‐71 ロ
ヾい
1422 TRANsFuS!ON volum0 49,Julソ2009
販後調査及び観察研究の
OR101NAL ARTICLE
CAZENAVE ET AL.
Us●ofadditiVe s01uti9nS and pathOgeh inacuvad6n treament Of
platelet comlohentS il aregionalb16odcentei3impaCt O五
ent udlzati9n dⅢ
p,tient outcotteS and cOmpo■
ing
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BACKGROUND:The Etabtiss6mentFrangaisdu Sang
Alsace(EFS Alsaca)succogsivelylmplemgnteduniversal use of platel€taddllivesolutions(pASs) and pathogen inactivalion(Pl) lor plateletcomponents(pCs). To
assessthe lmpactot thes€ changes,EFS Alsace avalu.
ated PC use, red blood cell (FIBC)componentuse, and
transfusion-relaled
adve6e evsnls atter imptemenlation
ol thEsenew technologi6s.
STUOYOESIGNANO METHOOS!EFS Atsacepro- .
spectivalycollectsdaia on production,distribulion,and
responselo transfusionof all blood componentswilh
gEater lhan 99.5% data acquisition,Adverse€venls
atlibuted to plalelet (PLT)trangtusionsw6rs coilected
througha mandatory activehemovlgilanceprogram.A
r€trospectiverevi€Wol prospectlvslycollecteddata was
conductedcoverlngthro€ p8riods:1) apheresisand
.wholeblootrerlved PCs in ptasma,2)apheresisand
whols blood-derlve.dPCs with PAS, and 3) pcs pre.
pared with Pl and PAS, oala on componentutitizalion
were analyzedfor a{l palientsrgeiving pos in each
period and tor lhe subsst ot hemalology-oncotogy'
palientsto evaluale PC use in an Intenselytransfused
population.Valuesfor all contlnuousvariableswe16
summaizod as mean and slandarddeviation,medlan.
and range.
.RE6ULTSTApproxhately 2000 patientsr6ceivedpCs
In each pedod. PLT and FBC use per patient was not
Increas€datt6r Pl (analysisot variance,F = 1.9 and
2.9, fespectivoly)and the lncidenceof acuts transfusion
r€aclims was significstly Fduced (p < 0.001).
CONCLUSIONS:UniversalusEof Pl was implemenled
withoutimpacllngcomponentuse, as indicatedby total
dos6 ot PLTSper pati€nt,and outcomesto lranstusion
were imoroved.
he Etablissement Frmgais du SangAJsace(EFS
Aisace)isthe soleproviderofbloodcomponents
for approximately 2 million inhabitants of the
AlSace region of France and issues approximately 17,000platelet components (PG) per year.Iri 2005,
the EFSAlsaceimplemented routine use of platelet addi"
tive solution (pAS)for production of pcs ro reduce recipi_
ent exposureto allogeneic donor plasma and to increase
salvageofplaima for production oftherapeutic and Aactionated p)asma.The following year, 2006,rhe EFSAJsace
implemented routine use of photochemica.l pathogen
inactivation (PCT) to reduce the risk of transfusion.
transmitted infeclion md adverse immune reactions
associatedwith transfusion of pcs.
Each of these interventions has the potential to
impact the therapeutic efocacy of pCs as wi:l.l_asimpact
utilization of other blood comlionents and patient outcomes in responseto transfusion t}lerapy.,.2Component
ABBREVIATIONS: CSDp = concenrated Eingle-donor plareler
(program); EFSAlsace = Etablissemenr Frangais du SangAlsace;
PAS(S)= platelet additiye $lurion(s); PC(s) = plareler
component(s); PCT = photochemical parhogen inactivation;
PI = pathogen inactivatiotr; TA-GitID = transfusion,associated
graft -ve6us-hst disease,
FFOm the Etabnssement Fran,als lu Sang(EFS)●
lSaCe,
INSERM UM≒ S949,and th,Un市
ersit`de Strasbourg,stras‐
bOЩ 3 France and cerus COrp,Concom,c・ alfornia.
′いs″″
r,"′
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ぉぉ":Jean,Pierre cazen″
4′
e,Etablisse‐
du Sang.AIS■
e,10 me sPleimann,BP 36,67065
■ent nanca、
Franc0 市
9‐
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Strasbourg cede、
plCrre cazenaveeeヽ
alsace fr
・
Recelved forlЧ
bHcationMarch 01,201Q●reす
6n tecelved
l u l y 9 , 2 0 1 9 , a n d a2c,c2e0p1t0e d J u い
do1 lo llll′
,1337:2995201002873x
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TRANSFIIS10N・
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v。lume'',・・" TRANSFuS10N l
utillzation ahd tfansfusion-related adverpe events wele
selected as outcome variables bemuse of clinical relevanceto patient management.A decreasein therapeutic
efficacydue to changesin PCtreatment could result in the
need for morb transfusion support. A change in the incidence of advene events associatedwith novel pcs would
be higily relwant to both patients md treating fhysicians.To assessthe impact of use of pASs and pathogen
inactivation (PI)treatment, EFSAlsace conducted a retrospectivereviewofPC u6e,red blood cell (RBC)component
use, and tansfusion-related adverse events dudng three
diferent periods to evaluatethe effect of each change in
'
platelet (PLT) prepuation. This ieview provided usefir}
information regarding the progresive effects of each
change for all patients supponed with pCs during each
obseruation period, md for specific patient popularions,
such as pediatric and hemarology-oncology patients,
which might be differentially affected by changes in the
manufacture of PCs
'
MATERTALS
AND METHODS
Overall
studydeslgn
component utilization becadse they are intensively transfused for prophylaxis olbleeding and provide a more stringent population in which to assesscomponentutilization.
Produciion of PCs
The wiables for preparation of pCs during each.of the
three periods ae summarized in Table t.Whole blood ms
collected into CPDA-I anticoagulant from volunteer
blood donors who met the EFS requirements for blood
donation. Whole blood-derived bury.coat pCs were prepared as previously described.a Single.donor apheresis
PCswere colleited from qualified donors using an apher.
esis system (MCS+,Haemonetics, Braintree, MA). Duing
the three periods, all PCs were leukoreduced by filtration .
(<l x 106white blood cellsJWBCsI/pC) to producea therapeutic PC ihat was stored for up to g days with reciprocal
agitation under temperature bontol (22-24.C) befoie
uansfusion.
Period 1
Whole blood donation had a mean volume 6f 462 a
i4 mL. Six whole blood-derived bu6, coat concentrates
were pooled and suspended in IO0% donor Dlasma.
Single-donoraphersis PCs were suspended in lO0%
donor plasma. Dudng this period, lwo larget doses for
apheresis compon€nts were used, 3,5 x 10rr or 5.5 x l0rtr)
PLTSper collection, Both whole blood-derived pooledO'\
bufly coat and apheresis pCs were irradiated with
2500 ccy, using a cesim source, according to establ.ished
indications for prevention of transfusion-associatedgraft.
versus-host disease(TA-GVHD).
The study coveredthree obseryation periods, each lasting
from 9 to 13 months in duation, The variable length of
each period was in part determined by the time required
for swirching between types of pcs and data for each
. period werc utilized only once productjon consisted
.
enurely ofthe new type ofpC product. period 2 was arbitrarilyshoner due to tie decision to implement pl as soon
as possible. Duing the l3-month period from January
2003 to February 2004 (Period l) all pcs derived either
hom whole blood collections or by.apheresis collections
were prepared in 100% allogeneic donor plasma. During
Peiod 2
the g-month period from September 2005 to lune 2006
Whole blood donation had a mean volume of
(Period 2) a.ll PCs were prepared in pAS (53%-68%)and
460 a I I mL. Sixbufry coat concentrales were pooled and
residualdonor plasma (32%,47Eo).
Duing the I l.month
suspended in approximatCly 35% donor plasma
period from September2006ro Augusr 2007 (period 3) aU
and 65% PAS (T-Sol, Fenwat, Inc,, La Chatre, France).
PCswereprepared br PAS(S3yo-68%)
md residual Dlasma
Single-donor apheresjsPCs were coLlectedfrom qualified
with PCT for PL During each of these three
132%-4707o\
donors using the MCS+ platform h'ith the concentrated
periods, data were coll€cted on the production, Eansfusjngle-donor PLT (CSDP) program (Haemoneti6) and
sion, ad trmsfusion-related adverse events for all
suspendedIn approxjmatelj' 4570donor plasma with 55%.
patients supported by the EFS Alsace.
Data were collected in compliance
with a national hemovigilmce progrm
_TABLE l,Variables fOr preparation o'PCs
with protection of patient confidentiality, and individual patient inJormed
WhO,bbOd(mL)
462± 1,
460± 11
461 ■ 11
consent w6 not tequired,3 Data on
AnJcoag」ant
cPDA・ l
CPDA‐l
cPDA‐ 1
PC and RBC component use were
Poo1 31zo
6
6
6
PIasrna target(%)
100
135
35°
analyzed for all patients receiving
PAS(・
/.)
0
65
65
PCs during each obsenation period
and for the sub.s€t of hematologyP,atrOrm
MCS+
Mcsγ
csDP
Mcs+′
CSOP
Tar901 dose(x10■
3 5 or55
45
45
oncology
)
patients,
Hematology.
PiaSha targot(%)
100
45
45
oncology patients were selected for
PAS(・/.)
sepilate anal)4is lvith iespect to blood
2 IRANSFUSIONVotume.'.'...
ROuT:NE uSE OF PATHOsEN‐:NACT:VATED PLT COMPONENTS
T-Sol. Durlng this second period, the collection tilget
for apheresis products was 6et at 4.5xl0trPLTS per
coUection. Both whole blood-derived pooled buSr coat
and apheresis PCs were irradiated with 2500 ccy
according to established indications for prevention of
TA.C!'HD.
hotus ofincubatibn using a compounfl adsorption device.
Apheresis PCs were released on Day I and pooled whole
blood-derived PCs on Day 2 (Fig. l). PI irealm€nt was
used in p,lace of gamma irradiation for prevention of
TA-GVHD. Residual amotosalen levels were measured in
l70 of Eeated PCsfor qua.lity control.
Peiod 3
Whole blood donation had a mean volume of
461 + ll InL Six buffycoat concentrbtes U'erepooled and
suspended.in approdntately 35% donor plasma and 65%
PAS 0ntersol, Fenwal, lnc.). Single.donor apheresis PCs
were collected from qualified donors using the MCs| ptatform and CSEP software (Haemonetics) and suspended
in approximately 45% donor plasma with 55% Intersol.
Duringthe thirtl pedod, the collecuon talget for apheresis
products Ms set at 4.5 x lort PLTSper collection. Both
pooled whole blood-derived and apheresis PCs were
processed (Fig. l) within 24 hours of collection using
mbtosalen-HCl and ltVA light photochemica.l PI teatment 0NTEnCEPT Blood System for Platelets, Cerus
Europe BV Amersfoort, the Netherlands) according to the
manufacturer's directions for use.s[n both cases,residua]
arnotosalen and photopioducts were removed aftbr 4 to 8
Trangfusion of PCs and hemovlgllanc€ monitoring
In i]l tlree study periods the PIJ cost and total PLT
content were determined for each apheresis PC. In the
fusr two periods, the PLI count and'PLT contenr of
pooled leukoEduced whole bloodderived bu8' coat
components were determined in a subset (3% for Period
I md l79o for Period 2) of components for process
conuol. In Period 3 PLI count and total PLI content was
determined for each pooled leukoreduced whole bloodderived buqt coat component. PLI counts wer€ mea.
sured by electricdl impedance with calibradon using an
optical PLt counter (SysmexXE 2100D, Roche Diagnostjcs, Mey,lan, France). Total PLI content of ransfused
components was determined based on PUf concentration md component volume expressed as toia.l
PLTsx l0rt.
IDayl
8 1012141618202200
IPFy2
2 4 6 8 1012
The EFSAlsaceblood center maintains a databasd to
compare between.PeriodI md 2, Period 1 and 3, and
monitor the production, issuance,transfusion, and utiliPeriod 2 and 3. All p values reponed were wo-sided, and
zation of all blood components. The blood center data.
significance was declared at d p value of less than 0.05
(p < 0.05).All statistical calculations were done witl combase contains informa0on on patient demographics and
clinical seryice location of uansfusion. In each period,
puter software (Excel, 2007 SP2 MSO, Microsoft Corp.,
pdmary care physicians ordered PCs for tmnsfusion
Redmond,WA).
according to French nationa.lguideline! published by the
French Agency of Medica.l Safety of Health Products in
2003 and basedon a recommendeddose of0.5 x 10rrto
BESULTS
0.7 x l0rr PLTSper ?kg in aduttsand 0.5 x l0rrPLTsper 5
Demographics
of pallentstranstuaed
wlthPCs
or 7 kg in pediatric patjents for suppon of thrombocytopenia. The respolNe to transfusion of blood compo.
ln each of the three periods, 167& to 2069 @nsecutive
nents was monitored through the national active
patients received one or more PCs (Table 3). Within each
hemovigilance program under the direction of French
period, the lilgest proportion of PLT uansfusions were
Agency of Medical Safety of Health Products.3Under this
adninistered on hematology-oncology cue serices
progrm, all blood tnnsfusions are monitored and poten.
(Table3). Patients ranged in age from less than ! to 106
tial uilsfusion adverseincidents ae evaluated for severyeils ofage (Table3).
ity and relationship to the fiansfused
component in a .tnnsfusion inciderit
TABLE 2 productioh and uti‖
zat:on of PCs
repoft. Declaration is mandatory
'olod l'
Pe‖
o02+
Period 31
for each transfusion, whether or not
13.241
a tlmsfusion. incident repon has
PLT cono耐σ“anすosed"mpohen、§
Mean dos●
′
unl(x10")
occured. The severity of incidents is
Median(文
lo")
6.4
47
classifiedbasedonWHO criteria: crade
Range(X101り
05‐7,3
l-absence of immediate or long.term
PC us″paJeni(n】
vital: threat, Grade z-potenual longPalonts
2.050
1.678
Moan
62b
55`
term morbidity, Grade 3-immediate
Mod an
210
20
vital threat, and Grade 4-death of $e
104
1・ 114
1‐
289
1‐
paden(. The relation of the transfusion
TolaI PLT losOわ
dにⅢ IX107り
¶
Moan
to the adverseeffect is eva.luatedusing a
26、
9
MOd an
109
94
five-poht scale basis: o<xcludes my
Ran9o
05・1,S02
causalrelationship, I-is doubtful, z*is
'PCs were prepaァ edin plasma D● "ng Polod,,PLT 9ontOnt of who o blood‐delved
possible, 3-is likely, md 4-is unqussrnpOnents
PC Was doleminedin 3%Of∞
tionable. The uansfusion incident
10d2,PLT content Of who O b10od
† PCS WOre lrepared n,asma with PAS Duang P。
‐dolved PC was determinod in 17%of∞ mponenls
rcports are submitted to regional
hemorigilance network coordinators
and entered into an electronic database.
PIず 2'b円=Pe,
"assu市
Pr m9 Sam響
ツ
Ъ
舅i留
￨}管
評鞘鵬3轟l珊棚ゎ
he晰
o 6二
o“
口
“
ぶ:3提
写'1背 :L∵譜
Statistical analysls .
Flg. l. Pc pro@slngwo*flowThe
dne ln hours stddngwlft
the day of collectlon (Day 0) ls tndlcated.Apher6ls
comDoneDts are
ihakere (22-24'C) followd by PI treatmen! ild lncubatlon ln a compound abrorptlon
contalner from a mlnfunm of 6 howe to a maxlmum of 16 hou! before relese for trusfurlon.Whole
blood ollec.
rtoEd ouimlght
d€vte{CAD)
tloN @ ttocd
on tempqstuE-@nrolled
dfter couecllon, On Day I buffycoat concentrateE.re loolated, pooled, ud treeted wlfh pt fott@d by
rnd releue on the beglnnlng of Day 2. rSerclogy/NAT I am.-3 p.m, dally. PI and CAD - psthogen Inactlwtlon
the INTEnCBPT Blood Syrtemi NAf = truclelc acld tsting,
owmlght
CAD lnflbatlon
uslry
●TRAIISFuS:ON 3
Vo umO",・・・
Descriptive anallses wele cdnducted
for the demographic and clinical vili.
ables.Valuesfor all continuous variables
were summuized as mean and standud deviation (SD),medim, and range.
A one-way anaJysisof riance (ANOVA;
shgle factor) was used to test the equality of PLT content per product, of the
number of PCs transfused per patient,
-dose
and of total
of PLfs received by
the patient between the three periods
sudied (Table2).When the diSerenceof
ANOVA during the three periods was
significant, a t test was used a priod !o
4 TBANSFUSIONVolume". " "
19 9quJ va"a,60'・
精
纏算
1群
警,Ii]儀
響照
鞘F尋
馬:盤
警珊:
¶ ANoVA The dr10rence t nol sb雨 Fcan fo「any∞ mpan10ns:F・
19,
TABLE3. Demographlcaol pallsnis lranstusad with PCs
Demographic
PEriod'!'
Psriod 2t.
Numb€r ot pati€nts
?050
1678
M€diar age (yeaF)
64
63
Age rang€ (years)
3-97
<,|.99
[4ale (%)
59
60
Ptoporlions (%) of patignl6lrtrsfused b!, cliniRl seryice
Hsmatology.oncology
56.1
50.5
Gen€/el r€dical
36.6
43.6
Cardiryascularsurg€ry
7.3
5.9
' PCs w6re p€par€d in plasma.
t PCs w€re preparedin plasma and PAS.
+ PCs wers prgparedin plasmaand PAS wilh Pi irealment
Period 3+
206S
E3
<1.106
62
58.1
96.9
5.7
０い
IDay,、
■
TIME 8 1012141618 2022 00 2 4 6
CAZENAVE ET Aし ,
ROUT,NE USE OF PATHOGEN・:NACT!VATED PLT COMPONENTS
Characterlsllcs
of PCs
Acute transtuslon reactiong
During the three periods the PLT content per component
changed as the methods of production changed (Table 2),
With the introduction of PASS, production methods
were adjusted to equalize the PLI content of apheresis
and whole blood-derived PCs that were ordered interchangeablyby primary 6re physicians.All PCstransfused
demonstrated retention of swirling whbn issued by the
blood center. PLI content per PC unit was significantly
less in Period 2 compared to Period I (p < 0.05) and in
Period 3 compared to Period 2 (p < 0,05) tTable 2). Dudng
Period 3, all the 13,241components were tested for PLT
content; the mean I SD PLI content was 4.2 x
lotr t 0.4 x l0rr and the mean I SD loss due to PI was
24 ! 4 mL containing 0.3x l0'r 3 0.07x l0r! PLIS. For
PCs ueated with PI, residual amotosalen levels were
measuredin l% of products (n = 201).The mean residual
motosalen concenuation for whole blood md apheresis components was 0.24 10.09 pmol/L (median,
0.22[mollLi mdimum, 1.25pmol/L).
Uilllzalion ot PCg
Utllizatlon of RBC components
Utilization of RBCs was determined
for patients who received one or more
PCs during each :observation period
(Table4). ln each observation period,
approximately 85% of patients transfused with PCs rmeived at least one RBC
unit No significant difference in utilization of RBCswas detected between the
three obsemtion periods.
TABLE 4 uti‖ zation of RBC compOnent8
Pelod l'
Number ol pali€nls tGnslu$d with PCs
Number (o/4of patienls transtused
wilh PCs and RBCS
Number of RBC unitss
Mean numbor RBC unils/paljent
' PCs werg prspar€d in plasma.
PeaOd 2+
2,050
1,715 (83.7)
1,678
1,355 (80.8)
24.693
14.4
1?132
13,1
Polod 3‡
2,069
1,749 (84.S)
. 23.824
13.6
t PCs were preparod {n plasma and PAS.
+ PCs w€ro prErErod ln plasma and PAS with Pl treatment.
$ ANOVA.Tho dlttersn€ b€twem the lhr6 perlods is not slgnlfi€nl: F = 2.9.
casesof transfusion'related sepsis were reponed in my
period. The incidence of transfusion-related adverse
elents per 1000PCs transfused was significandy reduced
with the implementation of PAS (p = 0.005) and further
rcduced with the implementation of PI (p = 0.021).Analysis of the lncidence.of ransfusion-related adverseevents
per patient demonstrated significant reduction after
implementation of PAS(p = 0.009) and further reduction
ivith the implementation of PI (p = 0.0779).
Ulillzation ot PCa by intensively
transfused patlsntg
To further characterizethe impact of changesin PC pro'
duction, the utilization of PCs and RBCSby intensively
transfused patients with hematology-oncology disorders
was examined. Eraluation was resuicted to Periods I and
3 since use of PASwithout PI was only m intermediate
phase in the evolution of the PLf production process
at EFSAlsace.During both Period I md Period 3 all PCs
were leukoreduced(<l x 106WBCs/PC),and rhe proportion of whole bloodderived bui[' coat and apheresis
PCs remained constant {62;38), Espectively. Mean PLI
content per PC was lower during Period 3 (4.2 x l0rr) comparedto Peilod I (5.2x 10tr)due to a decisionto harmonize the PLI contentof both t'?es of products,
Approximately similar numbers of hematologyoncology patienti were tmnsfused dwing Periods I
and 3 (Table6). Althbugh.the number of PCs tanstused
per patient was increasedduring Period 3 compared ro
Period l, the total dose,of PLTSper patient wN nor
increased (Table7). The lncrease i.n the number of PCs
was due td decreasedPUf content per unit in Period 3
compared to Period l.
DrscusstoN
TABLE 5, Adverse rcactlons alter transfuslon ot PCs
Pelo0 1:
Numbgr ot patienls lranslusgd
Number ot componenls lresfusod
Number of patients with adve.go roactions
Numbor of advocs 9v€niss
Numbor ol ngo alloantibodiesd€tectsd
Numbor ot RBC Elloanlibodi€VloooPCs
Number of translusDn reactions
Number of tolal r€actions/looo PCs
Number of Po{elatBd reactions/'toooPcsll
Patientswith PC reacllore (%)'ll
'PCs worO pppared n plasma
2,050
10,629
59
67
11
1.03
56
6.3
5.3i"
2.9.c
Polod 21
1,678
33
25
45
27・1
Poい od 3↓
2:o69
36
18
28
14b●
t PCS Wore prepandin p asma and PAS
幸 PCS WOro propュrod n p,asma and PAS inh PItreatment
dotecled lo RBC antigens
S TOta transFuslon reacl ons oanubodies
nc uding a‖
RBC a‖
‖T7ansfuslon reacuons exdudin9
symptOma,c
oanlbod●
●not assodatodh w“
=o o5,drerOnce r oo●
pく lP,_P2,p=ooOoa
reaoOns Ch.squaro b“
wnh α
bP2-P3,,=00214::Pl―
P3,p_ア
xl●t
ng RBC squaro
alloan“
Ch卜 teSt With
¶SymptOmalc reacJons to PCs,oxclud bodiosi
α=005,d“erenCe r pく
00''Pl_P2,p_o.oo9■ IP2-P3,p=O o77a°
Pl―P3,
・‐ TRANSFuS:ON 5
Volumo・・
,・
In 2005, the EFSAlsace regiona.lblood
center initiated chilges ii1 the routine
p rep arati on of PCswitJ| the intro ducti on
of PAS, which ms followed by implementation of PI treatment in 2006. Each
of these changes had the potential to
impact the PLI contett ofcomponents,
the utilization of components, and
patient outcoms. To assess these
potential impacts, EFS A.lsace conducted a retrosptrtive analysisof three
diferent periods, each of approximately
I yeu duration. The comparison ofeach
of these innovations with conventional
PCsin 100%plasma provided a memsto
assess the .impact in a controlled
mamer sincethesameblood center and
processingstafiprepiled PCsin each bf
6 TFANSFUSION
the observationpetiods. Although primary care physicians
were aware of the changes in methods of PLT production,
theycontinued to prescribe PCsbased on simiiar stmdard
ofcare guidelines in each ofthe observation periods. This
provided approximately similar clinical conditions to
monitor patient responsesin each of the periods.
This analysiswas based on a comprehensive longitu.
dinal databasethat tracked greater than 99% of PCs with
respect to patient demographics md utilization by
patients. In addition, thd response to trmsfusion with
respect to adverseoutcomes ws evaluatedusingm active
hemovigilance program3 for which data for $eater the
997o bf transfusions were reported in the EFS Alsace
region. This study offered a sique opponunity to
examine th-eimpact of these changes in PLI production
when implemenredin routine use for support of a broad
spectrum of patients. In addition, trus study included
a substantial population of intensively trmsfused
patientswto may have been more
hematology-oncology
sensitive to chmges in the methods of PC production.
TABL● 6.Age demographics of
hemat,logy‐
。n●
lents transtu:ed
111'飛
-.
DomogBphlcs
Numb€r oi palionls
Numb€r (%) ol infants-toddlersl
Number (%) ol childrens
Number('/4 ol adultsll
' PCs were pr€pared in plasma.
Period 1'
671
10 (.|.5)
49 (7.3)
612 (91.2)
Porlod 3t
699
5 (0.7)
' 49 (7.0)
645 (92.3)
t PCs \i,ere p@par€din plasma and PAS with Pl heatmonl.
t lnlanls and toddlerswgr6 t honth to l€$ than 3 years bf
aga.
S Childrsnw€re 3 to 17 years of agg.
ll Adults w€r€ greate. than 17 ys.s ot age.
IBLEス
U‖
p°
lens'y
」
織 L:1琳謡『謡ぶ肥
Numbor ot pationts
Numb6r of PCs lranstus€d
Mee : sD*
Medianll
Rsgoll
.
Total PLT dos6
M6an : SD+
M6dian
Rangell
Number ol RBC unils transfused
M6ang
M€dianll
RangeJl
' PCs wsre pr€parod in plasma.
40
1‐
264
1 ‐1 0 3
453=628
216
08・536
152■ 165
461 =861
184
1.5‐ 1189
_ 136■
0‐
93
t PCs were prepared in plasma with PAS and Pl t€atrnent.
+ Mean number at PCs lransfused p€r palignt.
t Men tolai doso ot PLT3(1011)por patienr.
S Mean number of RBC unlts per patieni.
ll Dala expre$€d p€r patlenl.
184
0‐ 272
卜い
The utiliation of PCs was determined
per patient based on tlie number of
compone[ts transfused and the tota]
number of PLIs trmsfused per patlent.
The latter was of specific importance
as the PLI content per component
changed according to changes in the
methods ofproduction during the three
periods (Table 2J. For each period, the
relative proportion of whole bloodderived and apheresis PCs remained
constant, approximately 6570:35%,
rcspectively.The mean number of PCs
gansfused per patient increased in
Peliods 2 and 3 compared to Period I
(Table2); hmever, the number of transfusion episod6s and the total dose of
PLTStnnsfusd perpatientwere not differentbetlveenthetwopedods flable 2).
AdveEe events after tlansfusion ofPCs were evaluatedfor
relationship to transfusion and all events classifled.as
doubdul, possible, Ukely,or unquestionablewere defined
as acute ttansfusion reactions..Theseeventsalso included
t}te obseruation of newly detected alloantibodies to RBC
antigens with or without evidence of hemolytic tansfusion reactions (Table5). Cumulatively, for all three
periods, 145 adverse events were reported, of which 46
were newly detected RBC alloantibodies without hemoly.
sis secondaryto concomitant transfusion of RBCsin 85%
of the patients receiving PCs (Table5). In Period 1, one
death due to volme overload was reported.All otherreac.
tions were Grades I (619o)and 2 (3370)jn severity.During
Period3 among the 18 reportedreactionsnot due to RBC
alloantibodies, eight were characterized by febrile reactions, three were characterized as allergic reactions, and
one episode of transfusion-ielated acute lung injury
(TnALI) associatedwith high-titer HLA antibodies from a
multiparous donor was rcported during Period 3 in association with transfusion of Pl-treated apheresis PCs
without exposure to my other blood components. Six
transfusion reactions were not chancterized further. No
CAZENAVE ET AL.
ROUT:NE USE OF PATHOGEN‐
treated with PI in this study is consistent with that
reported for severa.l other lilge postmarketing hemovigilance studies.ro12It is also similu to the Belgian experience of unlversal routine use of Intercept-inactivated PCs
for 3 years,that enables leuning ofhow well the products
function in broad populadons.t3 In addilion, the PI
process was used in place of gamma Lradiation for prevention of TA-GVHD and in place of cytomegalovirus
serologyresulting in the use ofa single PLTinventory with
elimination of these additional tests and Drocedues.
7.. Rebula P, Finazzi G, Marangoni F, Awisati G, Gugliotta L,
ACKNOWLEDGMENTS
9. Mccullough L Vsole DH, Beniamin RL Slichter SL Pineda
A, Snyder E, Stadunauer EA, Lopez-Ple f, Coutre S,
myelogenos leulemia N Engl t Med 1997;337:1870-5.
8. Eri Rhenen D; GullikEson H, Ceenave lP, Pamphilon D,
-Ljungman
P, Klutet H, Vermeii H, Kippers-loume M, de
Greef G, Laforet M, LioureB, Davis K, Marblie S, Mayau-
we thanktheclinicius df theA.lsace
regionandin particularhol
Radul Herbrecht and D! Bruno Lioue (Onco-Hematology
Dep[tmetrt, CHU de Hautepiene,Strasboug,Fluce) for tbet
constant
helpandsuppon,
Ttlerapeutic €6cacy ed saJ€tyof platelets treated with a
Rduion.
prccess for pathogen inactivation: the
Osselaer JC, C@nave JP, lambermont M, Ganaud O,
Hidajat M, Bdbolla L, Tardivel R, Defoin L, waller C,
Mendel I, Raidot tP, lGndel G, De Meuter R, Fabrigli P,
de la Rubia L Ariaga F, Lindes D, lanea L Cdpio N,
Marty ML, Sau MA. Role ofmethylene blue-teated or
ftesh-froren plmma in the response to plasma exchilge in
patients with thrombodc thrombocytopenic purpura. Br t
Haematol 2001;1,14:721-3.
3. Aldreu G, Morel P, Forestier F, Rebibo D, Janvier G, Herve
1994-1998. ft ilsfuslo\
4.
CeenavelP,
and
idcldent rcports from
20O2t4211356-64.
Nei'l B, lviesel ML, kforet
M, Isola H. In vitlo
waluation ofpooled bufy coat platelets tr6ted with photochemical pathogen inactivatio! using motosaleo. Vox
Smg 2004;86:201-2.
5.
Ianerzko K, C@nave lP, lcuter H, KienE D, Michel M,
Beris P, Uoue B, Hastka J, Marblie S, Mayaudon V, Lin L,
,
Lin LS, Conlu MC, Flment
I. Tberapeutic efficacy md
safety of photochemically treated aphersis platelets processed with e
optimized int€grated set. Tlusfusion
2005;
45:1443-52.
6.
TRAP Study Croup. Irukocyte
reduction ild
ullraviolet
B
Lradiation ofplatelets to prevent alloimmunization and
rehactoriness to platelet trestusions. N Engl I Med 1997;
337:1861-9.
Volume", " *
Rasongles P, AngellnlTibert MF, Simon P, CMie C, Isola
H, Klentz D, Slaedts M, tacquet M, SuDdin D, Lin L, Corash
pared with photochemical pathogen inactlvation ueat'
purpua. Vox Silg 2004;86:
tru$fuslon
using components prepqred
L, C@enave JP. Transfuoion of platelet coDponents pre.
246-51.
analy8is of immediate
of 5,106 platelet trusfuslons
Muphy S, Howatd F, Davis K, Lin IS, Metal P; Corsh L,
Koutsoukos A Ud L, Buchholz DH, Conlm MG.
Cid L Muncunill L Sasre IL, sanz C, PeEiE.\
Methylene blue-pho,toinactivated plasma vs. fresh-frozen
plasma as replacemetrt fluid for plasma excbege.in
P. Hemovigilance nehvork in FEnce: orgiliation
Espinosa A, Accorsl P, Iunge K, Iacquet M, Flamenl L
CoEsb I", A prospecrive observational cohon safety study
StrausoRG, Goodnough LT, FlideyJL, Raile T, Cable R,
CuposA;
2.
Osselaer lC, Messe N, Hervig T, Bueno L Cstro E,
Transfusion 2008;48:l06l-7 l.
REFERENCES
thrombotic thrombocftopenic
chemical treatment, Vox Sang 2008;94:315-23.
tl
treatment: the eUoSPRITE tria.l. Blood 2003;I0l:2426-33.
A, Del Rio L Bamirez c, Albo C, Pefls F,
I . Alvaw-ilndir
chdracrerizing tbe salety profile of 7{37
photo-
platelet transfusions prcpared with amotsalen
with photochemical pathogen inactivation treatment.
SPRINT trial. Blood 2004i104:1534-41.
I0.
loce'progrmme
don V, Flament l, Conlm M, Lin L, Metzel P, Buchholz D,
Corash L ltesfusion of pooled buffy coat platelet components preparcd u,ith photocbemical pathogen inactivation
photochemi€I
CONFLICTOF INTEREST
IPC is a memberof the Europem ScientificAdvisoryBodd of
lC is m empioyeeof CelusCorporation.Hl,
CerusCorporation.
C1{,IM, DK,ML, IPR,GK,md MLWhaveno couflictsof interest.
Dehenau D, Arrcyo JL, Padron F, Gouerec H, conal M,
Iacquet M, sudin D, Lin L corash L. An active haemovigi'
Tognoni G, Barbui T, Mandelli F, Sirchia G. The threshold
for prophlAactic platelet transfusions in adults with acut€
ment duing a Chikuguyq
virus epidemic in lle de La
Tlanstusion 2009;49:1083-gl.
Osselaer IC, Doyen C, Defoin L, Debry C, Goffau M,
Messe N, Van Hooydonk M, Bosly A, Lln IS, Lln L,.Corash
L; Universal adoption of pathogen inactiEtlon of platelet
components: impaci on.platelet and red blood cell cbmpo"
nent use; Ttansfusion 21}gi49il4l2.22,
et
∞０
Patient demographics, in terms of age, sex, and
primary care service for PC transfusion, rere comparable
between the thlee periods. Each of the obseryation
periods included between 1678 and 2069 patients with
trmsfusion of between9l5l and 13,24i PCs and 17,732to
24,693 RBC units. Thus, this observationa.l study encompassqsa large experience,indeed much larger thm that of
most clinlcal trials in transfusion medicine that have been
used to support implementation of maior chmges in
trmsfusion practice, such as leukoreduction md adjustment of the uansfusion threshold.5'7When adjustments
were made for differences in PLT content of individual
cornponents, there were no signincant differences in the
total PLI dose required per patient, either for all patients
or for intensively tmnsfused hematologyoncology
patients. Changes in the methods of PC production did
not impact utilization of RBCs, indicative of presewation
of effective hemostasis during periods of PUI trmsfusion
support. This obsewation is.of panicular interest with
respect to cardiovasculal surgery patients and general
medicd.l patients who have not been studied in the randomized clinicil triajs of PCs ceated with PI.t&'gwhile the
utilization ofPCs and RBCSdid not change in responseto
modificadons in PLI-processing,the incidencq of adverse
events imputed to txansfusionsofPCs decreasedonboth a
per-transfusion and a pe!-patient basis. This observation
is consistent with the signincant reduction in acute transfusion reactions noted in a prior large nndomized clinica.l
tial.e only a single case qf TRALI was reported during
each of these observation periods; this case was attributable to high-titer HtA antibodies in a multipaous apheresisPLTdonor. No ctres oftransfusion-related sepsiswere
leported in any period.
Tho conclusions regarding efficacy and safety that
may be drawn ftom this study are potentially limited due
.to the lack of a blinded, randomized uia.l design. However,
the study has the advmtage of comparative obseryation
fieriods in a single region in which the staff preparing the
PCs and the primary care physicians prescribing PCsand
monitoring patieni outcomes remained relatively stable.
Molewer, the study wds conducted in obseryation
periods when each of the Pc methods reflected routine
production practices. Thus, the study involved assessment ofthe changesin PC production under realistic condlttohs. In additiori, monltoring of patient clinical
outiomes utilized objective measures, such as utilization
of PCs md RBCS,and an active hemovigilance program
with oversight by clinlcal monitors who were not associated with the blood center producing the blood components. On the basis of these factors, we believe that the
data reported from this study indicate that PASSild PI
treatm€nt can be implemented into routine pracdce
without lnpacting either PC or RBC utjlization md with a
reduction in acute fansfusion reactions. The experience
with respect to the safety profile md tolerability of PCs
CAZENAVE ET AL.
:NACTiVATED PLT COMPONENTS
TRANSFUSION7
8 TRANSFuS,ON VolumO・
・・
."・
販後調査及び観察研究の
TRANSFUS10N PRAOTICE
Therapeutic efficacy of platelet transfusion in patients with acute
leukemia: an evaluation of methods
Torunn O.Apeketh,AysteinBruserud,ToreWentzel-Larsen,
and TorHeruig
EACKGFOUND:Clini€l eflect of platelet(PLT)lranslusion is monilored.bymeasuresof PLT viability(PLT
recoveryand survival)and functionalily.lh lhls sludy we
Evaluateand comparglransfusion€lfecl msasuresin
palientswith chemolhenpylnduced lhrombocylopenia
du6 to treatmsnlof acule leukemla.
STUDYDESIGNAND METHODS:Forty translusions
(28 conventionalgammir-lrEdiatedand 12 pathogen.
Inactivat€dpholochemi€l-trealedPLT concenlrates
[PCsl] were investigated.PC qualitywas analyzed
lmmedlalslybefore transfuslon.Sampleswere collected
lrom thrombocytop€nlcpatlentsat 1 and 24 houc lor
PLT lncrsmenlsand thromboelaslography
(TEG) wlth
assssmenls ol bleedingscore and intertransfusion
inlerual(lTl). Data war€ analyzedby Spearman'scorelation.Patientard PC variablgsinfluencingthe elfect ol
lranslusionwer6 analyzedby us€ of a mlxed-etfects
model.
RESULTS:PLT dose, slorag€ tlm€, and pathogeninac.
tivationcorelatad wlth PLT rs@very bul not with PLT
survival(includlnglTl), TEG, or clinlcalbleeding.Fever
ws negatlvolycorrelaledwith PUTsurvivalbut did not
atlecl PLTrecov€ry.Atler 1 and 24 houts, slrong cor€latlonswers obseiled wlthin measurgsol PLTviability
and betwBenPLT Incfomenland the TEG valuB
maximalamplitude(MA). Negativecorrelatlonwas
obseryedbetwoenlate MA Incrsmentand clinicalbleed.
ing slalus atlsrlranstusion 0 = -0.494, p = 0,008).PLT
count Incrementsdid not corelate to clinicalbleedino
$alus.
CONCLUSIONS:PLT dose and qualityof PCs are
lmpodanllor optimalimmsdlatetransfusionresponse,
whereasdurationof tEnsfusion etfgot is influenoed
malnlyby patlentvaiiables. The TEG value MA corr6.
lateswith PLT count incrementsand bleeding,thus
retlsting both.PLT viabilityand functionality.
llogeneic platelet (PLI) umsfusions ue used to
prevent (prophylactic umsfusions) and contfol
(therapeutic transfusions) bleeding in patients
receiving intensive chemotheiapy,r'sBut even
though the risks of severetransfusion reactionsmd tIusmision of pathogens are minimlzed due to technologic
progress and Fathogen reduction methods, PLtr trusfusions are not freeofcoinplications.6{ Itis thtirefore important to continue the seilch for an opti.rnal trmsfusion
policy in patients receiving PLI transfusions. Larle randomized clinical uials ffi nm performed aiming , to
define the optimal use of PLI transfusions;both by evatuation oftrilsfusion strategjesand by investigationsofthe
influence of variables like PLI dose and transfusion triggers on the results oftreatment.3!
The tests used.to assessthe clinica.l efficacy of PLf
uansfusion reflect different approaches to minimize
bleeding in patients. They inJluence routine trilsfusion
practice as well as t}le results of clinical PLI transfusion
studies.The clinical effect of PLf transfusion is monitored
by measures of PLI viability and fuirctionality. In studies
of thrombocytopenic patients, PL;I viability is usually
PC(s) = platelet concentrate(s); PgI = photochemical treated;
TEC = rluomboelasrography.
From the Blood Ballk`the S“
tion for Hematolo絣Department
of Medidne,and the Centre for Clinical Research,Haukeland
un、crsity Hospital,Bergeni and the cades lns,tute and the
lnstitute of Mediche,uni"rsity Of Bergen`Bergen,Noway
′'η“あ′″:Torunn Oveland Apeヽeth,MDi
4′′潜 Sた′rl●
Blood B,nk,Haukeland vnIVersi″ HOSpital,N‐
5071 Bcrgen,
Nort7av e‐
man:tOrunn 9veland apelseふ@helse‐
bergen no
ThIS■ Чdy VlaS fttded by a grant mm“
艶、e ttt,"he
dol 10 1111′
j153●2995290902540x
IRANSFuS10N 2010150:766‐ 775
50Àp‖12010
investigatedby Lnmediate PLI gount increments, reflect.
ing the PI.T lecovery together with late PLT count increment ild intertransfusion interval (lTI) which reflectsthe
PLI survival.j5,er2PLT functionality mdy be monltored by
point.of-care tests of hemobleeding assessmentsrer3.and
stasis and PLT function like the thromboelastography
{TEG) analysis.'tWhile PLI count incremdnts are fundamental in the prophylactic PLf trmsfusion stmtegy, the
therapeutic trmsfusion strategy is based on bleeding
assessments:
In our study .we aim to evaluate and compare
methods for measuement of clinical efrcacvin acute leukemia patients receMng regulu PLf uansfusions due ro
severechemotherapy-lnduced thrombocytopenia.
MATERIALS
AND METHODS
Study deslgn
This prospectiveobservational studywas approved by the
local researchethics cgmmittee (RegionUI, University of
Bergen, Bergen, Nomay), and patients were rccruited
from the.Section for.HematoJogy, Department of Medicine, at Hau-kelmd Univelsity Hospital from December
2006until April2007. During the studyperiod, all patients
diagnosedwith acute leulemia expected to be in need of
PLI Umsfusions. due to severe chemotherapy-induced
c!'topenia were invited to partiCipate in the study. With
one exception, all patients accepted. After informed
wdtten consent,wasobtained, 10 patients with acute leu' kemia were included.in the study, giving a total of 188
patient-dayswith chemotherapy-induced cltopenia. Of a
tota.l of 109 PII Uansfusioris; 40 PLT transfusions were
selectedto be chaacterized in detail based on the following criteria: daltime tnnsfusions md data collection
performed according to procedures. The study unlt was
defined as the PLTtransfusion.
ABBREVIATIONS: A?l = absolute plarelet inqemeDt;
ITI = inlsnlar.fuaira
interval; MA = mdimal amDlitude;
govemmental admlnisiadoi oF● e health senices h the
western pan of Non“ y
Rcce市ed for publca●
On June 22(290a re●
●on recelVed
October 12,2009,and lccepted October 13,2009
766 TRANSFuS10N Volum●
MONrrORING PLATELET TRANSFuS:ON EFHCACY
Pleparation of PLT concentrates lor transtuslon
All PLT concentrates(PCs)firlfilled the European requirements.rsSingle-donor PCs (n=17) were collected by
single-needleapheresisprocedure employingthe elutriation principle to provide leukoreduced PUls. (Fenwa.l
Amicus cell sepsator, Baxter Healthcare Corp., Deerfield,
IL). Prestarageleulofiltered bufly coat PCs (n = 23) were
produced by usb ofautomated procedures (OrbiSac,CaidianBcT, Inc., Lakewood, lO). Tlvelve of the 40 single.
donor and bufly-coat PCs were pathogen inactivated by
photochemical treatment using amotosalenand.UVAlight
(Intercept Blood System for Platelets, Cerus Corp.,
Concord, CA). Photochemical.treated (PCT) PCs were
suspendedin PASIII (lntersol, Fenwal, Inc., Lake Zurich,
lL) and conventiona.lPCs in PAS U (T-sol, Fenwa.l,Inc.)
with 35% to 37% autologous plasma. Conventional PCs
(n = 28) were gamma-inadiated irnmediately before
transfusion (25 Gy; Gammacell 3OO0Elm, Nordion Interiational, Inc., Ottawa, Ontilio, Canada), PCs were stored
up to 168 hours at 22 : 2'C under constant agitation in a
flatbed PtLincubator (Helmer, Noblesville, IN). Bacterial
testing was performed on all conventional PCs (BacT/
ALERT, bioMerieu, Inc., Marcll l'Etoile, France). The
prepilauon methodofPCs uansfused was not inJluenced
by the investigators.
Palients
All patients were treated accordinj ro the same institu.
tional guidelinG
with conventional intravenous
cytarabine-basedchemotherapy,.andall developed severe
chemotherapy-induced leukopenia with neutlophil
comts below 0.5 x 1o'g/L.PLI tnnsfusions were.requested
b], the patient's physician in accordance with international guidelines.3asProphylactic PLf trmsfusions were
given to nonfebrile and clinically stable patients with
periphera.lblood PLT comts below IOx10,/L and to
febrile patients when PLI counts were below 20 x lOs/L In.
patients with increased risk of bleeding (e.g,,befor€ invasive procedues or recent hemorrhage) or ongoirg bleeding, PLI transfusions wele adninisteled wtten peripheral
b l o o d P L T c o u n t s w e r e .b e l w 2 0 x 1 0 e . t o 5 0 x l o r / L . .
Patientswer; examined for human leukocwe antibodies O\
(FlowPRA Class I screening test, One iambda, Inc., O
Canoga Park, CA) and human PLI antibodies.r6 Beticulated PLIs were enmined regularly and used for prediction of hematopoietic reconstitutiori.r?
Investlgation procedure
A sample was dnm by sterile procedures ftom the PCs
immediately before Imnsfusion.,The following analyses
were perfornied for characterization ofPC quality l) PLT
dose,that is, number of CD6l+ PUfsin PC and CD6l+ PLT
microputiclesr0 (CeU-Dyn CD4000,Abbott Laboratodes,
RoundLake,IL); 2) metabolicwriables,that is,pH at 22'C,
pCOr, HCO3, pO2, and concentrations of glucose and
lactate (ABL 725, Radiometer Copenhagen, .Denmark;
Modular, Hitachi High:TechnologiesCorp., Tokyo, Japm);
3) PLf density (mean Ptf component) concentration
(Advia 120, Bayer HealthCarc, Tarrytom, NY); and 4)
Iactate dehy&ogenase (LDH; Modulat, Hitachi HighTechnologiesCorp.),r8!e
Prepantion method and storage
time were registered for each PC.
Blood smples from the study patients were collected
through a cenua.l venous catheter before {<8 hr) transfu:
sion,45 to 120 minutes afteruansfusion, and I8 to 24 hours
after transfirsion for exmination df PLT couns (Cell-Dyn
CD4000,Abbott Laboratories) and TEG tTEG hemostasis
system 5000 series, Softwue Version 4.2, Haemoscope
Corp., Niles. IL). For everystudy Eansfusion, the following
Volume 50,Ap口12010 TRANSFuS:ON 767
APELSETH ET AL
patient chtracteristis were evaluated:pretransfusion PLI
count, bleeding, patient weight, fever at time of transfusion, infection (i.e., patient diagnosed with neuuopenic
fevet treatment with antibiotics, md/or serum level of
C-reactive protein > 100 mg/L the day oftransfusion), and
treatment with steroids or griluloc!'te-colony stimulating
factor (G-CSF).Jn addition white blood cell counts, medication, ABO and HLA compatibility of transfusion, occurrence of trmsfusion.compUcations, trmsfusion seqtience
number, and ITI were registered lhroughout study period.
Event charts including transfusion pattelns, reticulated
PIX counrc,PLI couts, and duration of newropeniawere
made for all patientgand treatment cyclesto serveas basis
for interpretation of results,
Methods for documentation
of tlanstuslon effect
Posttransfusion absolute PLI increment (API) is affected
by quality and number of PUfs transfused, as well as the
dilution of PLTsin the patient's blood volume. According
to Europedn recommendations, we defined that m
acceptable immediate API (at t hr afrer transfusion)
occurred when PLf tmnsfusion iaised the PLI count
above the tmnsfusion threshold, that is, greater than
l0 x I0e/L.'3Toadiust for differences in PLf dose and blood
volume of the patient, the corrected count increment
(CCI) ms calculated by use of the formulae 20
C α=
According to international guidelines, a successfi.rl
lransfusion was defined as a CCI of more than 7.5 for
immediate clinical effect (P!T recovery) and a CCI ofmore
than 4.5 for late clinical effect (PLT survival).a,0 Body
surface area was estimated by the formula of DuBois md
DuBois.2l
ITI was defined as hours ftom onset of study trmsfusion to the bnset ofthe subsequent transfusion.When the
interal between tmnsfusioro was more than 240 hours,
which is longer than the expected life span of transfused
PLIs,22awe assuned that autologous PLT recovery had
occued, and transfusions were excluded ftom- malysis.
Bleedingassessmentsconsisting of physicalexmination and patient intewiew were performed each
morning by trained nurses working at the \dmatologic
ward.r? For additional clinical information, the medica.l
records of the patients were consulted. The bleeding
assessmentswere reviewed independently by two adjudicators and graded in accordance with the WHQ hemostatic asse$ments.rzIf disagreement occurred, the patient
data were eva.luatedby a third adjudicator and consensus
was achieved, WHO Grade of 2 or more was defined as
primary bleeding endpoint according to recent PLI
studies.r2'2''27
Accordingly therapeutic transfusions were
defined as transfusions given to patients withWHO Grade
768 nANSFUSION Volume50,Apnl2010
MONrrORING PLATELET TRANSFuS:ON EFFICACY
2 or more bleedings before trunsfusion. The proportion of
days withWHO Gmde 2 or more bleeding duing ndutropedia was ca.lculated.r3
To evaluateWHO bleeding assessments used for daily monitoring of PLT tmnsfusion effect,
we calculated the diference in IVHO bleeding status
before and after each umsfuslon.
The blood coagulation processin patients before and
after tralrsfusion was investigated by TEG in citrated
kaolin samples with heparinasecups to avoid contamiia'
tion of sample by heparin from the centml venous catlt.
eter. The ,following variables were invesrigated: l) R,
reaction time, the time to the begiming of clot formation,
rcflecting the level of coagu.lationfacto6; 2) angle (o), the
buildup and cross'linking of fibrin, dependent on suffr.
cient amounts of fibrinogen, thrombin, and PLTs;and
3) MA, the mdimum amplitude, a measurement of
milimum strength or stiffness of the developed clot,
reflecting the amount and functiona.l capacity of PLTS
including their interaction with fibrin.ta Referencelevels
were provided by the manufacturcr.
Statlstlcal analysis
Eescdptive statistics were performed by use of computer
software (SPSSi5.0 forWndows, SPSS,Chicago, IL) and
resultsare presented as mean I standard deviauon (SD)if
not otheruise stated. When anallzing PC characteristics
not influenced by individual patient effect3,two-sample t
testswere performed (SPSS,Ve6ion15.0).All patient data
were malyzed, adjusted for individual patient efects.
Analyses of dichotomous data were perfomed with
generalized estimating equations (packagegee, R Version
2.8.0;http://w.R.project.org,
The R Foundation for Statistical Computing, Viema, Austda), Correlation ana.lysis,
not adjusted for individual patient effect, was performed
by Spearman's correlation (SPSS,Version 15.0) due to
partly categodcal data. Confidence interuals (CIs) were
ca.lculatedas bootstrap BC. CIs (paikage boot, R Version
2.8.1,The R Foundation for StatisticalComputing).,3Differenceswere considered significant wheu p va.lueswere
lessthan 0.05.
To sepante the efects ofPC and patient variables on
tmnsfusion outcome measues, mixed-effects model
(packagenlme, RVersion 2.8.0,The R Foundation for Statistica.lComputing) was performed,2s.3o
If random parts of
the mixed-etrects model were unstable, genera.lizedleast
were.used.
squares
In this analysis we invesugatdd the
relationship between posttnnsfusion va.lues of PLI
posttransfusion
costs,
TEG values, arid ITI and the following variables: fever, transfusion sequence numbet
padent weight, bleeding ofWHO Gmde 2 or more, PLT
dose,storagetime, prepilation technique, and ABO identiry AnalysesofPL;f counts and TEG valueswere adjusted
for time and pretransfusion values. The selection of
variables investigated was based on previously published
drticles,:s'st're
md the number of vuiables was adapted
to the total number of study transfirslons. Mixed-efects
analysiscould notbeperformed for bleeding status due to
the.categoricalnatute of the variable.
RESULTS
PatlentsandPC8
Ten patients, four males and six females, djagnosed with
.acute myelogenous leukemia (eight patients) or acute
lymphoblastic leulemia (two patients), were included in
the study.Transfusioii requirements were folJowedby the
investigators from the administration of chemotherapy
(five remission induction and eight consolidation treatment cycles) to hematopoietic reconstitution (i.e.,
>0.5 x to'g/Lneutrophil granuloc)'tesin blood samples
and noneedforPLf tlansfusion), patientwithdmwal (two
patients), or death Of patient (one patient, due to infec.
tion). All patients (ages2l-62 yeals) had a history of previous pregnanciesand/or previous PLI tmnsfusions, but
no patient with previous splenectomy or disseminated
inttavascular coagulation was included in the study
Patients with HLA antibodies were transfused with HLA
Class l-matched PCs (three patients) according to international guidelines.eOne patient was diagnosed with
weak positive HPA utibody at the time of inclusion dnd
transfused according to routine practice without HPAmatched PCs. No padent developed HLA or HPA antibodies during the study. All tmnsfusions were AB0
compatible, by means of recipient having no antibodies
incompatible with the red blood. cell qpe of dontir. Qne
patient was diagnosed with neutropenic septicemia.
These transfusions (four) were grouped and malyzed
together-withthe transfusions giwn to pdtients with infec.
tion. In I1 uansfusions, patients received ueatment with
hematopoietic growih factors, Threaof these uansfusions
were given to acute lymphoblasric leukemia patients
treated according to the H'?er-CVAD regimen and eighi
transfusionsto acute niyelogenous leukemia patients due
to severebacterial infections. The mean PLI dose given
was 2.79 (Iange, 1,46-4.42)x 10r! per unit, and mean
storagetime ofthe PCwas 86 (range,2l-167)hours.The
metabolic status of the PC was as follows (m€an t SD):
pH (22'C)7.22! 0.I4, pCO, 2.98 t 0.47kPa, pO, 17.3t
2.1kPa, glucoseconcenuation 5.18 I 1.55mmol/L, and
lactateconcentration7.35 1 3.64 mmol/L. The LDH concenuadon was 135 (rmge, 2l-522) UlL, and.the mean
level of PUI micrgparticles was 26 (range, 6.750.6)x lo'g/L.
Effect ot PLT transfusion
PLT viability
PIII viability was eva.luatedby PLI count increments and
calculation of ITI. PLf transfusion increased peripheral
blood. PUf counts after'both I hour (mean increasei,
x 10,/L) and l8 to 24
12,5x 10,/L 95% QI, lO.0x l0r-1i1.9.
hous (mem increase, 7.2x1.0e/L; 957o CI, 4.7xlo'g9.7xlo'g/L). Significant correlations were observed
between pre- and positransfusion patient PLI counts
( a f t e r l h r , r = 0 . 5 6 9 , p < 0 . 0 0 1 . ;a f t e r 2 4 h r , r = 0 . 4 5 7 ,
p ; 0.005).
Forty-six percent of PLI transfusions raised the
patients'immediate PLI counts above the trmsfusion
threshold, that is, more than 10 x lo'g/Li and were thN
defined as acceptable according to tlie European recom.
mendations.e When evaluating Pllt viability by use of
CCIS,46% ofthe studytnnsfusions were classifie! m suc.
cessfirl after I hou, whereas 5370of uansfusions fulfi.lled
predefined criteria after 24 hours. Eight out of l0 patients
received more than.one transfusion per treatment cycle,
and all of them experienced both successfultransfusions
and transfusion failures (Fig. l). The results of compaative analysisofpatient and PC.characteristicsin successful
transfusions and transfusion failuies are reponed in
Table l. When evaluated by immediate response,the suc.
cessfulPLT trmsfusions were differentiated ftom transfu.
sion failues by superior PLf quality (Table l). In contmst,
successful PLI transfusions evaluated bi late response
showed favorable patient chamcteristics.Mean ITI was 4l
(rante, 7- l2I) hours, and there was no significantly highe! ^
ITI in PLI tnnsfusions characterizedas successfulby CCIs !
after either I or 24 hours.
-l
PLT tunctionality
Eight patients experiened minor bleedings (petechiae
and minor nosebleed), giving a total of 34 days (18.0%)
withWHO Grade I bleedings during the total studypdriod
(188 patjent-days). Only four patients experienced WHO
Grade 2 or 3 bleeds, giving proportions of 7.4 and 2.1% of
total padent-days, respectively.The time to frrst bleeding
(WHO Gnde > 2) varied between I and 15 days and the
individual proFiortion of days with Grade 2 or 3 bleeds
varied from 6.3% to 66.77ofor ihe affectedpatients (Fig. 1), .
No WHO Glade 4 bleed was obserued during the study
period. The bleeding event chart did ,not indicate any
associationbetween time to the nrst bleed and individual
number of bleeds; rather, it did illustrate the individual
differences in bleeding pattern among patients with the
similar diagnosis and PLI counts (Fig. l). In spite ofhigh
frequency of PLI transfusions, bleedings still occured,
and patients with the simllar morning PLI counts d.idnot
experience the sme number, timing, and sevelity of
bleeding. Significant correlations were observed between
l) WHO bleeding status before and after transfusion
(r=0.639, p<0.001) and 2) WHO bleeding status after
timstusion md ITI (r = -0.380, p = 0.020). No significant
correlation was obseryed betwegn pretransfusion PUI
comts and bleeding a3sessmentbefore and 24 hours
after transfusion, neither was anv condlation obsi:rved
Volume 50,Ap112010 TRANSFuS10N 769
MON:TORING PLATELET TRANSFuS:ON EFFICACY
APELSETH ET AL,
ing of R, increased angle, or MA incte'ment
after PLf transfusion when
evaluated by correlation analysis.
770 IFANSFUSION VolumeSO,lprtt ZOtO
7(41)
12(71)
4(24)
AB01dOnJcal transrlsion
Stora9o lrn。
(hrl
101'per uno
PLT dose(×
PLT concenlralon(x100/L)
V●りm,(mり
C(mttH9)
pH a1 22°
pC02(kPa)
￨
m。
Ll
HCOo(口レ
p02(kPa)
L)
01uCOSO(市“。レ
Laclale(mm01几)
ne→0
需
:1胎
:「
需認品ぽP° 0 た
し
OH(Uパ
⇒
8(4ηl
14(82)t
iO(59)十
3(15)
11(551
9(45)
13(65)
106=45‡
281=065
7 1 7 ±0 1 2 ‡
2181 =037‡
50=15‡
45=15キ
89■ 351
192=08辛
12(63)
12(71)
307 ±062‡
970=203
318■ 33
64■ 116
52亡 17
65=34
297=048
57■10
54=1,4
8 4 ■3 9
25■ 12
3 0 ±1 0 ‡
25± 10
162=lo9‡
103=64
' Flesullsarg prGenlsd as number (%).or mean : SO.
t p < O.O5lor dlfier€ncb bstween suc€sful ancl nonsuccossfullransfusions(lest tor dichotomousdala adiustod for lndividualpati€nl ettecl
,Rl)
l g●
●
‡p く0 0 5 f o r
d
rerence
belween
s u c c o s sn ls ur uO aЫ
mpbs,SPSS
n ns d l l ot ne sS ul cf cO ord se smn ldt ue lpS lOa に
Ⅲ
16
0).
When evaluated after 24 hous, correlatiors were obserued between PLT count
increments and fever, trmsfusion
11
1 43=11
17
47■
BofOre transFusion
82■
seqirencenumber, and pathoged inacti8+
52=9+
l hr arler trahstusiOn
68■16+
58±
vation. No significmt correladon was
10+
18
50±
24 hr anortransrudo口87■
0
49■
obserued between ITIS and the patient
' Tesl lar continuguEdata adjusled lor pati€nt eftect (packagg nhe, R). Results are pr€or PC variables investigated. Similady,
s€'ntedas heil : SD. n = 33.
I p < 0.05 for difigrence between postlranslusionand pGtfansfusionvaluel
no significmt corelation was observed
between the PLI functionaliry measure
bleeding ouicome and the investlgated
patient and PC variables.No couelation was obsewed for
at time of trmsfusion experienced a mean rcduction of
the TEG values R and angle, while a negative correlation
the ITI by 39% compared to nonfebrile patients (Table4).
was.obseryed between MA increment after 24 hous and
The mean ITI was 27 t I hours in febrile transfusionsand
patient weight (Table6). In summary, the results ofcorre46 t 30 hous in nonfebrile transfusrons.
lation analysis show that PLl-related factors maidy influ'
Whereasthe selected patient or PC variables showed
ence the immediate clinical effect of PlI tresfusions,
significmtinfluence on the measurementsof PIjrviability
(PLI count increments and ITI), no significant influence
whereas patient-related factors influence late clinical
wm observi:d on PlI functionality measured by TEG.
effect.
Mixed-effects analysis could not be pedormed for
bleedingstatus.
DtscusstoN
Conelation analysis of vatiabtes influencing effact o(
PLT ttansfusion
Spearman'scorrelation analysis was pedormed to separare between variables inJluencing immediate ild late
clinical'outcomeof PIjt transfusion.The ma.lysisincluded
bleeding outcomes ud was not adjusted for individua.l
patient effect.
The immediate clinical effect of PLI tiansfusion
elaluated by measurements of PLT viability (PLT count
indrements) showed strcng correlations to PLI dose,
storagetime, md pathogen inactiwtion by PCT (Table6).
In this study we aimed to evaluate and compare methods
used for documentation of clinlcal effrcacy of PLT trmsfusions in patients receiving regular PLI transfusions due to
severe chemotherapy-i.nduced thromboc'4openia Our
results illusuate the advmtages and dlsadvmtages of the
different methods when used for documentation of clinical efiect ofrtigularPLl transfusions.The challengesidendfied ae discussedbelow.
By statistical analysis of 40 PUI transfusions we,
observed that PLT vi4bility Ms affected by both patient.
and PC-related variables. The vdiables identified in our
Volum● 50,Ap市12010 TRANsFuS:ON 771
ＨＯＨ
.Variables influencing eftect of
FLt ltanstuspn
The effect of PLI uansfusion varies
n g . 1 . T h e b l e e d h g e v e n t c h a r t d iOs pClraaydse W2■ o r h i g h e r b l e e d i n g s , P L T
between individual uansfusions within
transfus:ons,and mOr●ing PLT∞ unt during neutroptnia fOr each patient and treat・patient
and ueatment cycle, but also
ed:
r i n g:●
ct」
o F 1 8 8 Pean●
t d a y 5 , a t O t a l o f W 5e 2r e b lr ee ep do ir nt び
m e n t c y.cDlu●
between patients. The analysis of vari34 mmor bleeds(WHO Crade l)and 18 clmicdlysuttncant 11,eds(14WI10 Crade 2
.ables influencing outcome of PLI
●nd FourWHO Crad● 3).The bleeding ewnt chart llustrates the mdivldual dttr‐
tmnsfusion was therefore adjusted for
bleedhg
patterll
arn,ng
patients
with
ule
simuar
diagnosis
and
PLT
counts,
ences I●
.indivjdual patient efect. We found
nt
uthdFawals(Patients
2b
and
9)and
one
death
Durlng thestudy period two patた
that the selected patient variables
C Curred.
餞 tent 10)。
(ransfusion
number,
sequence
bleeding > WHO Grade 2, fever, and
patient weigho and PC vsiables (storagetime, PLI dose,
between PLI cout increments ud change in clinical
prepdation technique, and ABO identiry) influenced the
bleeding status after transfusion. When ialcu.lating the
different methods for documentatiom of tlmsfusion
difference in WHO bleeding status before and after trans'fusion, no effect ofPLfuansfusion was obseruedeither for
effect differently (Iable 4).
Elevatidn of PLI dose by I x lotr per unit led to a
the total of trmsfusions (mean t SD,-0.03 1 0.73)nor for
mean increase' in posttransfusion PLI count by
the seven therapeutic uan!fusions when andlzed sepa3.2xloslL, whereas prolonged storage time"(by I hr) ot
rately (meil I SD,0.14 t l.0l).
pathogen inacti%tioq by photochemica.l treatment
The overall results of investigations by the TEG mareduced the postuansfusion PLI count by 0.04x loe and
llzer ile reported in Table 2. PlI transfusion had an
3.9 x 1O'3/L respectivel)a Corrdspondingly prolonged
imm€diate but transient efrect on initial clot formation
storage tine or pathogen inactivation reduced CCI by
thai was reflected in the R and angle variables, whereas
0.02xmzlL and 1.7 PLiIsx m?/L respectively.Additional
the efrect on PUf clot strength and stability, the MA value,
investigations showed reduced PtI dose and qualiry in
persisteduntil the next day.No effectwas obseruedon PLI
pathogen inactivated PCs (Iable 5). Patientsbeing fdbrile
dose or the number ofPUT micropdticles on Oe shortenL●oponla
0●●椰いn●
rtient vailables
FevBa
ぃrec10n
C・CSF
PLT Va"abbs
３
２
０６ｍ３１爛０︲９０９２６
051015202530
CCl afto7'hr
８２
９０
３０
２油″８
︲蜘調７
︲５
５
２
﹁２
７
７６
︲
９３
︲
How do the methods monitoilng
clinbal eftect of PLT transfusion
intercorrelate?
Coirelation analysesof the investigated
methods for documentation of PlI
transfusion were performed, and the
resu.ltsare pr€sented in Table3. Strong
correlations were obseryedbetween the
methods based on PLt counts (API,CCI,
ITf, and MA) when us6d for evaluadon
of transfusion efects after both I hour
and 24 hours.A negativi:correlationwas
observed between the increase in MA
after 24 hours ud the calculated
difference in. bleeding status after
tansfusion. Correspondingly, a negadve correlation was obsened between
MA increment after 24 hours and clinical bleeding status after tmsfusion
(r=-0.494, p=0.00S). No corelation
ws obseNed between PLf count increments and calcrilated d.ifference ur
bleeding status or clinica.l bleeding
statris before or aftei transfusion.
TABLE 1. Characterlsticsof successful lranstusiona versus transfusion tallur6s'
MON:TOR:NG PLATELET TRANSFuS!oN EFFICACγ
APELSETH ET AL.
TABLE 3,'Correlalion of m8thods for documentatlon ot trrnsfusion eftectr
Ы
Onoutomem:“
uにc。龍博
翻1::R:よ
よ
艦n:e畔
湘 2■1悧
器P鴇譜齢野暑淵蹄
■,ゴ
Ч
0308
05491
05181
︲
２４
２２
５ ” １６００
09181
09521
０ Ю 。 ↓ ００
API
Afl6r t hr
Afior 24 hr
CCI
i
Aft€r t hr
Aft6r 24 hr
Transfuslon inleryal (h4
Aft€rlhr-'
Aftor 24 hr
24 hr posttransfugiondiFference
in WHO bleedlng grads
After t hr
Afler 24 hr
Posttranglusionditfsrence
in TEG values
R (min)
'l
AftEr hr
Atlat 24 hl
Angle (degree)
Aft€r t hr
AftEr 24 hr
匈 406‡
0109
Ю 33tl
0052
0.5971
04601
04031
0155
o 410t
0 4401
0173
0427幸
“458‡
0001
0263
-03821
-0362+
0038+
■
´ 0100
0015
:
04o5+
0032
transfusions with lower PLI dose,33A
of bleeds defined as
or higher and higher
.Transfusion outcome moasuro
p valu€
Moan ditferonce
95o/.Cl
number of tansfusions has previously
APl(x10° /L).市=40
been described in patients being uansPLT doso(by l x 10'po7 un→
32
03to61
0 030
fused rjvithlow-dose PCs.t'?Themaiority
Oocreased APL
of ou study transfusiorls (28 of 40)
Stqrage umo(per hrl
would have been defined as low-dose
-39
-741o-05
0o27
Pathogen inaclivatbn by PCT(yOS)
OCI(PLTs x P/L).n=40
uansfusions according to this publicaDecreased Ccl
tion, and a low rmge of .PLTdose may
Slorago,me(per hう
002
“
05 toつ 00 0041
.
‐
therefoie explain why no conelation
Palhogen haclivatbn by PCT lyOSl
-17
⊇
71o06
0003
TranstuЫ
on hterveL n.37
wm obserueil between PLT dose and
・
/.Reductbn
bleeding in our study.
Fever(yOS1
39
14 1●
5フ
O oo8
Outcome measures based on
Analyzed by mixed'gtfects model (packag€ nlm€. R).
bleeding are complex becausethe clinical impact ofbleedings depend both on
severity and on location. A calculation
study de in accordance with previous publications.'z3J-36
ofdifference inWHO bleeding status before and after each
Evaluated by measures of PLT viability, PLI recovery was
tlmsfu sion implies treating bleeding as a continuous vadinfluenced by PC vuiables only, whereas PLf suryival was
able, which it is not. The use of bleeding asessments in
influenced mainlyby patient vuiables. Being a retrospecthe evaluation of clinical effect of PLI trarofusion theretive variable, the importance of calculated ITI in daily
fore requires a different approach. Webert and colpatients
monitodng of thlombocltopenic
is limited. It is
leagues2?have shoM that minor bleedings (WHO Grade
l) predict clinical significant ble€dings (NHO Grade 2, 3,
also dependent on the individual umsfusion uigger
chosen for each patient, which makes comparisons
or4) md that cumulative incidence furictions forbleeding
(Grade l, 2, 3, or 4) increaseswith tine. Correspondingly,
between patimts di.fficnlt.
we obsbrved that the WHO blgediirg status before and
PUI dose may influence both API and the calcu.lated
CCIs. As shom in ou study, higher PLT dose may be
after umsfusion was correlated. Webert and colleagues,
obsewed in transfuslons with lower CCIS.As discussedin
howeve! found that the risk factors for mild bleeding
a previous publication, this obseryation may be e:iplairied
included decreasedPLI count, an associationthatMs not
by the formula for calculation of CCI, which favors PLI
connrmedby our obseryations..Inour 40 transfusions,we
私B L E P●m に
耐a n d : Я
m ソh ・
uen.e●
d m ● higher nmber
轟: 害
路掘湘肝
WHO Grade 2
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PLT valabl●
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Storage umo(hrl
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pH at 22'C(mmHg)
pC02(kPa)
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Pathogen inaclvatod(PCη
PCs h‐12
53=2,7
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0004
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く
0001
0014
' Tesl lor@nlinuous dala adjuslod tor palionl €lfect (package nlmo, R),
t I lesl lor trc Independ€ntsanples (SPSS).
TABLE 6.patlent end PC va‖
Iransfusion out@me d€6ure
Couelation @'fliblent
95% Cl
,j
:濶二■ 1■ 1童
歓
R「
A贔
￨:議
I鍛
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「1
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i .
‐-0386 : 1`38
-0 631 to 0 0'4
Translu゛
on soquence number
Palh●
99n inamvttbn
ccl aner 24 hr(PLTs x m2/L)
ittuti:n轟
」
.n■
limb::1
Mfl:器
:II:譜
1,Irttm
_0392
_o406
6541o‐0048
6520→ 050
●
“
'
i
J51
匈1,:゛
‐
1:1挙
11 .I::::Bl:説
°
03γ l l 「 oΨ°
:
:°
Palent welohtt i
-0439
-07o9tO o 019
・Analyzod bソSpeamallt● ●7701atた
n(SPSS 130)and b001strap BC.Ci ca c11■ loO(B)
obseryed no sigrdficant correlation between pietnnsfusion PLI cqunrc and bleediag assessmentbefore md 24
hous after trffifusion,
neitler wro any correlation
obsewed between Plf count increments.md change in
clinical bleeding status after transfusion. This observation
correspondsto the results of Friedmann md coworkels3s
who fqund no relationship between the lowest PLI count
of the day and the risk of hemorrhage when investigating
2942 patients over a period of 10 yetrs. These difrerences
in conclusionsmaybe explainedbyinconsistentreporting
of bleeds (i.e., problems with sepilation of new and
ongoing bleeds) or individua.l diferences in grading and
interpretation of bleeds by adjudicators, yet the discrep:
ancy strongly indicates that rhe present bleeding ssess.
ment schemedoes not provide the information needed to
serye as documentation of clinical efiect of PLI trlusfusion. In accordance with Heddle and colleaguesu we
thereforerecommend a reevaluation ofthe present bleeding assessment
scheme,
p value
０呻叫¨¨
ｍけゆ・¨・
叫 ¨０
︲
・
・Resu,s shOwn as correlaJon coofnc10nt(Spearmanヽ
c。「
701ation,SPSS l'0).●
■40
1 Correlation is signllcant at the O ol 10vel
i COrre atbnにdgnmcan a mo o o5 bvel
03621
0306・
TABLE5. PLT vlabllitv 8nd iranstuslon charactsrlsllcs Dresentedaccordlnq to DreDaratlontechnlouea
Transfusionoul@m€ m€surE
and variabl€s
, 0019
'
As indlvidual patient and PC variables inlluence the
methods for documentation and: clinjcal evaluation of
umsfusion differently, a direct omparison between
tansfusion outcome measures was difrcult to perform.
By Correlation analyses,however,we found no consistent
correlation between measures of PLT viability and functionality. The strongest correlations.wereobseryed wlthin
measurements of PLT viability md between PLI count
incrcments and MA, which reflects PLI pmber as welJ as
functiona.lity of PLTS,A negative correlation was, howeve!,
obsewed between clinical bleeding status and late MA
inclement, indicating that a higb MA increment ma)abe
associatedwith less clinical bleeding. A previous publicatjon repons that nonactivated tfuomboelastography ms
sufficiently sensitive tb monitor changes after PLI transfusion in patientswith severeto mild thrombocytopenia.s?
Oui observations confirm that the efrect of PLT transfusion can be visualized by teG analysis,but by sbowing an
association to clinical bleeding status they also indicate
VOlum● 50,Ap"12010 TRANSFuS10N 73
MON:TOR:NC PLATELET TRANSFuS10N EFHCACV
APELSETH ET AL.
thatTEG maybe a potentially useful surrogate measure of
PIJI tunctionaiity.
Based on ow observations we conclude that further
investigations and standardization ofmethods are needed
for better documentation ofPLI transfusion outcome and
identification of patients at risk ofbleeding. Our obseruations also indicate that both PUt dose and high quality of
PC are important for achieving m optimal immediate
response to PLI $ansfusions whereas duration oftransfirsion effect is influenced mainly by patient variables.
Heddle NM, Blajchmu
MA, Meyer RM, Lipton IH, walker
granulocyte utigens
McFarland IG. Platelet ild
and anti-
Thorpe !G, Lwine MN. A landomized controlled trial
comparing the frequency ofacute reactions to pl6ma-
Bethesda: American A3sociation of Blood Banks; 2008. p,
29,
30. Pinheiro IC. Mixed-efects models in S and S-plus. lst ed.
removed plateleb and prestorage ltBC'reduced platelets.
,l
.i
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evidence fora fixed platelet
WeappEciatethepatienceudhelpfulness
shoubythe nunesat
the Sectionof Hematology,
Deparrmentof Medicine,Haulrcland
durlngthe couectionof patientsamplesand
UniversityHospita.l,
daily bleedingassessments
includedLothis work.Wealsothek
SolfridBjorsvtkand LindaSkordalat the BloodBank,Haukelud
Univelsity Hospitai,for technicalhelp and assistan@with the
tfuomboelastogtaph ana.lysisand Kristin Paulsen md Aina
Kvinnslandat the Inctituteof Medicine,UniversityofBergen,fo!
technicalassistucein measurements
of ieticrtatedplatelets.
l3
with R. lst ed. NewYorkl
Bishop IF, Matths
Kao Kt, Kicklbr T, I€e E, McFdland J, Mccullough L Rodey
G, Schifer CA, Woodson R. Factoc affecting posttransfu-
Br J Haema-
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CONFUCTOF INTEREST
NewYorkr Chapman& Ha.ll; 1993.
525-40.
ACKNOWLEDGMENTS
The authorsdeclarethat they have no @nfuctsof inrerestrelerut to the manuscliptsubmiiledto TMNSIUSION,
Efron B, TibshiEni RI. Ati introduction to the boorstrap.
bodies. la: Roback ID, editor. Technical manual.
Guidelines for the use of platelet lrasfusions.
ll
28.
IR, Sher GD, Constantini l"A, Pattelson B, Roberts RS,
gamma-inadiated single-donor
platelet concentrat6 duing long-tem stonge, Tlansfusion 2007;47:653.65.
Volum650.ADril2OlO
TRANSFUSION75
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Snyder E et al.Transfusion,2005 Dec:45(12):1864‐
75
Franceand Belgiumh,avebeenusingpathogenieduced
plateletsfor severalyears
Adverseeventson transfusedpatientsare reported
througha passivehemovigilance
reportingsystem
Frequ-ency
of reportingof adverseeventsis much lower
thanwhatwas reportedin SPRINTtrial
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speoifically
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彙= ・■4 ■ ■●■会
感染性因子低減化技術導入に係る費用対効果分析の報告(概要)
理由用資料
icorcmics of pathogen inaotivation
bohnology for plitolet concantrator
論文タイトル Jamn
of tho lhc oosfrffectivenoss
of pat{rogon
]ost-effsativemss
ヽ
ssOssmont of tho ooooomiC Valu●
of pathogen
'oduction tocfinology as ass6s6ed rehg a
nactivatlon for gldolot tfansfu3ion in tho lN rERCEPT bl●
●d system in 3o!givm
iletherlands
nultigla risk ruduction mdol
in
Illt J Haelllat 2004,80:31732`
目
性因子低減化を想定し、決定木分析によりCEを評
価する。
熙感染症のリスクも含め評価する。
とにより感染性因子低減化処理を施した場合の全血襲
日(PRT WB)及び血小板製剤 (PRTや 0)の費用対効果
ーニング法のCtと比較検討する。
OE)を現在のスグリ
∞st/LYG)で示し、直接及び固権費用と便益を含む
ベースライン分析及びモンテカル●シミュレーションを
用いた感度分析により評価した。割31率は軍 %とし
た。
・放射線照射・
細菌検査 (注:現状、未実施)等の中・
低減化処理経費を116ユーロ、製造工程中のPC損失
止によるPR■ PC(15単位)製造経費削減額10,908
分を1596と仮定する。この損失分を製造コストに上乗ゼ
円に対しヽ低減化処理キット等の増額分が20806
し、低減化処理費用を合算する。
正味の経費増額になると ′
円,差引き1.898円/baφ ｀
グローニンゲン大学病院における受血者のPC輸血豊
仮定。
′
のフ割を占める3患者群 (心臓病・
血液疾患・
卜児がん)
を薬剤経済モデルとして選択した。
・
、
処理により
感染性
評価モデルは低減 1ヒ
因子が
10096低減化されること、重篤な誦作用がないことを
前提とした。
けた乳がん患者、冠動脈′ヽ
イ′く
ス術を受けた患者群を
評価対象とした。
・
3通りのシナリオを設定し、導入効果をlCERにより評
価した。
シナリオ●検査内容等は現状通り。アモトサレン法によ
HOV HCV及び細菌感業のリスクが排除される。
りHⅣ ・
新興感業症は考慮しない。
シナリオ21 0acT/Alertに
よる細菌試験を中止、PC有効
で延長、期限切れ率を1/2、成分採血ド
麟間を7 Flま
ナーのALT検査、成分採血PCの放射線照射を中止。
シナリオ3:シナリオ2にカ
ロえ、成分採血PCについて、
NAT(HCV・HⅣ)、梅毒検査を中止。
輸血による新興感染症の感染リスクも考慮する。
ヽのCCを評価するo
分析対象として2007年を選択、同年のデータに基づき
乍業を行う。
検査方法は現状通りとし、低減化導入を想定。
レシピエントは、全年齢群、低年齢群 (0-39歳)、高年
冷群 (40歳以上)の3群に分け.評価を行う。
全年齢群を対象とする感度分析 (トルネードチャート、
取定した条件により、およそ70万本のPRT‐PC製
て401ユーロとなつた。なお、「部のケースではv線照
造に係る費用増額は、およそ273億円となる。
・アモトサレン法導入によるOALYについて各年齢、射費用30ユーロの節減が可能である。
・
ベースライン分析による各群の"t∞ st/LYGは、心臓
疾患別に算出した。ALLの 10歳児にPRT―PCを輸血
ー
ー
ー
した場合の99∞ 万円/QALYをベースラインとしt更病■74万ーユロ、血液疾患 678万ユロ小児ガン
261万ユ
ロであり、3群の加重平均値は554万ユーロ
こ新興ウイルスに感染するケース(感染確率
(■6094万円)であった。
1/10000)を想定すると、35∞ 万円/OALYとなる。1 ・
,アモトサレン法導入により費用対効果の改善が見輸血用血液の安全性対策は、相対的に高額のnet
cost/tYSで
あり、国際的にも許容されている。今回の
られる。
分析結果も輸血医療においては許容範囲内と考えられ
る。
:
感度分析から当該モデルは、回避されたウイルス感
染及び想定した固接費用の正確な金額を除外すること
轟も滉瞥翼覺諄窮ぴ輩幡警謝淳鞘『
・
感染リスクが1/10万回輸血になると、CEは 165万
-336万ユーロ、1/10∞回輸血では223万ユーロ
(■2450万円)に改善される。感染リスクは1/1oo
回輸血では、全患者群においてアモトサレン導入
グルニプのCEが優位(少額)となった。
・
ICCRは新興感染症の感染リスク、適応、患者年
齢にsensttvOで
ある。
=現在法に対し、アモトサレン法導入グループが優
2・3で、各々
位となる輸血感染回数は、シナリオ1・
1/1074・
1/1697・
1/1791回輸血であった。｀
である`
‐
低減(ヒ推定処理費用は 1∞ドル/回。
PRT導入により、感染リスクは、細菌て1,現状の
1/5011/235∼250万回輸血)、H8Vよ 1/10(1/153万 faI輸
血)に減少すると推定された。
PRT WB:こおける`CERIよ、1276万ドル/QALY(■ 102
億円 )となつた。この金額は低年齢群では平均より少な
く、高年齢群では多くなつた。
的
悪認議ち
雷猷撮鉤
会費用は含まない。
方
法
結果
馴麗L
は大きいことが示された。
ま米国では11万ドル (000万円 )/QALYてある。これに従
えば近年の輸血用血液の安全対策は何も実施てきな
ハ。低減化技術の導入に際しては、同領域の施策と比
欧することが妥当である。これに1ま、30方ドル(■2400
万円 )/OALYの S/0血漿.85Kl万ドル (■68億円)/OAЦY
つHCV NAT(フランス)が相当する。
アモトサレン法導入は、血小板製剤の安全性の改善に
苺与するともに、既存の製造工程の簡略化や新たな
隆査法の導入コスト等が節減可能になる。
Eン
テカルロ分析) を
行う。
現行の堅宋たスクリーニンク蘇査員用は4 4 トル/ トナー
9影
欝鑢称轟駐磯 ξ
糖齢猛需
幌
結論
Transhslon 20 101∞ :2461247(
3(
Transfusloll Medlcille 2006,16:17‐
Trallsfus10nヽおdlclne 2005;15:379‐
33,
.Cこ
の評lal結
果か0アモトサレン法の異馳は景当
医療の分野において国際的にも許容される範囲にである。将来の新興感染症発生時の潜在的リスク
あると考えられる。
し考慮するとき、同法はより有力な戦略といえる。
鸞
与 ζ9舞 ;I[彗し【i]り竹
譜``セi雪`:(I
と、また、アモトサレンの安全性が実験的には確認
されたものの、アモトサレン法処理PCの安全性は
不確実なレベルにあることから、予期しない副作用
により期待した便益が損なわれる可能性が否定で
きない。
￨
PRTや CにおIす
るICFRは、1423万ドル/OALY(■114
平均獲得余剣
者て
￨つた事調鷲
智 γ尋
野
感度分析の結果、PRT=WBでは細薗感染が、PRI―PC
では輸血による年間死亡者数が最も影響が大きい要素
であることが示された。
10ALY:成分採血●
bur“。atPO>成分採血ゃlasrna
iChPC)・
本研究結果から、患者の年齢及び身体の状況がPRT
'C2Eに対して重要な決定要因であることが示された。
PRTは有害事象のリスク減少という点で不確実な点は
姜る。
.
輸血R血液の安全性向上への取組みという点で、CE
)析を通してPRTに係る政策決定の情報を得ることがで
雪る。
費用対効果分析。晨なる臨床効果の冶療法を比較する場合に、発生する費用にアウトカム(QCL.余命)を加えて評価する分析法
ICER Cncrement cost Erecbvenesso:増分
Ra● 費用(対)効果比)
￨
ER=椰
一的に、この値が二定の値より小ざす
の増額分を右式により
小さければ導入は効率的と
れば導入は効率的と評濡できる。
評価できる。 Ю
新規医療技術等 (B)の導入に際し、現在の技術(A)から
算出する。
額分1右により算出
o9T般般的に、
'ω からの増
す
ず
:^[￨(覇
轟馨碧照違霧響警 l鎮幕について経済的評価を行う際、健康上の利疑数値化するために使用される方法。単に生存期間の延長を論じるのではなく、
生活の質 (00し)を表す効用値としてスコア化し、これに生存年数を掛け合わせt総合的に評価する。スコアは完全な健康を1、死亡を0とし、種々の健康状態をその間の値として計測する。
I
Ex)10ALY=完
全な健康状態で生存する1年
円換算レニト11ドルー80円、1ユーロ 110円とした。
また、カナダドル=OSドルとした。
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doirl0.lll 1r,1365.3148,2005.00609.x
ORIGINAL ARTICLE
C6St=effeOtivenCSS pfpathogen inaCtiVatiOn for plitelet
transfusiois in the Netherlands
´
露瘍脇淑器:挽
驚
穏材脇患
]揚
蹴〕
脇
糧お源乳淵務蹴=朧、
ル″“
Ica′
C aFrre Cra″
■.C“●R甲 ,r/1′
Ⅳ′
i撃 2"ι二S./br′
"らclὰ●/11C・
′g″′
Mα:″0,3SA,α"′qB∝ セr,M崚 ″ S″麟
電●
“″1赫 §
R′
ὰノ"の ′″￨`lρ́′ル′′め′
″"″ `力 ““
セαあ″′/′″′200,
suMMARy. The objcctive of this study is to estimate
cost-effectiveness.ofpathogen inactivation for platelet transfusions in the Neiherlands. We used decision
tree analysis to evaluate the cost-effectiveness of the
addition of pal,hogen inactivation of pooled platelers
to standard procedu{es for platelet transfusion safety
(such as, donor r€cruitment and scredning), Data on
transfusions were derived from the University
Medical Centre. Groning€n (the Netherlands) for
1997. Characteristicsof platelet recipients (patient
group, age, gender and survival) and data/assumptions on viral and bacErial risks were linked to direct
and indirect costs/benefitsof pathogen inactivation.
Post-transfusion survival was simulated. with a
Markov.model. Standard methods for cost-effectivenss were usedl C0st-effectivenesswas expressed in
n€t costs per life-year gained (LYG) and estimated in
baseline-and sensitivity analysis. Sensitivity was analysed with rcspe{.t to various assumptions including
s€psis risk; reduction of the discard rate and discounting. Stochastip analysis to derive 90% simulation intervals(SIs) was performed on sepsisrisk. Net
coslsper LYG for pathogeninaqtivation
w€reestimated €554000 in the baselinelweighted
average
.thre€
palient
groups
(90%
over the
SI: €354 0001092500). Sensitivityanalysisrwealed rhar cosreffeativeness
wasinsensitiveto viral risksand indirbct
costing,but.hiEhly sensitiveto the assumedexdess
transfusions. required and discounting of LYG.
Given relativelyhigh net cost$ per LYG that are
intemationallyacceptedfor blood trausfusionsafety
interventions.our estimatedcost-effectiveness
figures
for pathogbninactivition may reflectacceptable
costeifectiveness
in this specificarea,Two.tuain?r$umptionsofour m<jdelwerethat the pathogeninactivation
was 100%€ffeativein pr€ventingtransmission
of the
patlogensconsideredand was not associatedwith
major and/or costly adverse reactions.Validation
of severalciucialparametersis required,in particulai
theDutchriskfor acquiringanddyingof transfusionrelatedsepsis.
In the Netherlands, safety of.transfusion of blood and
blood products is largely determined by supply of
available technology. The.major goal of public health
authorities in this field has been to achieve maximum
transfusion saiety, For example, newer and beiter tests
for blood-borneinf€ctiousdiseases
are.rapidly iirtroducedin screningproceiluresfor blood donors,such
as nucleicacid amplificationtesting(NAT) for the
human immunodeficiency
virus (HIVJ. Next to the
'maximum-safety'criterion..cost-effectivencs
is
becomingan importantissuein judging new technologies,alsoin blood transfusion.Relativelyhigh costeffectiveness
ratiosareseeminglyaccepted
in ihe blood
transfusiongrea (Van Hulst el al., 2002;Yeh el a/.,
2002).For example,at.estimat€dcurrentDutch levels
ofrisk for HIV transmission
throughtransfusion,
Hry
NAT iosts severalmillibnsper lifc-ye:irgained(LYG)
(Postmaa al., 2001).This fnding is in line with
Correspondene:
Dr Maatto J. Posrma.
Associate
Ptofessor
in
Phamacoeonomic,
Universitylnstitrtefor Drug
Groningen
Exploration/Uniw$ity
ReearchItrtitut6 of
9f Groningeo
Phamacy,ArtoniusDeuinglaanl, Groningcn9?t3 AV, lhe
Netherlands.
Tel.r+3f 50 3612607;tu: +31 50 3632772:
e.hail:mj.postma@rug.nl
@'2005Blackwell
Publishing
Ltd
Keywords:cost-effectiveness,
pathogeninactivation.
pharmacoeconomics,
platelets.
計
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___二
Cosr-effecttvensssof pathogen ihacilvation in platelets
380 M. J. Postmaet al.
e Elimination of risk for parasitesand viral infections, suchas HIV, HCV and HBV.
r Elimination of risk lor sepsisdue to bacterial
infection.
r Blood bank processing
benefits,suchas improved
discardrate ofplateletsdue to prolongedshelfJife
potential
and
eliminationof gammairradiation.
o Elimination of risks for yet unknown emerging
. pathogens.
r PoFntial reduclionsin judicial claims following
fatal transfusion-transmitted
infections.
Cardiology
410/o
MATERIALS
Risks of pathogen tmission
AND METHODS
Given the existenceof thorough donor selectionand
routine donation screening for HIV, HCV'and HBV,
virally infected donations are very rare in the
Netherlands. European estimates for the risk ofwindow period donations in 1997were one in 2.3 million
for HIV, one in 620 000 far HCV and one in 400 000
for HB! (Miiller-Breitkreutz, 2000). In the model, we
applied reedt estimates that ard considered specific
to the Dutch situation at,one per 200 000 for HBV
and one per nillion for HIV and HCV (Health
Council, 2003).
Transfusion-related sepsis is most often related to
platelettransfusions.Approximately 80% of casesin
the UK were estimated to be telated to platelets
(SeriousHazaids of Transfusion (SHOT), 2001), An
internationally published (Yomtovian et al., 1993;
Ness et a/., 2001) risk of 0.04o/o per platelet transfusion was deployed in the model as upper bound and
investigated in sensitivitj, analysis (see below),
Corresponding cas€ fatality for sepsii was a$sumed
at l5% (Nesset a/.,2001). For the lower bound (also
invstigated in sensitivity analysis), 0.025% was
taken for platelet transfusion-related sepsis with a
related case fatality of lJ% (Morrow et al,, 199\;
Saama, 1994). For the baseline, the intermediate
risk at 0.0325% and intermediate case fatality at
160/owpte assumed, On top of these estimates, we
assumed that the recently implemented bacterial
screening only slightly reduces the sepsis risk by
epproximately 5% (almost 409/0of positive units are
General design
We developed a pharmacoeconopic model tha! links
chaiacteristicsof the population of platelet recipients
(agt, gender and outcom€ in tems of survival) with
economic aspects of pathogen inactivation. The pharmacoeconomic model.estimates cost-eflectiveness in
tems of nct costs per discilunted LYG, with inclusion oi direct and indirect costs and benefits. Diiect
medical costs relate to the costs ofpathogen inactiva:
tion. Direct benefits are related to costs of treatment
and care for transfusion-relatedviral and bacterial
inlections and elimination of gamma irradiation.
Indirect benehts are related to averted production
lossesrelated to aierted deaths due to infections.
Patienr popularion
l 2005Blackwell
Publishing
Ltdr TtoNf6ionMedicihe,l5,l7F3E7
Paedialnc
oncdogy
4%
Haematology
43'/"
Fig, l. Distribution of patients(upper) and tlansfusions
(lower)overpatientgroupsin the UniversityMedical
CcntreGroningen(data for 1997).
Table l. Pqcentagcdistribution ofplatelet transfusionsfor threepatient groupsin the Uniyersity Medical centrc Grbningen
in 1997by age and gender(r : 603 for cardiology,n = 120for haematologyand r : 30 for paediatriconcology)
Cardiology
Age group (years)
く1 0
10■20
211 30
311 40
40-50
51160
60-70
7∈ 80
>80
Total
Male (%)
Haematology
Female(%)
Male(%)
13
05
08
05
02
13
96
123
2.3
28.2
◎ 2005 BlackwdI Pubushing Ltd,ル
a可レs●"MCar′ ル,15,379-387
７
８
８”邦”口回２
ｍ︲
・５
，０
，
９
The phamacoeconomic model was developed for
three separate typical patient groups, as costeffectiveness for blood transfusion safety interventions may strongly vary between such groups (Van
Hulst el a/.,2002). For exarnple,application ofviral
inactivated plasma was estimated to cost US$59 000
per quality-adjusted LYG in trauma patients and
US$122 000 in cardiac surgery patients (AuBuchon
& Birkmeyer, 1994), Applicaiion of single-donor
platelets instead of pooled platelets was estimated to
cost US$200 000 per quality'adjusted LYG in cardiac surgery and US$470 000 in haematology
(Lopu..-Plaza et al,, 1999), In this srudy, we elaboiate
cost-effectivenessfor three patien! groups giving rise
to the major share of platelet transfusions in the
Netherlands: cardiology, haematology and paediatric
oncology.
Transfusion data of patients were gathered in the
University Medical Centre Groningen (UMCG, the
Netherlands) in- 1997. Figure I shows the distributions in terms of patients (Fig. la) and transfusions (Fig. tb). As shown, cardiac surglry
patients - primarily undergoing coronary artery
bypass grafting - represented almost 4lyo of the
patient population receiving platelets, whereas in
terms of platelet transfusions their proportion is
lower (23%). In terms of the number of transfusions,
haematology accounts for the major share. Table I
lists the distributions of plalelet transfusions over age
２００ ■ ９３一
９３１︲
︲︲２
７
In the presentstudy, we assessthe cost-effective'
nessof pathogeninactivationin platelets.The scope
of this article is limited to elimination of risks for
known bacterialand viral infectionsand imnrovementsin bloodbankproessingwith regardto elimination ofgammairradiation.Benefitswith r€spectto
reduced discard rates may have already been
achievedin the Netherlandswith the implementation
of bacterial screeningin 2002. Benefitsof averted
spreadof yet unknown emergingvirusesin platelets
and inclusionofjudicial claimsare ieft for discussion
and further work. Future applications of the
INTERCEPT{ Systems,comprisingthe whole spectra of pathogens(including nonenvelopedvirdses)
and products (including red cells and plasma),
enhance formal consid6ration of such further benefits, inclusive'of potential omission of any of the
usual tests on donor blood for viruses and bacteda
on the long-term.
Paediatric oncology
Female(0/.)
Male (%)
Female (Vo)
467
20‐
0
667
333
守酬Ｈ
estimats of NAT for HIV and heparitisC virus
(HCV) in other countries(Pereira.& Sanz, 2000;
Loubidreel a/., 2001;AuBuchonet al,,2M2).
Despite high levelsof safety achievedin Dutch
blood transfusion, risks still remain. Relatively
small residual risks have been estimatedfor HIV,
HCV and hepatitis B . virus (HBV) (Miiller-.Breitkr€utz,
2000).Particularly,for plateletsrelevant
risks of bacterialinfectionand subsequentsepsisare
€stimated, with significant mortality rates being
reported(Sazama,1994;Nesset aI,,.2001).Estimated
sepsisrisk afler transfusionis highest for pooled
platel€ts,with risks being suggestedup to one pet
2000units transfused(Sazana, 1994; Lopez-Plzza
et al., 1999).In the Netherlands,pooled platelets
refleat almost all utilization of platelet transfusions
(Sanquin,2000).
A new pathogen inactivation. technology-the
INTERCEPT@
PlateletSystems-achieves
reductions
in pathogenloadsin plateletsbelow detectionlimits
viruses- suchas HIV-I,
for all relevantenveloped
HIV-2, HBV and HCV - and many bactena- such
as Staphylococci
coli (Corash,2000).
andEscherichia
The INTERCEPTo PlateletSystems(furthei: pathogen inactivation) is based on psoralen treatment.
Application of pathogen inactivation for platelets
may achievebenefitsaccruingat variouslevels:
381
groups and gender. This distrjbution js the basis for
our pharmacoeconomiq model below. .
382
M. J. Postma et al.
not recalled,and over 90%.of recalled platelet units
are already transfused) (Beckers er al., )-005).
Excess morialities for HIV and HCV were set at 6
and l%o per annum, respectively (Loubid.re et al.,
2001; Postina, Wiessing et dl., Z00t). Mortality due
to HBV infection was neglected.
Costing sspects
跡
Ｕ
Ｗ
鼎
TBbl€2. Diregt cosrs for viral infectionsand bacterial
sepsisin € (pria level 2003) used in the model (costsfor.
humatr immunodeticimcy virus (HIV), hepatitis C virus
(HCV) and heprrtitisB virus (HBV) are lifetime discounted
costs) (Strujjs et al.,2000 Postma, Wiessinge/ ol., 2001;
Van Gestelet a|.,2002;Postmaer a/., 2005)
83200
19500
1100
20600
The costs for pathogen inactivation were assumed
at €116, the currently envisaged price for hospitals
(including margins for required production process
changes in the blood banks; personal communication
with the manufacturer), Additional costs are Doi€d
by pathogen inactivation that may potentiaily involve
yield loss6s. We.assumed a l07o inoease in the costs
per platelet transfusion unit to account foi this factor
(McCultough et al.,2O0l; Van Rhenen et at.,2003).
Additionally,
in
the
trials performed for
INTERCEPTo, exess transfusionswere required ro
achieve adequate count increments. In the US
SPRINT trial,.such exess transfusions were more
than 30yol in the European euroSpRITE trial, no
significant differcnce was found (McCullough er al.,
.2001;Van Rhenen €/ aL,2003), In our ahalysis,we
assumed l5olo excess transfusions .wlth pathogen
inactivation (0 and 30% in sensitiviry inatysis).
Excess transfusions were monetarily valuated at the
estimated cost price per platelet transfusion unit of
€458 for adult and €285 fot paediatric application
(Sanquin Blood Supply: price list as of I March 2003)
plus €l l6 for bacterial inactivation.
Finally, benefits of elimination of gamma irradiation were inserted in the model, assuming this elimination in l0oZ of transfusionsin haematology and
paediatric oncology at €30 per irradiation.
Phumacoeconomlc model
The distribution of platelettransfusionsin the UMCG
was the basis for our pharmacoeconomic modEl. This
distribution was conceived to reflect the prbbabiljties
that in individual unit is tiansfused to a patient of
specificgender,ageand patienr.group. For eachpatient
group, an age- and gender-specificMarkov model was
developed for post-transfusion survival. Suruival
results from death risks due to viral/bacterial infection
through transfusion, post-cardiac surgery death risks
and those due to other causes (natural mortality),
Details on transfusion-related infections are listed
be)ow; mortality for cardiac surgery, haematology
and paediatric oncology patients was estimated at I 7,
38 and 31o/o,respctively, in the firsr year (data irom
the UMCG for 1997) and t, 5 and 0.5yo, respecrively,
in gubsequent years (The Bypass Angioplasty
Revascularization Investigation (BARI) Investigators,
1996;Lopez-Plazaet a|..1999; Coeberghet aL,.2001).
Natural mortality was taken from the national statistics (source: Dutch Central Buriau of Statistics.
Voorburg, the Netherlands).
For the three pdtient groups considered, a
weighted avbrage for cost-effectivenesswas also calculated (proportions of. 'transfusions as weights;
@2005SfackwellPublishing
Ltd, TranfutionMedicine.
tS. 379-38?
Fig. l). As shown in Fig. I, th€ patient groups in our
model are estimaled to consume 70% of Dutch platelet transfusions.
Figure 2 shows above in the concept of a decision
Cost-effectiveness
was exprcsdd in net costsper LyG.
Net costsrefl€t the costsof pathogen inacdvation minus
its monetary benefits.Monetary benefitswere related to
either the elimination of risks for viral and bacrerial
infection or gamma irradiation. Monetary benefits and
LYG were estlmaled by comparing two options in ihe
model, In a fimt step,the financial cosrsand life-yearsIost
were stimatrd in the absenceof pathogen inactivation
with risks for'transfusion-related viral and bacterial
iniections as sprcified above. In the next step, pathogen
inacl.ivation was simulated, corrcponding with rero
risks for infectioirsofpathogens consideredin tirjs analysis:In addition, elimination of gamma inadiation was
assumed. Differences in costs and life-years in both
options were comparcd subsequenlly.
' Cost-eflectivenesswas estimated
in the baseline and
sensitivity analysis. Deterministic sensitivity analysis
was performed with respect to viral risks, bacterial
risk, reduction in discard rate and discounling of
LYG. For stochasticsensitiviiy analysis, Monte-Carlo
simulation was peiformed with rspect to the annual
number of tansfusion-related sepsis cases (poisson
distribution) allowing calculation of 90o/" simulation
intervals (SIs) for. cost-effectivmess. Microsoft Excel
97, @RISK 3.5 for Excel (Palisade, London, UK)
and DATA 3'5 for Health Caro (Tree,Age Software,
Williamstown, MA, USA) were used for computer
implementation and presentatiotr.
3g3
€69 300 per l0 000 transfusions in cardiac surgery
(10 000 also approximately reflects the annual number of Dutch platelet transfusions in cardiac surgery).
Of th€se benefits, 96% referred to averted cases of
sepsis (also for the other patient groups, sepsis
accounts for the major share of benefits; however,
additional benefits come in for elimination of
gainma irradiation at approximately 30% of tolal
benefits). Furthermore, per l0 000 transfusions in
cardiac surgery, approximately 4.4 discounted lifeyears were gained and cosrs of €2169 200 were
made, rendering net costs of €2099 900 and net
costs per LYG ar e474 000 in the baseline(90% SI:
€302 500-€940 300). Baselineestimareslor the orhe,
patient groups - haematology and paediatric oncol.
ogy - were €678 600 (90% SI: €434 000-€133S 300)
afld e260 700 (90o/oSI: €t66 800-€51 I 200), respectively. The weighted average over the thlee patient
groups was estimated ar €5S4 000 (90i" SI:
€354 000-€1092 500) As nientioned, SIs formally
represent potential annual fluctuations in cost_
effectiveness.
Sensitivity analysis revdaled that our results are
insensitiveto the exclusion of avertedviral infecrions
and exacl levels of assuiled indirect costs (not
shown). Model results were sensitiveto seosis risk
and relared case fanlity. the assumed.*".is rrunr.
fusions through inactivation and discounting .of
LYG (Table 3 lists results for weighred average
ov€r pattent groups). In percentage changes, resultr
were most sensitive to higher excess transfusions
assumed(r74% of baseline)and nondiscounting of
LYG (-38Yo of baseline)..
RESULTS
DISCUSSION AND
As an example,estimatedannual monetary benefits
of pathogen inactivation in the baseline accrued to
Cost-effectiveness of pathogen inactivation of platelet transfusionswas estimated at €554 000 p.. LyG
in the baseline as an average ove! three major patient
CONCLUSIONS
Tabte3. Sensitivity
analysisfor the cost.eff*tiveness
ratio
in net costs per life-year gained (LYG) (in €; prie level
2003)on sepSisrisk (and relatedcas fatality), exccsstrans"
fusionsand discountrate for the weightedavcrageoverthe
throe patieni groups considered(cardiology, haemarclogy
and paediatriconcology)
°
f LYGl山
Fig. 2, Decisiontreefoi the cost.effectiven$sa@lysisof
pathogeninactjvatioq.
@ 2005BlackreliPublishing|ud,Tra&I&ionMedieine,tS,3t9-38.1
∵灘
翡
締
淵
No cxoOSS transfudons
red req面 393 500
ExcOSs tran,Ⅲ
iOns rCquired at 300/0
961500
Nondis∞vAlng or LYG
341 200
ｎ︻Ｈ
AII costsin our analysis were estimatedal price levels
of 2003. If required, annual deflators of l.8ok for
direct and 2% for indirect costs were used
(Oostenbrink et a1,,2000), According ro rhe Dutch
guidelines for pharmacoeconomic research, future
costs (and LYG) were discounted at 4%oper annum
(Riteco el al., 1999).
, Lifetime, discounted direct costs for transfusionrelated viral infections were available from the oublished literature (Struijs et at.,2000; Postma, Wieisiirg
et al., 2001: Postma er al., 2005). Direct costs for
transfusion-related sepsis were based on a recent
Dutch study (Van Gesrel et a1.,2002). Table 2 lists
th€ cost eslimates as used in the model.
To enableestimation of cost-effectiveness
from the
societal perspective, indirect costs were included for
death due to any tr'ansfusion-related infection. i.e.
HIV death, HCV death and sepsisdeath. The societil
perspective is preferred in many international guidelines for pharmacoeconomic research, including the
Dutch ones (Riteco et al., 1999; Hjelmgren et it.,
2001). Indirect costs were estimatedusing the lriction
coshng.approach, as request€d by the Dutch guidelines for pharmacoeconomic research fRiteco el a/..
1999; Oostenbrink et a1,,2000). As opposed to the
human capital approach, the friction costing
approach only counts indirect cosrs of productioi
Iossesduring a period of a limited number of months
required to fill in the vacancy. The human capital
approach calculat€s production losses during all
future life-years that are lost due to prematur€ death.
Cosl-effectiven:essof pathogen inactivation in platelex
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舞請始
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0RIGINAL ARTICLE
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HepaJls C vlrusJike emer」
ng pathogtt waS,Inulated
7ed,highly Key words: emerging,. INTERCEPT,
^WidC ralge Of ICERs■ as obser■
Scnsitivc to the riSkerging
of o口 pat10gcn trans‐
vation, platelets, safery, fiansfusion
The risk of transfusion.associated
viral infectionshas
been significantly.
reduced.by the introduction'.of
donor-screening
and blood-screening
tsts in routine
practice.However,someresidualrisk of transfusion;
relatedinfectionsrc,mains.
This is because
of the wirrdow penodbetweeninfectionand positivetestiEsults
the
on
onehandand to somepathogenswhichcould
potentially be .transmittedvia transfusion,but for
whichscreening
tests.a.re
not pgrformedtoday on the
other hand (e.g. Cytomegalovirus[CMY], Human
T-lymphotropicvirus [FITLVJ...). In addition,viral
sareeningtests mai produce false-negative
resultS
(Lapercheet a1.,2003;Busch,2003).Recently,safery
measures
havebeenincreasedby includingNAT tests
for hepatitisC virus (HCV) and HIV detectionin
routinescreening
programs.However,currentsafety
Correspondenci:Dr KaE[ Mocrcmans, HEDM, Craygntraat 5.'
1000 Brusscl, Belgium.
Trl.: +12 3 E996l 19; far.+!2 3 899 61 09;
e-mail:kmoeremans@be.imshslth.com
O 2006 Blackwell Publi6hing Lrd
palhegsn in3gti-
initiativssconsistingof serologicalor viral antigen
testsaddress<inlyone or few selected
pathog€nsat a
time.Any newpathogenrequiresnewsafetymcasures
in additionto the alreadyestablished
syst-em.
Historical as well as contemporary.dataconfirm
that the risk ofnewly.emerginginfections
is nothypo- ,
thedcal(WHO, I998 (w.who.int); Leiby,European
?arliamenthearin! June,2003;Biggerstaff& Petersen,
2003).Dependingon their'clinicalcharacteristics
and
modesof transmission,
theseemerginginfectionsmay
presentan enormous threat td iransfision safety:
Scientific.
informationis often limited at the time of
emergence,
and the development
ofdiagnosticscreening teststakestime, Therefore,theseemerg:ing
ageits
requirenovel approachesto irevent transmision
(Leiby,.European
ParliamenthearingJune,2003).
As they are stored at roorn kmperature!platelets
are particularlyvulnerablefor bacterialcontamination. Therefore,bacterialscreeningis routinely per,
formed on platelet samplesin Belgium;however,a
potentialrisk of false-negative
resultsremains.
t7
∞Ｈ日
mission, underlying disease and age. In the most
conservative approach,
ICER
ranged
from
辮 :良送需
践::『鵠 sttdぽ観 t認 li鶏
3,459,201€/QALY in absence of emerging paLhogen
iⅢCIVatcs pathogcn、
alming at clminaung thc‖
sk
ro 195,364€lQALY. The mean threshold of emerging
。「lransmiting cllrrent inl emCttging pathogcis Thc
infection risk for trBSPdominance (saving money and
obJcctivc was t0 0,aluatc thc incrcmcntal
cOst‐ producing health gains) ranged from l/1,079 to
efFe←
tivencss ralo(ICER)fOr IBSP in,dgium
l/2,858 ttansfusions.
A decidOn modci compa■
ng a`WOrid with IBSP'to Considenng the high value auchoriries appear to
a`"o■dw“hout BSP'calclllatcs ltlme and
cOsぉ place on preventing accidental injury, and ICER of
`quali"adJuSted liFc,carS'(QALYs)fOlloWing platelet
rec€nt implementations in transfusion m€dioine
transfusion in difrcrent indicatiOns biscase‐
specinc lire (NAT: up to €2.3 million per lifeyear), IBSp can be
c21pcctancy and∞
nscquences oftransfuslonitransmlted considered cost-effective, taking into account the
infeCIons were Ob“
ned iom l"raturet TFanSrusi。
.
potential risk of emerging pathogens,
18
K. Moeremm
The INTERCEPT Blood System for platelets
(IBSP) is a new technology which inactivates different types ofpathogens through irreversible binding to
RNA/DNA
in the blood (BioDrugs,2003).
When new safety measures are introduced, there
is clearly a need to accurately de{ine lhe value of
these new initiatives, and decisionsregarding bloodscreening policies murt be based oD accurate
estimates of the increm€ntal saf€ty balanced against
cost and taking into account the potential loss of
donors {Busch et s|.,2003\.
The objectivo of our study was to analyse the
health and economic consequenc€sofpathogen inactivation using the IBSP in Belgium, taking a perspective directed to the future, including the risk of
emergence of a new transfusibn transmittable virus.
SUBJECTS STUDIED
METHODS
We performed la cost-effectiveness analysis in
Belgium from a societal perspective, including both
direct medical costs and productivity related costs
(expressed in euro), as well as legal and.liability costs.
A decision analytical model was developed simulating the clinical outcomes of patients requiring platelet transfusion, in a world with and in a world
wirhout,the INTERCEP-T blood sysrem.
Model
The model was developed using T*reAce orrnru
software. The model starts at thd time of platelet
transfusion and simu'lates the evolution of a cohort
of patients receiving transfusions of platelets inactivated with the INTERCEPT blood system compared
with the same cohort receiving untreated platelets,
taking into account the risk of bacterial infection,
HCV, hepatitis B virus (HBV) and HIV infection.
These infections are cunently tesled for in Belgium
blood syttem
19
and their residual transfusion-related infection risk
has been assessed.
In addition, the risk of a possible newly emerging
viral infection is included in the framework.
The overall risk of infection per patient is calculated in the rnodel as the risjdual risk per transfusion
multiplied with the average number of transfusions
per patient.
If no transfusion-related infection occurs, the average life expectancy is the one of the underlying diseases. If transfusion-relaBd infection occurs, the life
expectancy is reduced because of the mortality associated with the infection. The main decision analytical model structure js outlined in Fig. L
LiIe expectancy in the absence of nansfusion-retat:ed
infection
The average life expectancy associated with the considered underlying diseasEswas calculated based on
published mortality rates. By applying yearly mortality rates, average life expectancy can be calculated as
the surface below the survival curoe.
For both ALL and AML, I year mortality was
44% (Dini et al,, 2001). During subsequent years,
the relative mortality rates as reported by Soci€
et al. (19991 were applied.to age-matched general
moitality rates in Belgium (1997).
In patients with NHL undergoing early stem cell
iransplantation, a 5-year overall survival rate of
approximately 657o is reported (Dresse et al.,1999t
Martelli el a/,, 2003)..Patients surviving more than.5
years were assumed to have normal life expectancy.
In CML patiena, based on review of rec.entliterature (Carreras et al,, 2000;.Davies el al., 2001;
Elmaagacli et a1.,2002; Gaziev et a1,,2002; Pigneux
et a1.,2002:,Radich et a/.,2003), an averagecurnulative mortality l'ate of 50yo by year five was estimated.
For the remainder 50olo,long-term relaiive mortality
rates were applied to the age-matched general population (Soci6 et al., 1999)..
For CABG patients, a weighed averagelife expectancy was calculated from data published by
Weintraub et af , (2N3), including mortality rates up
to 20 years post-intervention. Although these patients
were operated many year's ago, th€ short-term mortality was not highgr than reported in more rebent
studies (Calafrore et al,,20M', Taggart et al., 2001).
For breasJ cancer patients undergoing Peripheral
Stem Cell Transtllantation (PSCT), life expectancy
was estimated equal to the weighed (for study size)
average median suwival reported in PSCT patients
(Farquhar et al., 2003).
PublshingLtd, Trmq[usiot
Mediciae,
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ＯＨＨ
The target population included patients with haematological malignancies undergoing bone marrow or
peripheral slem cell transplantation [acute lymphoid
leukaemia (ALL), acute myeloid leukaemia (AML),
and nonchronic myeloid leukaemia (CML)
Hodgkin's lynphoma (NHL)], breast cancer patients
undergoing stem cell transplantation and patibnts
undergoing dardiac surgery, whereby coronary artery
bypass graft (CABG) was selected as case. These
populations are considered to receive most commonly platel€t transfusions (Bell .et al., 2003\,
MATERIALSAND
Costeffectiveness of INTERCEPT
et al,
Fig. l, Basicstructw of drcision tree.QALY, quality adjustedlife years
Table I sunlmarizes the obtained average life
expectancyper underlying disease.
Risk o! known infections with untrcated platelet
comPonenE
Table 2 provides an overview of viral safety ti?stsperformed on blood components in Belgium today, the
fiequmcy of positive tests and th€ respectiveresidual
risks ofviral transmission per transfusion (Beigian Red
Cross2003,se Acknowledgements).As they are stored
a! room tenperatule, platelets are particularly wlnerable.for bacrcrial conlamination. Therefore, in Beigrum,
a sample o[ the platelet component is monitored for
O 2006Blackwell
PubliBbineLtd.Tr^slginn Ueditae, t6, It-10
bact€rial contamination throughou! storage timq using
the 'BactAlert system', Becauseof the absenceof mandatory reporting of any transfusion-relat€d ev€nts, there
is limited information on the actual risk oftransfusiolrassociaed bacterial infecuons in Beleium. For the
cunent analysis,Red Cross and clinical Jxpert estimates
were collected. The most gonservativeestimate,reporled
by the Red Cross, was a rate of transfusion-associated
bacterial infections of one in 5000 transfusions.
Rbk of emerging pathogem
To assessthe potential health emnomic consequenc€s
of the INTERCEPT blood System, the risk of future
20 K. Moeremansst al.
Cost-effectiveness
oJ INTERCEPT bloodsystem 7l
Tablel. Averagelife expectanoy
in the absence
of trans'
fusionrclatedinfectior
Average life
T,pe
expectancy (years)
AML aduts
AML chi:dhood
ALL adults
ALL childhOOd ´
NHL adults
NHL childhOod
CML
CABG
Breast canccr
17
319
3■
1 5 6・
59
26・
3
96
161
27
ALL, ailte lymphoidlcukacmia;
AML, acutemycloidleuksemia;
CABG, coronaryartery bypas$g.aftr CML, chronicmyeloid
leukaemia;
NHL, non-Hodgkin's
lymphoma
Effcacy and safety of IBSq
The following path6gens are inactivated by the system (approved indications); HIV l, HM,
HBV,
HCV, CMv, MCMV and aerobic bacteria.
The following inactivation claims have been recently
approved by the Irish Medicines board: HTLV I,
HTLV II, Trepbnema pallidu,m (Syphtlis), proiozoa
(Trypanosoma cruzi, Chagas disease,Plesmodim falciparum, malaria) and anaerobic bacteria,
Other inactivation studies on dltemative pathogens
are ongoing (Leishmaniasis, Babesiosis,Qandida atbicans, Boruelia bugdor/eri, West Nile virus, Paruovirus
Bl9 - last update July 2004).
The results of an extensive series of lz yitro and
!n vivo studies have not demonstrated any toxicologi€lly
relevant effects on platelet concentrates
prepared by the INTERCEPT
Blood System
(Ciaravino et. al., 2001).
In the model, thg inactivation system is progrdmed
to eliminat€ the risk of the considerdd known transfusion transmittable infections as well as to eliminate
transmission of the simulated emerging virus. Two
main assurnptions under'lying thd model were that
Tsble 2, Viral safety.measures
and residualdsk of platel€ttranslusions(Belgium)
Screeiringtest
HBV
HCV
HIV
: HbsAg
Anti‐ HCV
NAT
Ahti,HIVl and 2
NAT HIVl
Donations (Wallonia, 2002,
seeAcknow)edgements)
Donations (Flanders,2000,
seeAcknowledgements)
Tested+
True +
Testcd+
54/100,000
93ノ
100,000
l η1 0 0 , 0 0 0
17/100,000
1 2 1 / 1 0 0 , 0 0 01 り1 0 0 , 0 0 0
119/100,000
6/100,000
111/100,000
0/100,000
103/100,000
True +
03ハ00,000
Rcsidtal risk拿
1く/ 2 0 0 , 0 0 0
く
1/200,000
1/703,571
く 1プ
ト3 mio
く1/4 6 mio
HBV, hepatitis B virus; HCv, hepatitis C virus
SouG: B€lgian Rcd Cross.
'Risk of fa;smisior\p€r'transfusioh'.
@ 2006 Blackwcll Publishing Ltd, Tt@rhsion Medicine,16, l'l-30
Fig, 2. Structureof sublre related to
tmnsfusion-transmittcd
inf@tion with
hepatitisB or C. Under each bmnch,th€
probabilityoftransition from the left to
the right healthstateare shown.The
probabiljtjs undertbeleft hand sjde
branchs represnt possiblepathwaysat
model start;at the lime ofinfection. At
this time, patientsein eitherhaveonly
acuteinfectionwithout be@minga carrier QoVo)or Vcome @ftier (80Y.j.
Subsequ€ntly,
eniers may develop
chronicomplietions, posibly evolving
over chronichepatjtisto cirrhosis,liver
failure or carcinoma.Thc probabilities
shownundertheright handsidebranches
representthe likelihoodof possibletmnsitionsfrom one stateto another.The
probabilitleswae obtainedfrom pub.
Iishedliterature(Parcim,2000;Sevinir,
2003;Girdon, 1998;Hu, 1999;Tong,
1995).
Onlytheprobabilityofdeveloping
chronichcpatitisis diffqeot for HCV
vereusHBV:0.212 (Sevinir,2003;
Psreim,2000)and 0.224(Sevinir,2003;
Gordon, 1998)resprctively.Other dis.
ese progrcssiol rat6 wer! programed
equallyfor HCV and HBV. HCCA, '
Asympbrutic
ceier
Chronic hapatitis
Cirhosis
Chronichepatitis
Cirh6is
Liver fsilur.
HCCA
HCCA
Dcath
Livertsihre
HCCA
Derlh
hepatoetlularercinoma.
pathogen inaqtivation is 100% effective and is not
associatedwith major or costly adverseevents.
Additional benefits of the IBSP
The INTERCEPT blood system is anticipated .to
have an additjonal number of future benefits, supported by a recent. international forum of experts
(Engelfriet et al., 2003).
First, it is estimated that, in the future, some of the
currently applied screening tests, leading to platelet
waste, may be eliminated. These may include
BactAlert testing, NAT testing (given the high burden
and low yield) and Alkaline Phosphatasis(ALT) testing. It must be noted that, at present, the elimination
of NAT testing is only possible.for siirgle donor platelets, becausefor ra4dom donor platelets, the tests are
needed to ensure safety of the obtained red cells and
plasma. However, pathogen inactivation for red cells
may become available in the future. Neverthelbss,
given the uDcertainty of its timing, in .a secondary
analysis (not in the basecase), we considersd this
potential benefit only for Single Donor Platelets
@2006Blackwcll
PublishingLtd, TtNf6ion Me&cinq16,11-30
(SDP)platelets.Secondly,studieshavedemonstraled
that the INTERCEPT blood systemis at least as
effectiveas f-irradiation for the inactivationof Tcells(Lin et al,, 1997;Grassel a/., 1998).Hence,the
secondpotentialbenefitmay be to rhakef.irradiation,
which is performed on the majority of platelet
componentsin Belgium loday, obsoleto..
The third
benbfit consistsof a reduition of platelet wasle.
Today,in Belgium,of the 41808 platelertransfusion
bagsdorlatedannually,approximately8% 4rewasted
o[ storagetime overdueand 1.9% because
because
of
contaminationor positiveviral screeningtests(Red
CrossBelgium).In the past,the plateletstoragelime
initiallysetat 7 dayswasreducedto 5 daysmainlyfor
increasingrisk i:f bacterialcontamination.With the
INTERCEPT blood system,the previouslyapplied
Iimit of 7 dayscould.poientially
be re-introduced.
In
addition to the above-mentioned
current potential
b€nefits,pathogeninactivationqay avoida proportion
of supplementarytests in the future for potential
emergi4gpathogens,which will not be requiredfor
SDP,Conservatively,
the latter benehtis not consideredin theeconomic
evaluarion,
〇銀Ｈ
known or unknown emerginginfectionsweretaken
into account,Becausethe characteristics
of a new
emergingvirus are unknown,it wasdecidedto simulate an economic,inorbidity and moltality impact
Qomparabl€with HCV, The simulationof infection
risk lor this new emergingvirus can be basedon the
historiel eriolution of HCV virus transmission
through transfusion, although it could be argued
that, comparedwith the .1990s,a new virus today
would be identihed sooner after its emergence
becauseof scientificprogress,and hence,that transmission rates will probably not reach the level
obsgrvedfor HCV at the time. But, on the oth€r
hand, a lot dependson th€ diseasecharacteristics.
A
long asymptomaticperiod following initial infection
may significantlyincreasethe time to identification
&nd th€ time to linking the infection with blood
transfusion, Thc American Medical Association
(2000,seeChamberland,2002)describedthe historical evolution of transfusion-related
transmissionof
HCV in the United States.In the 1970s,the risk of
HCV infectionwasveryhigh (>1./100).
The improvementsin donor scregningand testinghavecombined
to resultin substantialdecreases
in transfusion-transmitted infectionsduring the I980sand 1990s.On the
oth€r hand, other factorsalsocontributeto the incidenceratesoftransfusioir-related
infectionsthacmay
be reachedsuchas the window period for the emerging pathogen,its incidenceand prevelancein the
donor population..,(Chamberland,
2002).Our economic evaluationwas performedfor differentlevels
of emergingviral infectionrisk betweenli 100and l/
I00.000transfusions.
22
ス〔ルイὸ″“αtt Ct al
Asymprom.tic HIV
Cosi-effectivenesof INTERCEPT bloodsystem 23
Table 4. Cost data for diseasestages related to yiral
infection
Asymptonaac HⅣ
Annual cost(C)(SD)
E_・
ly symptonatic
Hlv*
StageA: Asymptomstic
StageB: Symptomatic
StageC: Aids
aョ y sy嵐p10mllc
Early syコptOmattc
Hepatitis
Viral Degativ€
. Acute hepatitisCt
Chronic hepatitisI
CompensatedcirrhosisI
D&omp€nsted cinhosisl
Hepato€llular carcinomal
Liver transplantdtion,lst ycarl
Livertransplantation,'
subsequentyarcl
ArDS
Early sympω、31c
HIV inFeclon
Go symptomatic
LatOり “pl●
Inatlc
AIDS
*D*ock et al (2001),'
to@urring ir approiimately
(Harbarth et a/., 2000).
lwong & Nev€ns (2002).
DcaCl
,ate Symp10nlalc
A:DS
Flg. 3, Structureof subtreerelatedto
transfusion-transmitted
infection with
HIV. Under eachbranch,tbe probability of transitionfrom the lef! to the right
h€lth stateis shown.The probabilitics
wercobtainedfrom publishedliteralure.
(Miners,2001),
Impact of tr'ansfusiontansmit ted infections
The impacrof transfusion-transmitted
viral infections
was calculatedby simulatingthe clinicalprogression
mtes over differentdiseasestates(Figur€s2 and 3)
obtainedfrom literatureand assigningcostsClable4)
and utilities to €achstate.Utilities are valuesrepresentingthe quality of life in a certainhealthstatus.
Utility valuescan range between0 and I, with 0
representing
deathand I represen(ing
a stateofperfect
hEalth,The time spent in a certain health stat€ is
multiplied by the correspondingutility weight to
accountfor the quality of life in that particularstate.
The Dtility valuesappliedin the modelwereobtained
from previouspublishedresearch(Table3).
Regarding bacterial inf€ctions,9.770 have been
reported fatal and 26.5Yolife threatening(France,
Andreu el al.,2002). For the current analysis,non:
fatal infeitions werenot attributedany reductionin
quality of life given their limited duration. Fatal ot
life-threateningbacterialinfectionswereattributeda
managementcost derived from previous research
showinga tdtal costper sepsis
relatedto severesepsis,
episodeof €l 7,988(SE = I 145)(Larerreet a\.,2002).
Table 3. Utility weights applied for diseasestagesr€lated
to viral infection
Ullり (95%CI)
HIV
I
ASymptoma●o
094
3)lTengS 02)
(CD4>500 odis rnm・
'
C D 4 2 0 5←0 0 c e n s m m ・
082
CD4く 200
079
AIds
0.77
Hepatils
Vlrai negative
1
Chronic Hcpa薔
tis
0 8 2 ( 0 ●■ 9 )
Compcnsatcd CiFrhOSiS
0,78(0,49)
D∝ ompenmted Cirrhosis
065(03→ 88)
Hepatocellular Carcinoma
025 ol却 ‐
5)
Li“r transplantaton,Ist ycar05(01:つ 7)
Finally,
the calculation
25%
2300
‐ 125
250
8060
10,000
50,llllQ
8700
of
HCV
of indirect
transmissions
costs incurred
infectionsis summarized
from transfusion-associated
in Table5.
Costdata
Scenariosevqluated
The costsper transfusion
of €371.84for SDP and
€274 for averageRandom Donor Platelets(RDP)
wbreobtainedfrom.officialsotrrces(RIZIV/INAMI,
In the basecase
scenario,
the implementation
of the
INTERCEPT blood systemis assumedto eiiminate
the risk for HIV; HCV, HBV and bacterialinfection.
Table5, Methodsfor indirrctcostelcuiations(adults)
Productivityloss @lculations
Haematologiel cbncer
Br€st €nftr
CA3G
Employedprior to undalying diagnosis*
Average
z daysper yearactive'
Percentresumeactivity post trmtmentt
Annual a days lost ifinfetedt
Duration of produclivity loss'
48%
218
o/
70:
From month 6
10 end stage$
39%
167
6'l
44
From month 6
to end stagd
2s%
218
100
uftr cosls
Unit cost per hou.(€)
5 years{
23**
Thc same ut"ity values wcre aplucd
roF卜
●
C vims as for
patRヽ
hepaltis B virus rdatcd hcalth statcs(Dushako
′
′
′
,1995) ι
CABC. coronary artery bypus graft.
rAge and s9x matched natioral data(National Itrstitute for Shtistics, ?001, availabje at \w.srarbel.fgov,b€).
tBradley & Bednarek (2002).
{The annual nunber of days lost it infected = % active ptevr'ouslyx n working days/year x 70 who would resme agtivity dgspit€ under,
lying diseasein the absa@ of inf@tioo (e.g. 48% x L18 x 61yo = 10).
{B@ausethe employmrnt ntg applied js basedon calculationsfor the entire aduir populatios up (o all ages,thc age at diagnosisdoeshor neei
to be taken into a@una for progmmming duration of ac(ivity. However. durinE the rnd stageol thc underlying dis@se,no prodrctivity iE
assumedin th, absn@ of infetion; hence,no productivily loss an be attributed.
!l?0% of patients arc undrr 60 year6of agc at the time of inteden(ion. 25% of thes are actilc for aD estimarcdfurther durariot of 5 years.
Beyold this duration, no productivity is Numed in lhe absenc. of rnfection; hence, no producliviry lo$ can bc arrributed.
r*lncludes di@t wag$ + mployers chargcs(National tnrlit!te for Statisti6, 1996, avaihble ar 'M.sratbel.fBoa.bc)
“!:Pubishing Ltdi暉
rr“
"νear,F.16,17-30
ぉl。
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@ 2006Blackwelt Pubtishing Ltd. T,esfusion Medicne, 16, 11-!O
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2231(1955)
7899(7070)
25,736(20,76o
Red'CrossBelgium).Thesecostsincludef-irradiation arid donor screeningtestsexceptNAT.
The cost of inactivationusingthe INTERCEPT
blood systemis estimatedas €125 per inactivation
session,heDceper platelet transfusion.This c6st
includesthe costfor the systemitself(€ 90, including VAT) as well as the costsfor ma[erialand personncl to perform the procedure(potential savings
at the level of plateletprocessing
not taken into
account).In the model, the averagerransfusion
cost per patientis calculatedconsidering
the basic
transfuslon
cost,thecostof theINTERCEPTblood
systemand the averagenumber of transfusionsper
patrent,
With regard10legalcosts,we assumedan average
per bansfusion-associated
costof €100,000
infection
with HIV or with emergingvirus, based.on law suits
or governmentalaction reporisfrom differentcountries,includingBdlgium(Pressconference
Minister of
PublicHealthBelgium,l9 September
2001,Hof van
beroep;Gent,I'kamer,24 April 1998).
Althoughfor
other infection types, there have been legal procedures startedin Belgium,We.havenot includcd
thesecosts in the model, becausenone of the law
suits have beenfinalized(someare ongoingfor up
to l0 years).
24 K. Moeremanset al.
Including prOcessing benertts of INTERCEPT,
rcsulting in a tcduccd cost For,la"10t proCessing
and tcsting,leads to lower cost‐
cfFectivcncsS ralos
CaOIC■)and dohinan∝ Of IN「ERcEPT aheaay
at an cmerglng lnfccJo■
rlsk o「
1/1000・
Theや ‖。Wing thresholds oFcmγ
ging infecJon isk
for thc IN「
ERCEPT system tO become dominantin
all indicaJo,sa"。
bservcd DOnlinancc is prcscnt aS
frOm an clncrging isk 1/107,tranSfu●
o「
Ons■ sce‐
nano l,1/1697●anSfusions in scenaJo 2 and 1/1791
in sccnario 3(Table 9)
(costiQALY)scenario
Trble6. Costeffstiveness
virusor emerging
virusl/100,000
| - no emerging
DISCUSSION
ALL-A
_
Thc Objccavc of thお
stuly Was tO assess thc cost‐
cffccuVeness oF tht INTERCEPT blood systcmi For
this purpose,a health cConOmiq modd was dcvel‐
9ped, cOmpariig thc bveral outcome in a world
with IN「ERCEPT, wherc infectlons bccauè of
blood traisfusions are prevcntcd,to a"orld without
INTERcEPT whereinf● ctibns ttay 6ocur
Threc sccnarios wcrc dcvclopcd including different
levels ofINTERCEPT benctits rrom thc prcventio■
o「
inFeclonS up to hiltiple ccsslng
pr●
benefIヽ
: redun‐
d a n c y o f b aJc ttce」“
r a l s c r c e n i n g‐
tarnad トγ
ing,宙
assulllptionS undcrlying odel.wcre
the“
that pathOgen
inacJvation is 1 000/。
ercct市c and is not associatcd with
7ersl even“The IMERCEPT
maiOr or costly ad■
,9reCning for infccJo,s l thari prcvents thetanSmis‐
jon ofncwlathogcnsbcroic thcyha17ebecn iden119d.
RESULTS
The cost-effectiveness
ratio is highly sensitiveto the
risk of infectionwith the emergingpathogenand to
the indicationandage group considered.
Scenariol: In the absenceofemerging virus, the
cost-effectivenbss
ranges between 3,459,201€per
quality adjusred life year (QALY) to 195,364€l
QALY. At the lowestsimulatedrisk of the ernerging
pathogencontamination(l/l 00,000),the cosi-e(Tectivenessratios rangebetween3,355,308€/QALYand
165,05t€/QALY,dependingon the underlyingdisease (Iable 6). With increasingrisk of emerging
pathogen transmission,the cost:effectiveness
ratios
steadily decrease(improve), with a maximum of
Z,594,l20elQALy at l/10,000and of 223,255at
l/1000.(Iable 7) and INTERCEPT beingdominant
in the majority of cases,maning cost savingand
producingexrraQALYS.Ar l/100, rheINTERCEPT
blood systemstrategybecomesdominantin all sases,
'点
胤騰
識淵∵幣:II譲
:畷:蝋論器
Absent
Pre.lent
.Absenl
AML-C
.lr
.
Preient
Absent
Present
ALL'C
Absent
Prcseni
NHL.A
Absdnt
Prgsent
NHL-C
Abssnt
Prescni
Cヽ`L
Absent
Prcsent
Absent
Present
Wlthout INTERCEPT
42フ 9
With INTERCEPT
5915
Withott INTERCEPT
4292
■lth INTERCEPT
5915
Without INTERCE'T
4277
ヽ
Vith INTERCEPT
5915
Without INTERCEPT
4295
With INTERCEPT
S915
ヽ
Vithout INTERCEPT
4290
With INTERCEPT
59i5
WIthout IN「
ERCEPT
4304
Wih INTERCEPT
591S
Without INTERCF_PT
4275
With INTERCEPT
5915
VithoutINTERCEPT
4290
ヽ
With NTERCEPT
b915
ヽ/ithout INTERCEPT
4502
ヽ
Vヽ
th rNTERCE'T
6161
Without INTERCEPT
4522
NVtth INTERCEPT
6,61
Without lNTERCEPT
4455
Wlth IN「ERCEPT
6161
Without INTERCEPT
4473
With INTERCEPT
61 61
Without INTERCEPT
3638
With INTERCEPT
4929
Wlthout INTERCEPT
3659
With INTERCEPT
4929
WIthout NTERCEPT
360
With IMERCEPT
493
Without INTERCEPT
361 3
WIh INTERCEPT
49'9
Mar」nd
l● ●
rC/E
EFrlcacy† ettcacy†(lCER)‡
1・
99953
200000
199952
200000
0・Ol1047
000048
3199162
3200000 000838
31 99019
32000110 000981
1625
1611
1640
1624
1659
1639
1706
1688
０
７
鸞欄
AML・A
V a r 」n a l
Cost● cost*
締爵趙
Stratcgy
299929
300000
1 000071
299927 、
3=Ol10110
0 00073
1599602
16.00000
1599562
1600000
000398
000438
3,459,201
3,355,308
195,364
165,051
2,280,181
2,196,998
411,522
370,981
599850
6'00000
599843
600000
0100157
2599302
26100000
2599200
2600o00
000800
210,949
0・00203
636,067
0・
00216
586“
S9
0:00032
422,784
999797
1000000
999784
1000000
15,99968
1600000
1599967
1600000
000150
000698
1,105,343
1,045,085
24■
59〕
000033
395,535
implcmentalon Of diagnosic screening tes■
would
BRCA
Without INTERCEPT
1000
Absent
299984
takc tlmc,during whlch the pathogen can
ergce轟
a,d
With INTERCEPT
'380
300000
000016
2,328,169
“ight catse numOro,s transmisslons
WithOut INrrERCEPT
1003
Prestut
2.99983
Historical data on the rlSo of transfusiOn‐
isso・
With INTERCEPT
:380
3・
00000
0.00017
2,285,263
ciatcd infectlons with HCv,HBV and HIV havc
shown thitthc●sk can r“
ch vew high lcvelsfore
bё
A, adltts; ALL, aate lymphoid lcukaemiai AML acuto myeloid leukaemiai C, chjldhood; CABG, @ronary 6ncry bwass gmft; CML,
scrcening measures haVc bcen dwcloped For implc‐
chroric mycloid leukaemia; ICER, incremental 6st,effectivqc!$ rario;.NHL, oon'Hodgkin's lymphoma; QALY, quality adjusbd life year.
icost and marginal cst in €.
mcnt1lon in dO■ o「screening s9hedules Aヽo
lEfficacy and malginal efliecy in nunb€r of QALYs.
reCClly,thcre has been an epidclnic 9f Wcst Nib
cost€Ilecliyetrassin €/QALY gaincd.
lMarginal
virus in thc Uniteo StatCs,a virus which was shown
to bc transmittablc via blood transfusion Thc rlsk of
prompt introduction of expensivescreeningteits in
2005). In our siudy, the rate of infection with an
transmission thrpugh transfllsion at thc epicentrc of
the US transfusionsafety progamme (NAT tests).
emergingvirus wassetat differentlevelsrepresenting
the epldcmic(1999)has been eslnated as high as onc
However,consideringthe time of first det€ctionof
differentstagesof emergence.
in 3700 to onc in 5555 trans●
jons h high‐
￨“ arCas
West Nile virus in .the US.(1999)and the time of
In the absenceor at veri low-risk levels of
′,2003).Esimatcd mcan risks in
(Hardngton′′α
implemBntationof NAT tests in routjne blood
emergingvrrus,of <l in 100,00blransfusions,
the
o ne in 6667 1ot o,,1■
811 1ona‐
2002 rangOd fro摯
screening(2002),the'lag time betweenemergenie cost-effectiveness
ratios were high in somepopula。
lfr総
was 3 years(Allain et al,,
and blood safetymeasures
tions, dependingon the underlyingdiseaseand age
器 :ゝ鷺L滞隻胤棚 :設 i講照犠
・
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P“ushiig Ltd,rr“
"MCaic誡
′
30
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ＮＮＨ
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i br platttt、
¨tc Two haln
Emergl電
Type
︲
９
Additional processingbenefits(seefurther scenarios)
are not consideredin this scenario.Given the evidence,it is clear that a risk of emergingvirusesin
the future is existent;however,the timing and levelof
risk is unknown. Therefore, the assumption of
neither the presenceof viral risk nor the absenceof
viral risk gan be supportedas a reflbctionof reality,
Therefore,it was decidedto presen! the basgcase
scenarioas a double scenario,taking into acoounta
similar probability of absenceand presenceof an
emergingvirus.To theemergingvirus,differentlevels
ofrisk wereattributedbetweenI in 100,000and I in
1000.The highestand lowesi risks are shownin the.
first scenarioin TablesI and 2.
In the secondand third scenarios,the implementalion of the INTERCEPT blood systemis assumed
to
eliminatethe risk for HIV, HCV, HBV, bacterialand
emergingHCV likd virus, and in addition, a set of
processingSenefitsare considered.In scenario2, the
elimination of BactAlert testing(corresponding
cost
and platelet wastereduction),the storagetime irrolongationto 7 days,leadingto 5004decrease
in overdue plat€lets wast€, th€ elimination of SDP ALT
testing on SDP platelersand the eliminationof .firradiation were assumedto be associatedwith the
INTERCEPT blood system.In a third scenario,the
following benefitswere assumedin addition to the
benefrtsin scenario2: the eliminationof NAT tests
and syphilis tests(VDRL) on SDP units-.leading
to
reducedcosts (NAT costs eliminated).Scenarios2
platel€t
proand 3 imply a reductionin the cost for
cessingand testing.
Cost-effectiveness
of INTERCEPT bloodrystem 25
26
Cost-effectivenessof INTERCEPT
K, Moeremans et al.
Emerging
virus
AML、 A
Absent
Prcscht
AML‐ C
Abspnt
Prcsent
ALL―A
Absent
Present
ALし C
Abscnt
Prcsent
NHL‐A
Absent
Presenl
Absdnt
Absent
BRCA
Absent
Prcsnt
WithoutINTERCEPT
ヽ
Vith INTERCEPT
WithOut IN「
ERCEPT
ヽ
Vith INTERCEPT
4290
5915
5736
5915
31 9916
320000
31 8486
320000
29993
30000
29973
30000
WlthoutINTERCEPT
With INTERCEPT
WithOut IN「
ERCEPT
With INTERCEPT
4275
5915
5781
5915
WithOutINTERCEPT
ヽ
Vith INTERCEPT
lrERCEPT
Withollt I●
ヽ
Vith INTERCEPT
4502
6161
6492
6161
W,thoutINTERCEPT
With INTERCEPT
WithOutIN rERCEPT
With INTERCEPT
4455
6161
6251
6161
ヽ
Vithout INTERCEPT
With INTERCEPT
Wlthout INTERCEPT
With INTERCEPT
3638
4929
5791
4929
WithOutINTERcEPT
Wlth INTERCEPT
ヽ
Vithout INTERCEPT
Vith INTERCEPT
ヽ
360
493
522
493
WithOutINTERCEPT
With INTERCEPT
ヽ
V“houtINTERCEPT
With INTERCEPT
1000
1380
1317
1380
1638
-164
1625
179
1640
134
1659
-331
1706
-90
1291
-862
159960
160000
159565
100000
519985
60000
59918
6.ooOo
259930
260000
258903
260000
99980
1 ●0 0 0 0
99845
10.0000
15・
9997
16 oo00
159979
160000
29998
30000
29997
30000
00o16
223,255
AML C
00084
195,364
0 1514
-1084
ALL A
000o7
00028
2,280,181
164,960
ALL C
00040
00435
411,522
3086
NHL A
00015
:
0 0083
1,105,341
,40,109
NHL C
00070
0 1097
244591
-817
CML
0.0020
636,067
00155
-55,479
CABG
0 0003
422,784
00021
-14:039
BRCA
010002
00003
2,328,16,
190,448
A, adults; ALL, scute.lymphoid leukacmia'AML, acrtc fryeloid leukaemia; C, childhoodi CABG, coronary artery bypa$ graft; ICER
incremmtal @st-cffetivcncss ratio; NHL, non-Hodgkin's lymphona; QALY, qrality sdjusted life year.
*Costandmarginalc6t in €.
lEffiacy andfrarginalefficacyin numberof QALYs.
in €/QALY gaincd.
iMarginalcost€ffectivencss
group. In children, the results were much more
favourable.
Considering the cost-effectiveness of other,
rec€ntly establish€d interventions in transfusion medicine, the INTERCEPT blbod system compares well
with these interventibns, especially taken into
ac4ount that only the economic implications of
Cost*
WihoutINTERcEPT
With INTERCEPT
Without INTERCEPT
ヽ
ヽ
lth INTERCEPT
4292
5329
4292
5276
1 9995
20000
1 9995
20000
ヽ
VithoutINTERCEPT
ヽ
Vith INTERCEPT
Without INTERCEPT
With INTERCEPT
4295
5329
4295
5276
ヽ
VithOutINTERCEPT
With INTERCEPT
Without INTERCEPT
Wlth INTERCEPT
4304
5329
4304
5276
31 9902
32o000
31 9902
320o00
29993
30000
29993
30000
Without INTERCEPT
With INTERCEPT
WithOutINTERCEPT
With INTERCEPT
4290
5329
4290
5276
159956
160000
15・
9956
16 0oo0
ヽlthoutrNTERCEPT
With INTERCEPT
WIthout INTERCEPT
Wth INTERCEPr
4522
5552
4522
5496
5,984
60000
59984
Wlthout INTERCEPT
With INTERCEPT
Without INTERCEPT
With INTERCEPT
Without INTERCEPT
LVlth INTERCEPT
WithOutIMERCEPT
Wlth INTERCEPT
4473
5552
4473
5496
259920
260000
259920
Without IN「
ERCEPT
With INTERCEPT
WithOut I卜
『ERCEPT
ヽ
Vith INTERCEPT
WithoutINTERCEPT
With INTERCEPT
ヽ
Vithout INTERCEPT
With INTERCEPT
361
444
361
440
3659
4441
3659
4397
1003
1244
1003
1231
Etlicacyl
Marglnal MarginJ C/E
eFI●
a Oy十 (ICER)￨
00005
‐
00005
2,143,435
2,032,6,6
00098
105,389
00098
99,924
00007
1,398,458
00007
1,325,297
00044
00γ 4
237,275
225,028
00o16
6 0 0 0 0,〔0 , 9 1 6
８
７
Prcsent
4277
5915
6079
5915
3,459,201
Marginal
6t*
Strategy
３
８
CABG
WithoutINTERCEPT
With INTERCEPT
Without INTERCEPT
With INTERCEPT
AML A
00o05
Scenario
７
３
Prcsent
1 9995
20000
1 9985
20000
Type
２
８
Absent
4279
5915
5568
5915
. Incr C/E
(ICER)I
260000
99978
:00000
99978
100000
159997
1600o0
159997
160o00
29998
3 0000
29998
3 0000
00080
1 90o80
656,438
620,812
134,763
127,783
00022
:
00022
340,449
00003
248,647
00003
361,091
235,227
0 0oo2
1,459,408
0 0oo2
1,383,572
A, adults; ALL, acut. lymphoid lskaemia: AML, acute mltloid leukaemia; C, childhood; CABG, coronary arrery bypass grafi; CML,
chronic myeloid l€ukaemia;NHL, non,Hodgkin's lyinphoma; QALY, quatity adjustcd life year.
"Costandmarginalcostin €.
tEfffcacyandmatginalefli@cyin numb€rof QALYs.
in €/QALY gained.
lMarginalcosFcffectivenN
curr€ntly tested pathogens were included, whereas
currently not tested pathogens may also induce costs.
This result is confirmed.by the results of a previous
health economic evaluation of the INTERCEPT system for platelets within the US health care system (Bell
et a1.,2003), as well as in d European setting (Postma
et al., 2005). For example, NAT tests, recently
implemented in rogtine donor-screening prograrrmes
in many countries, including Belgium, showed costeffectivenessratios ranging flom €25,000 to €2.3 million per life year gained Ueh et al.,2002). NAT tests
for HIV have consistently been associated with costeffectiveness ratios over €l million per' QALY
(Jacksoner al.,2003; Marshall et a\.,2004).
@2006Blackwell
Pubushing
Ltd, Trusfusion
Mediche,16,11-30
O iOoegtack*,;ltPutlishingLtd, Trwf'bn
Medcine,76,11-30
ｍ倒Ｈ
iCML
WithoutINTERCEPT
With INTERCEPT
WithoutINTERCEPT
With INTERCEPT
Marginal
efficacytr
３
２
Prcsent
Effieacyl
９
７
NHL‐c
Marginal
cost*
Strategy
27
Table8: Cost eflectivenes(cost/QALY) r"un"rio, j and 3 - emergingvirus l/100,000
(cost/QALY) scenarioI - no emergingvirus or emergingvirus l/1000
Tsble 7. Cost effectivcness
Typc
blood systm
Hence, these very high cost-effectiveness
ratios
have noJ preventedtheseblood safety measuresto
be introducedin many countries.When considering
also the cost-effectivensss
ratios for other interventions to preventaccidentalinjuriesor death such as
traflic safety measures;it seemstha! society or at
leastauthoritiestendto placea very high valueon
28
K. Moeremans et al.
CosFeflectivenessof INTERCEPT
:
Thresholdemerginginfectidn risk
Type
S@narioI
Senario 2
Scenario3
AMLA
AMLC
ALL A
ALL C
NHL A
NHL C
CML
CABG
BRCA
1/789
1/1107
895
1プ
1/925
1/1205
1/1057
1/1675
1/1222
1/8,8
1/1230
1/1722
1/1400
1/1439
1/1905
1/1644
12692
1/1932
1/1306
1/1297
1816
1ん
1/1476
1/1510
1/2004
1/1738
1/2858
1/2037
1/1380
Mean
1/1079
1/1697
■/ 1 7 9 1
A, sdulb; ALL, acutc lymphoid leukaemia; AML, acute myclojd leukaemja; C, childhood; CABG, coronary ariery bypass gafr; CML,
chronic hyeloid lcukarmia; ICER, incremental cost-effectivenss ratio; NHL, non-Hodgkin's lymphoma.
ACKNOWLEDGEMENTS
We thank the following partiesfor providing valu.
able informationwith,rEgardto blood safetyand
policiesin B€lgium.
blood transfusion
j Red crossservicesFlanders:Dr L. Muylle
o Red crossserviesWallonia:Prof, D. Sontae
. HaerhatologyDepartm€nt, University Hospital
Ghent:Prof L. Noens
! Hasmatology Deparhnent, University Hospital
Gasthuisberg
Leuven:Prof M. Boogaerts
r.AnaestheSiolory, University Hospital Ghent:
Dr L. De Baerdemaeker
. Anaesthesiolo$/,OL Vrouw Hospital Aalst:
Dr L. Foubert
o Centrefor vaccinology,
UniversityHospitalGhent:
Prof G. Leroux-Roels
. HCV patientsorganisation:
Mrs Colinet
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relatcd
L.R. & Marhn, A.A. (2003) West Nile Virus intection
・ d o n o r p a r r o w t r a n s p l a n t a t i o n : a n u p d a ttransmitted
e o f t hby
e blood
c x p c itransfusion.
‐
Trarcfusion, 43,
e,cc 6r the ltabai pOne Marrow iransplant CrOup I 0t 8-t 022.
ゎgた,,86,451456
(GITMO)Irae″ὰο
Hu, K.Q. & Tong, M,J. (1999)The long.tem outcomesof
Drcsse, MIF,Boogaerts,M"Vcnnylen,C,Nocns,L,
paticntswith compensatedhepatitisC virus-relatedcirrFoFant,A,Schots,R,Doyen,C,BIoh,D,3cmernan,
hosis and history of parenteralexprcsurein the United
Stales.Hepatology,29 (4), l3l l-1316.
Jackson,B.R., Busch,M.P., Stramer,S.L. & AuBuchon.
cxpcHencc in unrcllted dOnOr bone marrowsplanta‐
traり
J.P.(2003)The cost.effectivenssofNAT for HIV, HCV,
.6on:idcnditttOn Of∝n■r OxpCience as al impprtant
and HBV in whole.blooddonations.Transfusion,4S
(6),
't2t-729.
m″ο
々 lCat 84,637ヽ
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ル,16,17-30
,レ雄 ″ε
ヾＮ［
measuresto reddceunintentionaldeathsand injuries
by Yeh
$eh et a1.,2002),Therefore,it wassuggested
et al., (m07) that transfusionsafetymeasuresshould
evaluated
be
usingcost-effectiveness
thresholdsthat
are higher than those typically used by healthcare
decision makers,reflecting.the higher value placed
on suchtypesofinterventions,whereit. is considered
lunfair' ifpatients haveno accessto the bestpossible
protection ffeh et a1,,2002),
Also the cost-effectiveness
analysesshould take
into accbuntall p_o-tential
benefitsof a newintervention such as processingbenefits,indirect costs from
productivity loss(Yeh et al.,2002).
When a morepro-activeviewpointis taken,from a
public healthper'spective,
the apparentrisk for emer'
ging virusesshouldbe taken into account.At emerging viral risksbeyondl/1000 to l/2300transfusions,
the INTERCEPTslrategybecomes
dominant,that is
savingmoneyand producinghealthgains.
In conclusion,consideringthe apparentlyapplied
thresholds for cst-effectivenessin the field of blood
transfusions,the implementarion
of .theINTERCEPT
blood syslemcan beconsidered
cost-effective
and even
a dominant strategytakinginto accountthe potential
of a newpathogenin the future.
risk of emergence
29
Dusheiko,G. & RobertsJ.
Treatmentof chronic
・
m甲
°
・ tt°
°
“
type B and C hepatitiswith interf,eronq: an economical
'H
'7SIⅢ
11り
糧
Tl総,・ "lcVI喘remiaνin HCv infCCtiOus appraisal.Hepatology,22, 1863-1873.
Busch,M Pi(2003)VcryI。
BrallCy,C J tt Bednarek,H.L 12002)Emplbyment pat=
Table 9. Threshold valuesemcrgingvirus risk for INTERCEFI dominane
blood system
TRANSFUS10N 00MPL101T10NS
3O K. Moeremarc et al.
Laperche,S., Morel,.P.,Deschassux,M., Bouchardeau,F.,
Alimardani,G., Guillaumc,N., Rouger,P. & Lefrdre,J.J.
(2003)HtV antibodyscreening
remainsindispensable
for
ensuringviral safetyof blood componentsdespiteNAT
implemcntation.Trarcfusion,43, | 428-1432.
hten€, P.F., Mocremam,K., Gitis, P. & Annemans.(2002)
Sewre sepsis:clinical lrial wrsus daily practie. A @st
analysisin Belgum. Valuein Health,5 (6), 561-562.
Un, L., Cook, D.N., Wie*hahn, G.P., Alfonso, .R.,
Behman, B., Cimino,G,D., Corten,L., Damonte,P.8.,
Dikeman,R., Dupuis, K., Fang,Y.M., Hanson,C.V.,
Hearst, J;E,, Lin, C.Y., Londe, H.F., Metchette,K.,
Nerio,A.T., Pu, J.T., Rsme, A.A., Rheinschmidt,
M.,
Tessman,J., Isaacs,S.T., Wollowitz, S. & Corash,L.
(l 997)Photochemicalinactivationof virusesand bacteria
in platelet conentrates by use of a novel psoralenand
fong.wavelength
ultravioletlight. Trwfus ion, 37, 423435.
Marshall,D.A., Kleinman,S.H.,Wong,J.8., AuBuchon,J.P.,
Grima, D.T., Kulin, N.A. & Weinstein,M.C. (2004)
Cost-eflectiveness
of nucleicacid tqt screeningofvolunteer blood donations for hepatitis B; hepatitis C and
human imunodefici€ncy virus in the United States.
Zox Sanguinis,86 (l), 28-40.
Marteffi,M., Gherlinzoni,F., De Renzo,A., Zinzani,P.L.,
De Vivo, A., Cantonetti,M., Falini,8., Storti, S.,
Meloni, G., Rizzo, M., Molinari, A.L., Lauria, F.,
Moretti, L., Lauta, V.M., Mazu. P., Pescamona,L.,
Pileri,S., Mandelli,F. & Tura, S. (2003)Early autologous stem €ll transplantationversusconventional chemothcrapy as front Unetberapy in high risk aggressive
non Hodgkin lymphoma. An Italian Multicenter
Randomised Tial. Jownal of Clihical Oncology, Zl,
t25s-1262.
Miners, A.H,, Sabiq, C.A., Trueman, P., Youle, M.,
Mocroft, A., Johnson, M. & Beck, E.J. (2001)
Asessing thc @st-effetivenessof highly active antiretrovinl therapy for adults with HIV in England. H.f/
Medicine,.2,52-58.
Pereira,A. & San4 C. (2000) A modet of the heatth and
e@nomicimpact of post transfusionhepatitis C: applioation of cost-effectiveness
analysisof further expansion
of HCV screening prot@ols. Trarcfusion, 40 (lO),
I 182-ll9l.
Pigneux,A,, Tanguy, M.L., Mjchallet, M., Jouet, J.P.,
Kuentz, M., Vernant, J.P., Milpied, N., Ifrah, N.,
. Cahn,J.Y., Gratems,N., Reman,O., Cure, H.; Caillot,
D. & Witz, F., Pillier.Lorietre,
C., Tron, p., Reiffers,
J. &
Soci€ti Francaisede Greffe de Moelle. (2002)Pfior tr€arment with alpha interferon does noi adverselyaffect thc
outcomeof allogeneic
transplantatjonfor chronicmye.
foid feukaemia.BritishJournal of Haenatology, 116(l),
r93-201.
Postma,M.J., van Hulst, M., De Wolf, J.T.M. & Botteman.
M., Staginnus,U: (2005)Cost-effectiveness
of pathogen
inactivationfor platelettransfusionsin the Netherlands.
Trcnslwion Medicine,15 (5), 319-387.
Radich,J.P,, Gooley,T., Bensinger,W., Chauncey,T., '
Clift, R., Flowers,M., Martin; P., Slattery,J., Sultan,D.
& Appelbaum,F.R. (2003) HlA-matched related hae' matopoetic
@ll tratrsplantationfor CML chronic phase
usinga targetedbusulfanand cyclofosfamidepreparative
reg1men.
Blood,t02 (1),3l-35.
Seveni!,B., Meral, A., Ozkan,T.,6zuysal, S. & Sinirtas,
M. (2003)Increasedrjsk of chronic hcpatitisin childlen
with qner. Med PediatrOncol40, 104-110.
Soci€, G., Stone,J., Wingard, J,, Weisdqrf, D., Henstee"
Downey, P., Bredson, C., Cahn, J.Y., Passweg,J.,
Rowlings,P.A.,Schouten,
H., Kolb, H.J.,Klein,J., BenderG6tze,C., Camitra,8., Godder.K., Horowirz,M. & wayne,
A. for thclaleeffsts working@mitte of theintemational
bonemarow transplantregistry.(1999)Long tem suruival
andlatedeathsafGrallogcneic
bonema[ow transplantation.
TheNewEnghndJourrulof Medicire,!4| (l), l+21.
Taggart, D., D'Amico, R. & Altman, D. (2001)Effecr of
arterialrevasillarisation
on survival:a systematic
review
of studiesomparing bilateral and singleintemal mam,
mary arteris. L{ncer, 358, 87S-875.
Tong M,, El-Farra,N., Reikcs,A., er a/. (1995)Cljnical
out@m€s after transfusion-associatedhepatitis C.
N Engl J Med,132, 1461-1466.
Weintmub, W., Clem€nts, S., Van-Thomas Cds@, L,,
Guyton. R., Craver,J., Jones,E. & Hatcher,C. (2003)
Twenty-ycarsurvival after coronary artery surgery.An
institutioral persp@rive from Emory University.
Cir culation, 107, 127l-12'l'7.
Wong, J.B, & Nevens, F. (2002) Cost-effectivenssof
peginterferon
alfa-2bplus ribavirin ompared to interferon alfa-2bas initial rreatment of chronic hepatitisio
Belgiufi . A ctq g6 rr oenl:er
ol, 65, l -2 (extendedabstract).
Yeh, J.M., Bolteman,M. & Pashos,C.L (2002)Economis
of transfusioq, Infusion Therapy and Transfusion
Medicine,29.218-225.
@ 2006 Blackwell Publishing Ltd, Ttawlusion Medicine,16, 17-30
The cost-effectivenessof pathogen reduction technology as
,
assessedusing a multiple risk reduction model
Brian Custer, Maria Agapova, and Rebecca Haulir Martinez
BACKGROUND:Pahogen reductiontebhnology(PBT)
lor labilebloodcomponontshas lhe potentialto reduc€
lhe risk ol many advaFo €ventsassociatedwilh irans.
tusion,Becauseot lhe polentialbroad-spectrum
risk
reduclloncapabllilyof PFIT,the health.economicsot
PRT could bs an importantconsids(alionin decislon
makinglor this technblogy.
STUDYDESIGNAND METHODS:Decislonanalytic
modelscompadngcutrontblood salety screensand
inleruentlons
to riboflavln-bassd
whole blood PRT (currenlly in developmenl)and sepactely to plalelets
(PLTs)-and.plasma
PFT from thg healthcar€ system
perspectivsin Cariadawere us€dlo assosslhe coslutilityof PRT in roducinglhe lollowingadverseevenls:
humanimmunodeticiency
virus,hepatltisB virus, hepalilis C virus,humanT-lymphotropic
vlrus,syphilis,Wesl
Nile virus,bactorlarChikungunyavirus,cytomegalovirus, Trypan@oma
cruzLg€tl.ve6us-hosl dlsease,
febrilenonhemoMictransfusionreacllons,and
lransfusion-felatsd
lmmunomodulation.
PBT was
modeledas sn addilionto ratherthan a r8placemsnttor
cur€nt intgryenlions.
Tha potentlalof PRT to redu6
the risk ot an-unknom paihogenwas nol assesssd,
RESULTS:Whol€blood PRT was estimatedto have a
cost-ellectivmessot $1,276,000/quality-adjusted
liteyear (OALY;96./6contidencelntsrval[Cl] approxlmation, 600,O0O-3,313,000)
comparedto currentscreens
and interyentlons.
PLTs-and-plasma
PRT was estimated
lo have a @sl€tlectlvenessot 91,423,000/QALY
(95%
Cl approximation,
8il4,OOO-2,818.000)
on an alllranstusionsbgsis.
CONCLUSTONS:
Bocauseof the complexityof transfuslon risksand prastlces,the cosl.ellecliveness
ol whole
bloodoI PLTs-and-plasma
PRT can be modeledprovidsd that a$umptlons and simplitications
are made.
Uncertajntyremalnswith respeclto the risk reduction
lhal can be achlsvsdtor some advarseevenls,Never.
theless,ths rssultsof this cost-eifectfueness
analysls
€n be used to IntormpolicydecjsionsregardingPRT
lechnologyIn th6 contextot other initiailvesdesignedto
improv€ transfuElon safety.
.
wo methods for pathogen reduction technology
(PRT),also known m padlogen inactivation, use
a photoactive compound (riboflavin or amotosalen) md ultmviolet {UV) light teatment to
prevdnt DNA or RNA replication, These methods are being
adopted for !he treatrnent of platelets (PLTs)or plasma in
some Europeari'countries. Consensus statements from
the panel of the Canadian Consensus Conference on
Pathogenlnactivationin 2007and summary statements,
such as from one of the 2008 US Advisory Committee on
Blood Safety and A%ilability meetings, indicate that eco'
nomic evaluations of PRT should be conducted and
included as part of the information used for making
implementation decisions.Ir Previous economic malyses
of photoactive compomd/UV light PRT focused on
human immmodeficiency virus (HIV), hepatitis B virusS
(HBV), hepatitis c virus iUcv), human T-lymphotroplcCl
virus (ffTLV), and bacteda.3-6These
malyses assumedthatthe treatment process i9 100% effective (residual risk of
these Fathogens is eliminated in PRT-treated PLTs) and
reported results for specific patient populations Iikely to
receive-suchtrmsfusions. The likelihood that these same
patients would receive unueated red blood cells (RBCs)
and/or plasmatrmsfusionswas not addressed.Moreover,
while analyses restricted ro specific patient popularions
ABBREVIATIONS: FNHTR(s) = febrile nonhemolytic trustu"
sion reacrion(s); PRT = pathogen reduction technology;
QALY = quality-adjusted llfe.yed; TRIM = rrostusion-relared
immunomodulation; WNV = W6r Nile Wus.
From Bldod Systems Research Institute,.San Fmcisco,
Califonia; the Phamaceutical Outcomes Resealch and policy
Program, Universiry of wdhingron,
Seattle, Washingtoni ed
Cambridge, Mssachusetts.
AUr6s reprint requet s toi Brian Clste! Blood Systems
.. R6ercb Instituie, 2?0 Masanlc Avenue, Se FEncis@, CA
'941 18; e-mail; bcuste!@bloodEysrems.org.
Hflird
Universiry
-Receivedfor.ptrblication May 7, 2OO9;re\4sion recelred
March 19, 2olo, and a@epred Mdch 20, 20t0.
doi: I0.l I I I /j. 1537-2995.2010.02704r
. .TqANSFUSION 20t0is0i246t.2473.
Volume50, Novemb€r2010 InANSFUSION 2461
COST‐EFFECT:VENESS OF PRT
CuSTER ET AL.
based on trmsfusion indication ile informative for
assessingwho is most likely to benefit,7they do not help
blood safety decision makers faced with selecting interveDlions to enhmce ihe safety of components intended
for.all transfusion recipients.
We developed a new health economics model to
assess the cost-effectiveness of riboflavin-based PRT
(Mirasol PRT system, CuidianBCl, Lakewood, CO) in
mitigating the risk of transfusion-associated infectious
md some noninfectious threats,The first model examines
the cost-effectiveness of a technology in development,
whole blood PhT,6To model the technology that is curently available in some settings, PlTs-and-plasma PRT,
we modified the whole blood PRT model, incorporating
data on PUI prcparation procedures and uansfused components to adiust the risk reduction achieved.
diseaseoccutrence,butcomes, and costs come from published literature specifc to Canada,When data were not
available for a specific diseaseor condition; we used data
ftom other countries with preference for US data when
available.In accord witi the recommendations of the US
Panel on Cost-effectiveness in Health and Medicine,
future costs and effects are discounted at 3% per yeurr'r'z
andwereallowedtovaryindependendybetween I and5%
in sensitivity ana.lysis.
We constructed the model and perforrned malyses using computer sDftware (TreeAge Pro
2009,TreeAgeSoftwile, Inc,, WillianstoM, MA). Aspects
of the model not covered in deta.i.lunder Materia.lsand
Methods, such as amual mortality probabiiities and
disease-specificmodels and variable values, are provided
as an electronicTechnicalAppendix (avallable as supponing information in the ori'lineversion ofthis paper);
MATERIALSAND METHODS
Overview
Structure of the model
The models simulate the costs and consequengesof the
following infectlous and noninfectious adverse events:
Hry, HBV HCV HTLV syphilis,WestNilevirus (WNV), bacteria Chikungunya virus, cytomega.lovirus (CMV), fi.ypa.
nosom crwi, graft-versus-host disease (GVHD), febrile
nonhemolytic transfusion reacuons (FNHTX), and
trmsfusion-related immunomoiiulation (TRiM). Eoth the
set of and the prevalence of adverse events included in
each version of the model cm be adjusted to reflect
setting-specific epidemiology or disease.In this analysis
we neither included an mknom, emerging pathogen nor
re$ospectively included a scenario for HIV or HCV when
either virus had the highest preva.lencein blood donors.
Our reason fornot includingthese pathogens or scenarios
is ihat it is relalively easy to construct a set of outcomes
with a disease burden profile that is favorable to PRT.
However, such a scenailo in the context of $ying to
address or mitigate cuirent risks could cloud the assess.
ment of the ef6cjency of PRT.
We analyzed the cost-utility of PRT for Canada.
Canada represent$ an appropriate country for such an
analysis because tiere re I) nationally representatiw
health care data, ?) active hemovigilmce and trmsfusion
suweillmce systemsin some Provinces,and 3) interest in
implementation of PRT.Similar to othe! economic analyses in blood safety, this malysis is ftom the health care
system perepective and costs aelimited to the costs ofthe
safety interventions and the dkect medical costs associated with infections or other adverseevents.eThe results
reponed here do not include the cost of lost producrivity
or related lnduect costs incurred because of transfusionassociated adveFe events.We used 2007 as the analysis
yeu, so all monetaryvalues are adjustedto 2007 Canadian
dollars using the health md personal care component of
the Canada consumer price index.ro Data souces for
246i1 TBANSFUSION Volume50, November2010
The model has a decision analytic format and is a cohort
simulation with separate diseree-specific Maikov submodels to back the progession of each adverse event.
Each version of the model conslsts of four sections.The
first section is a two-armed decision tree: current scrcens
and interyentions .compared with PRT added to currcnt
screens,The second section is focused on two charactelistics of blood recipients that influence the likelihood of
suwival: age at uansfusion and immuocompetence. The
model can be run using surviva.ldata for three agegroups:
l) an overall goup that reflectsthe age distribution ofthe
entire transfused population, 2) persons 0 to 39 years of
age, and 3) persons 40 years or older. These categories
were def,ned based on availablepostuansfusion datd that
indicate that the probability of swival ls similar withih
these latter two broad ege categories.r3't5
The population
of blood recipients is also separated i4to those with and
without underlyiri immunocompromise, because a
subset of the population requiring transfusion may b€
immunocornpronised due to a medical condition, such
as cancer,organ uansplantation, or specific infections like
HM T[ese patients may be at increased dsk fo! more
severeadvene outcomes from transfusion.16Estimates of
the size of the irnmuocompromised subpopulation are
not available for Canada. Data from the National Blood
Service in the United Kingdbm suggest that as majly as
5090 of blood recipien$ ue lmmunocompromised to
some degree,with 25% having moderatb or severeimmunocompromise.rT
We included immunocompromise in
our malysis by assumingthat 2570ofthe transfusedpopulation hm underlying irnmunocompromise. In the model
tiis patient goup is at increased risk of monality and
faster disease progression, which we included:as 509o
incleased postuansfusion mortality in the first yeil after
fiansfusion, and increased risi of morbidity from each
adverse event.
TABLE 1. Percsntageol patlenls lecelvlng lranstuslons by
componenl combinatior trom Brltish Columbld 8nd Yukon
trsnstusion rgglslry data and assumed riak reduction 8chleved In the
PLTs-and-Dlsme PRT model
n": :
Translosed ib●
i¨●
mp●
comЫhalbnsòr 2∞
7
.
184,842
compOnent)
(n・
ABCl onlソ
Pocen● ge aavlng
eaCh,pe of
Ю
a COmponent
75 7
Plasma・
c●
ntaining tFnslusiolls
99
None
｀
00
Mは
‐
還‐
S・驚騨「
冒
認llttasm:品
:朧
) ::83
PLT coltahing,7an8fuSiOns
14 4
i鰈
鼈
sド
Assu""P3Tわ
duO On a■
u゛menl
ractOr(PRT^F),
plaima. Components are not assujhed
to come from the same blood donor and
so carry the independent risk of each
adverse event, but the adverse risks for
each component would be mitigated in
a single inactivation ifwhole blood PRT
beconres available. The number of
cansfusjons.received in an episode has
not been modeled. A.lthough the risk of
spectfic infectious agents and of noninfeitious huards varies according to the
type of blood component transfused,
component-speciflc residual risks are
mosdy unreported and are not included
in the whole blood PRT analysis.
::‰
Mlxed
:諄l'F
T A B L E 2 B b o d s a f e t yo ●
hs t ea rn vd●
e●
3n1■
m e d o●s t s
Per
donalion
@sl
Cosl elom€nt
CurOnt Screen3
‐
HIV antlbody
HIV NAF
HCV OいOb●dy:
HCV NAT
HBV surace anlgen
HBV core an“body
,
VVNV NAT
Rmgstor
sonsinvity
ahalvsls
_
`
HTLVOハD antbOdy
SbrObglo lest rr●
syp"lls
Tola1
44 0o
33 00・
5500
Bactelal cuture
Bacterほ culture'
2500
1875‐
3125
arter diverslon
‐
1288
CMV anlbody
10 00
7 72‐
500
375・
625
Gamma“ radiat on. :
PRT
l∞
00
7500‐ 12500
The third section of the model differentiates recipi.
ents into three grcups based on the t)?e ofblood components received. Published data consistendy show that
recipientsofPLTSoi plasmaalone or in combination wiIh
RBCshave redgced long-term suryival compared to RBConJy recipients,lsreData on the percentageof transfusion
episodes that include each blood component type were
provided by the Bdtish Columbia Prcvincial Blood Coor'dinating Of6ce for the year 2007 (Table1). We assumed
that the component combinations transfused in British
Columbia md Yukon are representadveof rhose for the
endre country.We aajucted the mortality probabi.litles for
PLI recipients and si,paratelyfor plasma recipients using
clata published byWallis md iolleagues.r'g
The fourth section ofthe model addressestransfusion
outcomes thlough detailed accounting of disease and
adverseevent progression md costs.Details of how each
adverse event is modeled are prol'ided in the Technical
lppendix
In the model edch trmsfusion recipient is assumed to
experience a single transfusion episode consisting of I
unit ofwhole blood or the equivalent as RBCS,PLfs, and
Ettectlveness ot PBT
Curreut blood safety interyentionF used
in Canada de listed (Table 2). In tNs
analysis, we assumed that all of these
interyentions would continue md that
unlvercal leukoreduction would, con'at
tinue. fhe effectiveness of PRT
reducing the risk of each Eansfusionassociatedadverse erent is dependent
on the inteNentions already in place,tQ
the likelihood of adverse event occur- N
rence, and the pathogen-specific per- r'-l
formance of riboflavin-based PRT
Actual estimates of the efectivenels of
PRTunder conditions of normal usewill
only be availableafter sufficient posthalketing surveillance data have accumulated. To project
the effectivenessof PRT we assumed pathogen-specific
risk ieduction factors (Table3). Risk without PRT is 6ased
on the observed frequenry of the event, the leld of
screening, or estimated residual.risk given current safety
measures.Forexample, ihe current estimated residual risk
of HBV infection is-l per 153,000transfusiols.2o Good
animal models to demonsuate a specific Ievel ofpathogen
inactivation for HBV tre not available. Studies of
riboflavin-based PRT have.shown that it can successfully
prevent pol].merase chain reaction amplification of HBV
at concenBatioDsup tD 29,4OOgeql mL.2rWe assumedthat
ihe risk reduction achieved by PRT would be l0-fold
greater t}lan current testing (hepatitis B surface mtigen
and anti-hepatitis B core antigen) givlng an. estlnated
residual risk after use ofPRT of I per 1,530,000.
Costs
The cost of cunent scieens md interyentions applted to
every donation in total sum to $44.00 per donation
(Table 2). No serologic lntewention for I cruziwas used in
Volumo 50,NOvomb●
:2010 TRANSFuSiON 2461
CuSTER ET AL
CuSTER ET AL.
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TABLE4. Cost8 and etlscts ot currsnt Int€rventlons, wtth PFT 6nd incremsnlal coal-sftsctlveness of PFT by
transluslon recloient sqe orouo tor whole btood PRT
'
,
_
Tolal costs for curonl &rgseiinteNentions ($cAD\
(OALY)
Efiocts wiih cunent scr€eng4nleryentions
Tgtal cost {or PRT adoptlon (SCAD}
Eftectswith PBT adoplion (OALY)
Incrementalcost of PRT ($cAo)
Incromentaleftecdv€ns$ of PRT (QALY)
Increm€ntalcost€fI6ctlwh€solPBT($CAD/OALY)
(9570Cl approximation)
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Both one-way ald probabilistic sensitivity analyseswere
conducted. All sensitivity malyses were performed using
$re overall (a[ ags) blood recipient popuJadon,agespecific sensitivity anallres were not conducted. In oneway ana.lysis,the influence ofa single model.variableover
the likely range of possible valugs fo! that vsiable is
assessedwith respect to its impact on cost-effectivenes.
The one-way analyseshave been aggregatedinto tornado
diagrams, one for the whole blood version of the model
and one for the Plls-and-plasma model, showing the
decreasinginfluence of model mriables. The top tS.most
influentia.lvariabldsspecific to each model ae included in
each tornado diagrm. Uncenain vuiable values md
assumptions such as the residual lisk of each adverse
event, PRT risk reduction factors, and tieatment costs
werevaried by:50% ofthe baseline esiinate, Tlie costsof
blood safety inteNentions including PRT md amual
postEansfuslon mdrtalitywere varied by t2570 indicating
a477
7.a85246
158.30
7.885335
113.53
O.OOOO89
$1,276.000.
(600,000-3,313,000)
C6ts and €(€ct6
l-tosg@
44.92
19.550197
158.3'1
19.550463
113.40
0.000266 .
$426,000
. (197,000-1,173,000)
44,76
7.3t1080
158.30
7.311161
113.54
O,OOO08I
$1,405,000
(653,000.3;693,000)
E probabillty of baclerial contam,: 0.00003 to 0,00001
E mortatlry probabltity ln year ot trandfuslon: 0.10 to 0,30
S cost of PRT per donatlon: 75 to 125
Z probabltiiy of sepsls death, immunocompetent.: 0,5 to 0,3
El dlscount rats for €ffects: 0.01 to O;05
m QoL welght in ysaF tollowlng transfusion: 0.99 to 0.86
S QoL relght tor consequencesof sepsls: 0.59 to 0.79
iE component use adjustmenl taclor for PRT: 1.0 to 1.20
N annual mor,tallty after trsnsfuslon: - to +25%
I component specific mortality 8en€ltlvity analysis: O to 1.5
D probabliiiy of T cruzl: 0.OO0OO75
to 0,0000025
X PRT adlustmenl tactor for FNHTR: Z.Sg to l:Ot
E probablllg of death In acute T, cruzl stata: 0.03 to o.0ol
E dlsutility welght for FNHTR:0.02 to 0.005
N PRT adiustm€nt factor for bactsrla: 90 to 10
A probability of FNHTR:0.002to 0.00057
E probabllity of PLT8 transfuslon: 0,094to 0,194
I
Incremental
Sensitivlty analysis
Overati(altCges)-
nesuttsetegory
dosUEffectiveness
Fi8, l. Tornado dlcgtq
QoL welght for tnnsfuaed patient: 0,99 to 0.81
($mllllons/QALY)
shos'lng the range of values used ud
resulr6 froh one-wsy sen"ldvity ualyels of the nosr lnfluentlal wl.
b6r Ellacts tlre f ug€ of adiacent valus llsted on the rlghl Ruge6 @ prcp'lth the left atrd rlghr ends ofeach horlzotrral baL QoL - quallty of ltfs.
vided from low to hlth ot high to low In corcspondene
ablo in Oe whote blpod PRT model, Ecch horlantal
severa.lof the factors.related to FNHTR, such as the
probability of FNHTRs [attdbutable to residual white
blood cells (WBCsI evln in leukoreduced blood) and the
assumed risk reduction, de influential in the whole
blood PRT model. Evidence of the effrcacy of UV light
and photoactjve compoud PRT to reduce the occur.
rence of FNHTRs continues to emerge; both riboflavinbased md amotosalen-basedPRT have demonstrated a
decreasein these adverseevents duing active hemovigilance s$ditls.aa It is expected these benefits would be
mostly iimited to Plfs and RBC prqiarations. However,
in order to assessthe cost-effectivenessof PRT without
considering a potential FNHTR benefit, w set the
residual risk of th.is event to zero which removes this
2466 TRANSFUSION.
Vdwe 50, Novsb€r 2010
adverse event and associatedcosts from the model, The:
whole blood PRT resu.lt increased to $1,364,000/QALY
representing nearly a 7% higher cost-efectiveness
ratJo.
Appropriate values for the current residual risk for
pathogens that are not universally screened for are dificult to knN with certaint]4The influence oftwo infectious
threats, bacteria and T. guzL was assessed jointly. If the
underlying residual risk of bacterial infection for all componenF is I in ?5,000and for T, cruzi is I in 250,000,the
cost-effectivenessrado for whole blood PRT increasesto
$1,876,000/QAIY (95% CI approximation, 812,000.
5,295,000),Teprsenting a 47% higher cost-eFectiveneEs
ratio.
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2464 InANSFUSION Volume50,November20l0
Canadain2007, and so no scteeningcostsare included for
this agent. CMVmtibody add gamma irmdiation costsne
.assumedto be incurred only for the units intended to be
uansfused to patients with underlying immunocompromise. The estimatedcost ofPRT ($100on a per donation or
component treated basis) covers the cost to implement
t}re suategy including labor and overhead. In the case of
bacteria.l cu.lturc, costs are not incurred for all components as screening is conducted only on PLTS.PLTScomprise l0-15% of a.ll components transfused in Canada.'?2
We used a cuffency converted, inJlation-adiusted cost
estimate for bactedal culture from the Netherlandss to
determine a cost of $25 for bacterial culture per PLI
prepila$on.
The potential risks of riboflavin-based PRT include
c)'totoxicity, genobxiclty, and reduced efficacy ofcomponents. It is pgssibleproc€ssing mistakessuch as under- or
over-exposure to. W .light may lead to these consequences, but available laboratory and aninal model
studies conducted to date have found only minimal widence of these adverse events.z3It is expected rhat BBC
and PLI efficacy cou.ld be reduced by the ueatment
process,but the oneavailableclinicalstudyof PLTstreated
with riboflavin.based PRT did not demonsuate increased
trmsfusion in the PRT treated compared to untreated
arms of t}le trial.za2s
Nonetheless, we included a component use cost factor in the model to accoui foi potential
additional transfusion of components due to the PRT
ueatment process.We reflected increasedcomponent use
by assuming a l07o increase i.nblood component screening and preparation costs t}lat would be necessary to
achiwe the same therapeutic efficacy in the PRT arm of
the model. In sensitivity uallsis we varied this additional
cost factor between D and 20%.
COST‐EFFECTIVENESS OF PRT
CuSTER ET AL:
deFendent on the pooled PLf pleparation method. The residual risk ofbacteria in plasma-rich PLI preparauons is
higher than in bufry coat or apheresis
preparationsi thus PRT treatment of
PLfs prepared using this method yields
greater benefit and a more favorable
cost-effectiveness profile. As the
percentageof slngle-donor apheresis
collections
increases, the
costeffectivenessratio increasesin a nonlin€il mmne! and at I00% single-donor
collections, the
ratio
exceeds
$2,000,000/QALY
TABLE 5. Costs and sllecls ot _currentinterventlons, wlth PRT and incfemental cost-effectlveneasot pFT by
.
lianstusjon reclplent rgs group tor PLTs-and-plasmapBT
;
R 酬時 c a t eり
g ●:
警]『
齢期i騨ツ
4437
7838611
4465
4436
1945o178
轟
hittT辟
d PRT,C,0/°
ALYl(8141″
:部
湖橘器:“
::♀
:,00
6
E
S
Z
[!
!
E
E
E
Z
(!
E
g
.“
総:::,∞
。 19651濯
1 9:,∞
Q
mortalityprobabllityIn y€sr ot tianaluslon: O,1O
to 0.30
componentspeclflc mortatityadjustment:Oto '1,5
donor exposurcr non.bactqrialagents per plateletprgp.;6 to t
donor exporures bacterlatper platglsi prep.: 6 to I
prcbabitltyof sepsiadeath,immunoqomp€t€nt:
0.5to 0.3
dost ot PRT pd d onatton: {.75to 1251.0.25
dlscountEte for sffects:0.01to 0.05
OoL w€lght for oonsequencesol sripsts:0,59to 0.79
OoL wolght In yoars tollowingtransfuston:0.99io 0,86
componentuse adlustrnentfactorfor PRT:1,0io 1.20
ptobabilityof T cruzf: 0.0000075
tq O.0oO0O25
% dsk reductlonadlustment
mir€d compan€nltEnsf.: 0.75to 0.25
PRTadiustmentfscior for FNHTR:2,99to 1.01
annualmortalityalbr annafusion:- to +25Vo
probabllityot deathIn acutET. cruzi stat€: 0,03to 0.001
dlsutilltywElghtfor FNHTR:0.02to 0.005
probabllltyot FNHTR:0,0002to 0.00067
mortalityadJustmont
tor lmmunocompromised:
1.0to 1.8
0%
40%
8%
ノ
一
″
',イ
(lmillionsrOALY)
showlng the range of values u6ed md resulto from one-way sensidvlry uallsts
abts tr rh€ P[Is-and-plMs
pulded
ftom lN
PlTs-.nd.plasma
PRT model. Eeh horizontit
to htgh or ldgh to low tn corspondonce
bu relles
the mge
wlth the left ud
PBT
We rcpott the costs and consequences of PLTs-mdplasma PRT compared to current screens and interuentions used in Canada (Table 5). When evaluated on an
all-transfu sions basis, the incremental cost-effectiveriess
of PlTs-and-plasma PRT is $1,423,000/QALY (95%.CI
apprcximauon, 834,000-2,818,000).The mean gain in
quality-adjusted life expectancy is I I minutes per patienu
even though the incremental cost is also lower, the
cost-effectivenessof PLTs-and-plasmaPRT compaJed to
cdnent screens and lntepentions is less cost.effective
than for whole blood PRT.This result is expected because
of the decreased overall risk reduction achieved using
PITs-and-plcma PRT compiled to whole blood PRT.The
pattems ofcost-effectivenessfor older md younger Eansfusion recipients ari: similar to those seen for whold blood
PRT with estimated Lost.effectivenesscif $42S,0OOiQALY
of adl@m
vdus
of the mGt lntlu€ntlal
wrl.
llsted m rhe rlght, Ruges ue
bu. QoL e quality of lue,
rlght €ndc of each horlzontal
(9590Cl approKimation, 256,000.805,000)in trmsfusion
recipients 39 yeds or.younger in age.
PLTs-and-plasma PRT sensltivlty analysls
In bne.way sensitMty analysis; the factors that are influential in the PlTs:and-plasma PRT model in order of
decreasin! influence arc monality in the year of transfu.
sion, mortality associatedwith t'?e ofblood comporents
received, the number of denor exposuresper pooled PLT
preparation, the probabiiity of death due. to sepsis, the
cost ofPRT per donaticin,and the djscoun! rate for effects
(Fig.2). We examined the sensitiviry analysisresults with
respect to donor exposures in more detail b1i evaluating
the influence of the percentage of single-donor PLT
(apheresis) collections on the cost-effectivenessof PRT
based utren the pooled PLT method is eirher bu6/ coat or
Volume 50,November201o TRANSFuS10N 2407
s1yo
_
1@yo
of PLT preparatlono fiom slngle-donor aphsGls
collectlons on tha lncremental cost-efrecti@Gs ratlo (ICER) of PUI8-md-plssma
(reens od lnterentlons.
(+)
PRT compiled to mt
Bufrycoat randm-donor
PLTs; (+)
plasma.tleJr tildom-donor
PLT!.
′′
Flg' 2. Tbmado dlsgrm
Piobabillstlc sensitivity anslysls
60%
Psrcenttge ot PLTs frdm single.donor apheresis colloctions
Flg, 3. lrlluence ofthepercentage
´′
・
／／
!
S
Z
E
F
lncromeni6l CosUE foctlvenesr
7266393
3 1各帥
Ⅲ 蘇 Ⅲ
︵
ンヨく０あ︶α”０一
T●
●l crlst rOr.υ
″ent s●
7●
●nJ":07Ven"Ons(sCAD)
e c l s u t h c u m nr l●
E“
o∞
n s nハt e r v oO nn “
s(oALY)
The cloud diagr6ms of the incremental
costsand effects,gerreratedfrom prcbal
bilistic sensitivity malysis of whole
blood PRT and PlTs-and-plasma PRT
prwide an indication of overall unsertainty, As expected, the simulauon
resuJl plots show that both the incremental cost and the incrementat effec- .
tiveness of whole blood PRT are lrigher
than for PlTs-and-plasma pRT (Fig.4).@
In addition, .the possible valueg forN,
incremental effectiveness of wholed
blood ue more uncertain thm those for
PlTs-and-plasma PRT as demonstmted
by the greater hbrizontal dispersion of
individual simulation resulB.
DISCUSSION
In this analysis, we assessedthe costeffecdveness of PXT for whole blood
focused on the dLect cost of blood
safety interventions and medical care.
0,m000 0.00oGt 0.00005 0.00m8 0,0m10 0.m013 0.00015 0.0001! 0.00@0
While such a technology is cunently
.
Incrcruntd Efioc{vgn.ss (eALy!)
unavailable, clinical studies of candidate technologies ani under way, We
Flg. 4. tnqemental coat ud effectlwness scatterplot6,from 2000 probsbiltstlc 6tmuestirnated the cost-efiectiveness of
lations for whole blood Piff compded to cuent
scEetrs ud PlTr.ud.placmq
PRT
adding whole blood PRT In Canada to
to culmt ercss. Soltd lhes repsent
comped
dre mes lnqemqtal
@Etcurent screens and intetrentions to be
€F@tlveness ntlo ud dashed llno represent the 2.5 od 97.570 wlu6 of the costRecognizing.that
$1,2?6,000/QALY.
RBC
efrectlwnG retlos hom the dlctrlbutlons ofthe slmulodons u'lth polnr forwhold
'risk
would not be mitigated by cur.
blood PRT shm
ln gray ud potnts for PlTs-ud-plsma
PXT ln blqck; llnq re ln
rently available PRT we modjfied the
reverse graysele so thFi tiey can be vlsuallzed on top of esch correspondlng cloud
model and used it to estimate the increof pohrs,
mental cost-effectiveness of adding
PlTs-and-plasma PBT generating a
result of $1,4?3,000/QALYcompared to current screens
Plasma-rich prepilation6 (Fig. 3). When no PLIS are prepared using single-donor colleciion methods, the increand interuentions. The cost-efectiveness of a PLTs-andmdnlal cost.effecti-rrenessof PlTs-and-plasma PRT is
plasma PRT was most dependent oq the PLf collection
2468 TFANSFUSIONVdume50, Novomber2010
COST-EFFECTIVENESS
OF PFI
and preparation methods used byblood centers.The most
important factors ddving better cost-effectivenessresults
are the lisk of bactedal contamination and other infections r*ulting ftom higher donor exposwes in pooled
PLls. Since Canadian blood centers collect and prepare
Plirs via single-donor apheresis or bury coat prepilaton
methods PRT technglogy will be less cost-effective in
Canada than in counl$es which primarily supply plasmarich PL'IS.
The analysesreported here with respect to the costeffecdvenessof PLTs-and-plasmaPRThave foosed on the
mix of PLT preparation methods used by Canadian Blood
Sewices. HemaQuebec, the other blood operator ln
Canada,which servesthe Provirrce of Quebec, uses a different combinatlon of preparation methods. Approximately 80% of PLTscollected by HemaQuebec are from
single-donor apheresls collections with the remainder of
PLTSproduced in 2007 being plasma-rich PUfs averaging
five donor exposures.Tbis combination of PLT preparation methods leads to a result of$1,389,000/QALY(95%CI
appmximation, 713,000-2,944,000)for.Plits-and-plasma
PRI The same percentagesofsingle-donor apheresiscollections and bufu coat-derived instead of plasma-rich
PLfs as now used by HemaQuebec would lead to a result
of $1,775,000/QA!Y (95% CI approximation, 1,021,0003,364,000)for PLts-and-plmma PRT.
On the one hand, ifPRT were to be adopted it coutd be
more cost-efective than reported here.The residua.lrisk of
Fmsfusion-uansmitted viruses of greatest concern is
alreadyvery low particularlyin Canada, due to the ef0cacy
of current screen6and intewentions, and in this analysis
we did not a$sume that any of these icreens or interyentions would be discontinued or modified. However, it is
likely that blood collection agencies would seek changes.
Interyentions tlat potentially could be eliminated include
bacteria.lculture for PLfsand gamma lrradiation. Interventions that could be modified include universal tesung for
WIW md HTLV For example with an available whole
blood PRT'discontinuattoir of testing forWNV or elimination of outbreak seasonindlvidua.l donation nucleic acid
testing (NAT)might bepossiLledue to the more than 5 logs
kill achievedusing riboflavin-based PRT,2'and discontinuation of bacterial culture of PLTSalso seems feasible for
eitber a whole blood or a Plls-and-plasma PRT.z8
Each of
these changeswouJd favorably alter the incremental cost-.
effectivenegsof PRT Avoidance of T cruzi screening also
seens likely given the obserued ability of riboflavin-based
PRTto inactivate this and other pdasites.'?s
On the other hand, ifPRT were to be adopted it cou.ld
be less cost-effectivethm reponed here. The potentia.lfor
ilireased component uEe,adverse events forblood recipients, increased treatment costs, md increased total costs
to the heajth care system could result from the use of
riboflavin-based PRT. For exmple, the formation of
neoantigens is possibl€,Basedon other PRTmethods that
do not use riboflavin as the photoactive compound, this
could be an issueforRBC units prepared from PRT-treated
whole btood.3o,Another possible concern is for PLTS
ueated with PRT where clinical studies including the
MIMCLE trial have shoM that the corrected count increment (CCD is lower for PBT-treated compared to
untreated PLTS.25
Lower CCIScould lead to increased risk
ofbleeding.
The cufent analysis does not consider other infections such ashuman paryovirus Bl9, rabesia, ortheund€fined value ofPRT in preventing transfirsion trmsmission
of un-knom or reemerging pathogens, The safety and
health edonomic benefit ofPRT in the face of m emerging
agent could be considerable. Most infectious agents
(except prions) would likely be at least partially susceptible to PRT.Weelected not to include such an agent in this
analysisbecauseit is reladvely easyto constluct the set of
6sumltions regarding th€ pathogen so that resujts create
a very attractive economic profi.lefor PRT.Adopting PRT
could be thought of as insurance against the risk of a
future large epidemic of an un-known virus, bacteria, or
parasite uansmitted to transfusion recipients, th the tace
of a prevalent emerging pathogen it.is highly likely that
whole blood PRTwouldbecomemuch more cost-efective
than PLls-and-plasmaPRT alone becauseoi rhe reduction of the threat in all blood components.
The residual risk of many infectious or noninfectious
threats is imporlant for tle cost-effectivenessof PRT,but
limited data are avbilable on objectively measured risks of
many potendal adverse events associatedwith uansfusion. For example, the mo$idity and monality of
bacteria-contminatedRBCsarc notwell defined.Quebec
hemovigilancedatarepon that bactedal contamination of
RBCs occurs with a prevalence as high as I in 36,000,,?
whereas others have estimated the risk to be approximately I in 250.000or lower-rr The frequency wirh wNch
such units result in detectable clinical morbid.ity or mortaliry afects the calculation of cost-effectiveness.In our
analysiEwe assumed that the baseline residual risk ol
bacterial contamination was t in 50,000and that 40% of
nonimmunoiompromised patients who received nonPRT-teated components containing bacteria would
develop fatal infectionsiActive capture of data via hemovigilance may provide reliable estimates,but the availabi!.
ity ofmore precisedata would improve the accuacy ofthe
analysis of infectious Jisks acloss all blood component
fypes.The importance ofcu[ent residual dsks ofin-fection.
was also exhibited in oiher sensitivity malyses. When we
reduced the dsk of bbcteria md I cruzi at the sme time.
the overall cosi-effectiveness ratio of whole blood PRT
incrdased by 47%.
Our analysisof the cost-effectivenessof whole blood
PRT h6 impo(ant li.mi(ations. To model the question of
the cost.effectivenessof PRTwe had to make severalsimplifying assumptions. ln one simplification, we msumed
Volume50, November2010 TFANSFUSION2469
CuSTER ET AL.
that $ansfusion episodesile one-dme events with exposure to one whole blood unit or its equiva.lentcomponents. This does not reflect clinical practice because
transfused patients may recdive mu.ltiple transfusions on
difierent occasions, and even in the same tarisfusion
episode patients could receive mywhere ftom I unit of
any component type to dozens of units. The model does
not account for tnnsfusion of different nmbers of components or multiple uansfusion episodes.The swival of
recipients of a large number of units in a singl e tran sfusion
episodeis signific'dn0ylowerthan recipients who receivea
smaller numberofunits.rs,rsIfwe were able to account for
thjs in our model; the cost-effectivenessratio of PBT
would be larger than reponed here.
Akey frcior relatedto blood recipients thatwe camot
addressin the ma.lyslsis the possibility that curent posttansfusion swival acrcss all component types, but particulnly for PLI recipients,maybe lower than the supiva.l
probabilities we used.'Changesin practice pattems such
as increaseduse of P[fs in patients with poor prognosis
and reduced life epectancy wordd lead to larger costetrectivenessratios. While clinicims may recognize that
current survival lates.are lower for palients who receive
specific blood components, only published longer-term
suMval data are appropriate to include in malyses of the
cost-effectjvenessof blood safety interuentjons. By necessity long.term posttransfusion swival data relies on
tansfusions that may have occured as long as 20 years
ago. Policy analysesthat rely on posrtransfusion suryival
data carinot circumvent th.islimitalron,
Anothel potential limitation is the inclusion of some
noninfectious advene events such as postoperative infectjon that might occur as a resu]t of TRIM. The debate i,s
ongoing as to whether this is a real phenomenon leading
to jdentifiable health consequences.s233Nonetleless,
assumingthai the phenomenon is iea.lthe idea thatTRIM
is influenced byWBCs ls less conuoversial. PRTwill inactivatel trBCsthat afeirot removed by leukoreduction, pre.
venting antigen presentation that could uigger recipient
inmune system respoirses.In this analysis, we assumed
that PRTmuld achievea 50%reducrionin the residuai risk
ofoccurrenceofTRIM. Moreoverre modeledpostoperative infection atributable to TRIM by assuming that the
dskreduction couldbeas lowas l% or * high as a twofold
hcrea,se.In sensitiviiy analyses,no aspect of TFIM.was
influential includingthe assumedrisk reduction achieved
using PRT.
Arother posslble limitation is that there is currcntly
only emerging clinical data to support a redriced rate of
FNHTR after the adoption of PRT.However, the mechanism for at least some FNHTRs is thought to include
residual WlCs and PRT could reduce the freouencv of
FNHTR as has been observed in clinical studies. These
benefits would be.expected in componen$ that carry
higher risks of FNHTRS:PLTSand RBCS.In the model,
2470 TBANSFUSIONVdume50, Novembsr2010
FNHTRS arc relatively high-probability and lM-cost
eventsthat desomewhat intluentlal. IfFNHTR risk reduction is excluded froin the model, for whole blood PRT the
cost-effectiveness mtio increases by approximately ZVa
(meaning PRT is less cost-efrective when FNHTRs are
excluded). However, the 7% efrect oi the ratjo shows that
FNHTRS are not overly inJluential with respect to estimated cost-effectivenss.
The PLls-md-plasma PRT model also hm imponant
additional limitations. Chief anong.them is i}lat, except
for donor exposuresassociatedwith PLTs,the model does
not account for difrerential risk trsociated with di$eren(
component types. For example, the model csigns the risk
for plasma equal to that of PLIs for rhe uansmission of
enveloped viruses such as CMV or H'[LV and for FNHTRs
risk reduction. Ifother infectioss or noninfectiou$ threats
di.ferentially partition to specifc labile blood compo.
nents, th€n the model does not fully reflect these differendal risks. However, we did account for one of rhe most
important influences on the residual risk of bacteria.l
contamination-the method of PtI prepuatlon3'-and
showed th3t the cost-effectiveness of PLTs-md-plasma
PRT vilies depending on PLI collection and preparation
methods.
Another importanr considerarion is how we modeled
the residual risk of each adverse event in the PLTs-andplasma PRT anal)sis. The infectiousness of a blood com- O\
ponent is dependent on multiple factors; these include N
the stageofdonor's inJection atthetime ofdonation [viral H
load and antibodylevels), therecipient's immune system,
and the interaction between the two,r among other factors.3s36
An additional factor for component.specific use
of PRT i$ also present and is related to the approach we
used for modifying the residual risk of uansfusion complications based on the combination of components
transfused. For persons who receive transfusions that
include both pathogen reduced and nonreduced components (RBG), the residua.l risk of an adverse event is
adjusted to reflect a blend of the lower risk in the
pathogen-reduced component coupled wirh the residual
risk of the norueduced component.
Emnomic evaluations of simild PRT processeshave
previously been reported. For example,studies ofthe costeffectiveneqsof amotosa.len-basedPRT for PLTsfomsed
on patients with specific conditions requidng transfusion, l
A study conducted in the US setting reported results for
four different latient groups (pediatlic acute lymphocytic
leukemia, hip artlroplasty, coronary artery b)?ass grafts,
and adult non-Hodgkin's lymphoma). and with and
without bacterial culture. Depending on the patient population, baseline results ranged from $4,8 to $23.0 million/
QALYwith bacterial culture snd $1.4 to $4.5 milion/QALY
without bacterial cu.lture for apheresis PIJIs.3For pooled.
PLTS;the cost-eflectivenesswas $1.0 to $6.0 miuion/QALY
under assumptions oflow faiality atdbutable to baclerial
COST・EFFECi:VENESS OF PRT
COST・EFFECTIVENESS OF PRT
less uncertainty, AII remaining model variables were
vried within specifica.llydefined ranges based on published literature or standardized methods.
Probabillstic sensitivity analysis (Monte Cdlo simulation) allows for an overall assessmentofthe uncertainty
given the range of poseible values or probability distdbu.
tion of eachvatiableused in the model. We ran 2000 computer simulations of each analysis and ob{ained an
afrprcximation of the 95% Confidence Interval (CI) for the
cost-effectiveness ratio; reprcsented by the 2.5 and the
97.5 percentiles of the distdbution of results from each
simulation.
PLTs-and-plasma PRT
We modified the whole blood model to estimate the cost
effectiveness of PRT for the technology that is curently
approved for use in some Europedt jurisdictions, PLTsmd-plasma PRT.To do so we added an additional secrion
to t}le model focused on PLI preparation metiods. As in
the whole blood model, transfusions containing PLTsare
separated from transfusions not containing PLTs; this
design also allowed us to include the PLI prepilation
method (single donor or pooled PLIs). We assumed single
donor PLIs represent 25?oof the total prepaiations and
bufly coat PLT preparations represent 75% of the total
prepilations (percentagesthat approximate the prepilations issued by CanadianBlood Services).Thebaseline risk
for PLTSin this vercion ofthe model applies to slngle donor
preparations and.a donor exposuresfactor is included to
increasethe baseline riskfor each adverse event aciordirg
to.the numbei ofdonor exposues for recipients ofpooled.
PIXs, In the PlTs-and-plasma analysis,except for bacterial
contarnination, we assumedthat therisk ofplasma was the
same asthat of?[fs and that PRTreduced those dsks to the
same degree in both products.
Fj€ept for transfusion episodes that include both
PLTsand plasma, which are included in the PLIs arm of
the model, trmsfusions that include plasma are considered in another separate um of the model. PLTs and
plasma account for approximately 25% of the components transfused in Canada'! so the effective cost of PRT
on m all uansfusions basis would be approximately 25%
of the bost ofwhole blood PRT if fixed costs are not considered, However, the risk reduction achieved for this cost
is not 25% of the overall risk because different combinations of blood components are transfused to patiehts. To
estimate the averageexpected eFectivenessof PLTs-andplasma PRTfrom the perspective ofall components transfused,,we adiusted the risk reduction achieved using
whole blood PRT.We assumedthat patients receiving RBC
only traasfusions would continue to have the same
residual rlsk with no benefit from PRT For patients
receivlng iransfusions that de exclusively PLTs and/or
plasma, representing nearly 15% ofthe transfused popu-
lation, we assumedthe riskrcductionwould be equivalent
to the overaJlrisk reduction achieved for whole blood PRT
(Table l). For the. remaining lQ% oi the uansfused
padents receiving combinauons of RBC,s,PLTs,and/or
plasma tFnsfused, we assunied half of the current dsk
would be mitigated, meanlng that the residual lisks.for
recipients ofRBCSwith PLTSand/or plasma is the average
ofthe curent residual liskand the expectedlower residual
risk obtained by the use of PRT for PLTsand plasma.
RESULTS
Whol€bloodPRT
We repon the estimated average quality-adjusred life
expectancyfor the trmsfused population overall and for
sprcific recipient age groups, th€ average healthcarerelated costsincured per donation with current intenentions, md incremental cost-effectivenessof rqhole blood
PRT ccimpared to current interyentions used in Cmada
(Table4)..For all recipienk, on avetage individuals are
expected to gain approximately 47 quality-adjusted life
minutes. ln a cohort of 100,000tlansfusion recipients this
would represent a gain of approximately I qualityadjusted life yeals. The incrementa.l cost-effectivenessof
whole blood PRT compari:d to current screensmd interventions is $1,276,000/quality-adiustedllfe-yeu (QALY
95% confidence interval [Ct] approximation 600,000Fortrmsfused padenr over40 yeils of age,the
3,313,000).
incremental cost per QALYsaved is higher, but similar to
the ovemll result given that the averageage of tmsfusion
is approximately 65 years in Cmada. However,for recipients 39 yeals of age or younger the incremental costeffectiveness is $a26,000/QALy (95% CI approximation
197,000-1,173,000).
Whole blood PFT sensttivity inalysis
One-way sensitivity analyses are shown as a tornado
diagram for the overall recipient population (Fig. 1). In
order ofdecreasing influence, the model is mdst sensitive
to the risk ofbacterial containination, arnual mortalltyin.
the year oftransfusion, dre cost.of PRT per donation, the
probability of death due to sepsis, the discount rate for
effects, did health, state quality.adiustment preference
weights for patients requiring transfusion in the years fol.
lowing transfusion. Bacterial contaminadon risk js the
most influenual vuiable and a low dsk for bacteria
(1:100,000) leads to a cost-effectiveness of nearly ,
The lmpact of posttransfusionmoilality
$2,200,000/QALY.
in the year oftransfusion is shown in the second horizontal bd of the figure. Low amual monalitywould lead to il
incremental cost-effectiveness of whole blood PRT of
$850,000/QALYwhereashigh amual mortalitywould lead
to an incremental cost-effectivenessof whole blood PRT
of$l,550,000iQALY.
Volume50, Nov€mber2010 YRANSFUSION2465
contamination and improved to $460,000to $i.8 miluon/
QAIy assuDing bigher fatalily due to bacterial contamination, Similar analyses for specific patient populations
were conducted for Belgium, the Netherlands, and
Iapan.'6 Arother study from the Netherlands found the
cost-;ffectivenessofPRT for PUls to be 92,8million/QAIY
(approx. $3.6 millionlQAlY) when added to bacterial
culture and €382,000/QALY(-$497,000/QALY) without
bacterial cultw in rmdom-donor PLfs for the average
recipient.eThe maiority of these results suggest a costeffectivenessof PBT.that'is less efncient than we report
here. These pleviorxi aiialyses did not include the broad
range of infectious ild specinc noninJectious tfueats that
were included in our analysis. In addition, many other
analy$isassumptioDsrlveredifferenL maklng direct comparison of our results to these studies dif$crdt. Nonetheless, one common thread is apparent: bacterial
contamination is the most impdrtant knom adverse
event that PRT addresses.
Our xesults also indicate drat the age of the patient
popu.lation is an important determinmt of the costeffectivenessof PRT, In the previously published costeffectiv€nessstudies ofPRT for PLTS,the best incremental
cost-effectivenessratio was a.lwaysevident for the pediat. .
ric population.3{ We conducted our analysesfocused on
different age groups to show that there ae subgroups of
uansfused patients where PRT has a relatively atuactive
econoiric proflle. Thgse analysesare intended to indicate
that for rhe expected benefrts to accnre to subgroups of
patients, it may be necessaryto adopt PRT for all blood
collections.Only ifseparate b[ood supply inventories were
kept codd recipient:specific use ofPRT be an qption. The
copplexity ofmaintaining separateinventories on such a
large scale has not been carcfully studied, but in many
setdngsis likely not feasible.
Model var.iablesrelated to the age and heajth statusof
the uansfused population had important inJlu€nce on
cost-effectivenessresults, ln addition. the discount rate
for effdctswas influential. Discount ntes reflect time preferencefor health and money, with higherpreference given
1o havlng health and money today as opposed to in the
future. These model vuiables are not directlv related to
PRT and are often influential in anallses oi any blood
safety lntewention. Moreovet the influence of life expectancy, quality oflife, and discount rates is applicable to all
cost-effectivenessanalysesregardlessof medical practice
area. Both appropriately accounting for quility-adjusted
life expectancyacrossbroad population grcups and determining what discount rates lo use are uroesolved methodologic controversies in health economics. While the
influence of these variables in the analysis is evident,
whether these varlabl€s have meaning with respect to
decision maling about PRT adopdon is unclear
Relative to the cost.eflectiveness of interventions
aheadliin use in Canadaand many other developedcoun-
tdes, $uch as minjpool HIV and HCV NAT, which exceed
the estimated
$1.5 miUion/QALY in the United States,3'.3o
preadbption cost-effectivenessofwhole blood PRT and of
PlTs-and:plasma PRT is consistent with established
thresholds for ra.lue in blood safery In developed counuies that have very low risk ofuansfusion transmission of
infectious diseases,wen if some curent screensor interventions re discontinued oi.modified, it is unlikely that
any PRT tvill approach an incremental cost-effectiveness
ratjo:threshold of $100,000/QAIY ;qJthoughexpensive on
a cost-per-QALY basis in comparison to interuentions
adopted in other sectorsofhealth care,given blood Safety.
expeitations that lean toward f'zero rjsk" for infectious
thats; commonly accepted thresholds that are regarded
as cost-effectivein clinicaj practice do not seem relevant.
There continue tobe multiple difrelenthsards associated
with transfusion including thosg considered in thls analysis and other ones not amenable to the use ofPBT such as
trmsfusion-related aote lung injury ahd transfusion of
the wrongblood type. TNs cost-efrectivenessmalysis provides additional information that was.not previously avai!
able and may help to support decisions regarding thls
technologywithin the context of competing interyentions
and other threats to the safety oftransfusion.
coNFLtcToF TNTEREST
o
This resealchwassupportedby an srestricted grmt ftom cd- fv.)
idianBcT (Lakeland,CO)..CaidianBcl proridJd no editorlal H
controlovei the resealchor the manuscript.
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Klein HC, Anderson D, pemardi MJ, Cable R, Carey W
Hoch IS, Robitajlle N, SiviloItj M!, Sm€iI F. Pafiogen
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2007;47:
2338-47.
2. Kiein HC, Anderson D, Bemardl Mt, Cable R, Carey W
Hoch ,S, Robitaiue N, Sivtlottt ML, Smaill F. Pathogen
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preliminuy
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3, Bell cE, Bottemu
Pashos CL, Tdulzi D, Sraginnus U. Cost-efectiveness of
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Moeremans K, Wdie H, Annemans L. Assessment of the
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5. Postma Mt, vatr Hulst M, DeWolf fI, Botteman M, Staginnus U. Cosl.etrecilvenees of pathogcn inactivation for
platelet tlansfusions in the Netherlands. Transfus Med
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Volume 50, November 2010
TRANSFUSION
2471
CuSTER ET AL.
COST・EFFECT'VENESS OF PRT
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Volum●50,November2011 TRANSFuS:ON 2473
わが国における感染性因子低減化技術により生じる使益
について (要約)
東京医科歯科大学大学院
‐
医歯学総合研究料環境社会医歯学系専攻
医療政策学講座政策料学分野
河原和夫
‐
方法
￨
`
輸血用血液製剤に感染性因字低減化工程を加えた時にいかなる費用便益を生じるがにつ
術が確立し、い
血血製剤ヤ
剤を含●すがて
￨
P,小 f製
?摯「準
1技
FI愚発警懲SIPイ
,経済計算は、疾病や障害を有する者の生存期間を無価値的に提えたり結果が感覚として
わかりにくい QAIⅣ(QualityAdJusted LIfe
Yё
ar)で
はなく、
具体的な金額により便益を算定
した.
保管検体で陽性が確認された過去約 10年間の感染性因子の件数から1年当たりの予想さ
れる感染事例を算定し、感染が成立した場合の予後の推移等をもとに「
直接医療費」「
休業
損失」および「
早世による遺失利益」を求めることにより便蓋を算定した。HBV、 HCV、
HIV、細菌感染、とトパルボウイルスB19、HEVが対象感染性因子である。
考察
￨
:
わが国では HBV感染者が多いが、これは「
直接医療費」と「
体業損失」の大半が HB▼
を原因としていることにも表れている。成人のHBV感染の場合、慢性化しにくいことから
1年目の医療費等の出費が増大するが、
以後ほとんど影響を及ぼさない。HCVについては、
慢性化する割合が高いものの、IIBVに比べると絶対数が少ないことiし
ょり、同様に経済的
影響は少ないものとなった。HIVにっいても同様である。他の感染性因子による感染が考
えられる事例にっいても数が少なく慢性化しないものが多いことから便益は小額になつた
ものと考えられる。
まとめ
本稿では新興。再興感染症の流行の問題を考慮していない。しヽ
かなる感染症まで対象を
広げて経済計算を行うがきか、そして血液の検査や製造工程にどの程度の経済資源を投入
す人きかについても議論が必要であろう。
ＮＯＨ
結果
平均的動労者 (平均年齢 411歳、年収 2945千円)をモデルとすると感染性因子低減化
「
技術の導入により肖1減できる年間の「
直接医療費」は 24,298,786 Fl、
体業損失」,ま420,150
早世による遺失利益」は 1,088,669円
となり、合計 25,8521698円
が
円となつたょカロえて「
便益となる。
￨
わが国における感染性因子低減化技術により生じる便益について
はじめとする新技術の導入は一般に高コストとなるものである:
そこで、輸血用血液製斉Jに感染性因子低減化工程を加えた時にいかなる便益を生じるか
を調べた。但し、感染性因子低減化技術が確立してぃる血小板製剤以外の製剤も含むすべ
ての輸血用血液製剤による感染を想定した。
東京医科歯科大学大学院
医歯学総合研究科環境社会医歯学系専攻
医療政策学講座政策科学分野
:
、
どで身体が不自由になつ■場合の生存期間を健常人が 1年生きる価値があぅのを 03QA∬
に補正するなど障害の重み付けに主観が入ることや、疾病や障害を有する者の生存期間を
無価値的に捉える問題があるもカロえて結果が感覚としてわかりにくいことから、本稿では
河原和夫
緒言
:
なお、弩済計算を行つている多くの論文では、生活の質 (QOL)で重みづけを行い生存
fe“ar)を求ゅでいる。レ
ust,dL■
期FF5に
″￨え`牛活の質の評価もできるQttLY(QualityAф
かし、QALYぼ健康な人が 1年生きた場合の生存期間を lQALYとするのに対し、脳卒中な
'
￨
,
多くの方が直観的にイメ‐ジしやすぃょぅに具体的な金額により便益を算定する方法を採
高齢化に￨よリョ騰すo医辱費をいかにfrp制
するo)が、政●の主たる政策的謀題であるが、
医療技術あ進歩も医療費を高しさせる要因の 1っである。
￨
￨
用した。
現代の医療技術は、超音波、CT、IIRI、PETなどあ診断治療技術と人工呼吸器、人ェ臓
器(経静脈栄養、ICUなどの延命的技術が主体となつている:対象疾患も長期・慢性の経
過を示す生活習慣病である。治療期間が長いうえ:基盤は光学技術や電子工学などの最先
方法
「
i
査や血液製剤の製造技術も同様に高度かつ高価な技術基盤に基づくものである。N_ATやウ
医療費出費、外来や入院にともなう休業損失、早期死亡による遺失利益を減少させるとい
イルス等め感染性因子低減化技術もこうした技術に属する。しかも、旧来の検査 ,製造技
ぅ社会経済効果をもたらすものと考えられる。
術を併存しながら最新技術を付力日しているのである。
血■分画製剤の不活化は技術としてシステムとし`確ユしている,論ネ年、輸血用ユ液
製剤への感染性因子低減化技術の導入である。
検査技術としての NATは、血液中のウイルスを高精度で検出する技術であり、血液製斉J
の信頼性の向上に大きく寄与している。しかし、費用便益面から考えると問題を有してい
る。NATという大規模技術の導入に当たっては医学面のみではなく経済的観点からの検討
ならびに導入後の多角的評価が必要であらた。しかし、それは十分にはなされてこなから
た。感染性甲子低減化技術も費用便益的観点なら,分析・評仰が分とは言
。￨う
4な !ヽ
す
した大規模技術は社会経済的インパクトが大きいにもかかわらず、医学的観点からの論議
のみが先行し、そのほかの各分野の専門家、国民、行政、関係者を変えた議論の展開や合
意の形成が欠落しているのである。
本稿は、感染性因子低減化技術などの最新技術を導入することが、医療ゃ社会にどのよ
うなインパクトをもたらし、導入した技術をシステムとして維持していくために検討を要
する課題の二部を整理したものである。
￨
輸血用血液製斉1の安全性確保のために潤診の強化や NATが行われている。また、血漿分
画製剤には不活化が製造工程で加えられ、安全性を飛躍的に向上させている。現在、これ
に加えて輸血用血液製斉Jに対しても不活化を行うべく議論が進んでいる。しかし、NATを
自未赤十宇社には輸血後感染症情報が医療機関等力ヽ
ら奇せられ、保管検体をもとに原菌
ウイルスか否か同定することになる。これら報告のうち、検体陽性が確認された件数をも
i鳳
こ
替
lご
:お
こ
ど
桑
勇
1訴
ど
軍
[,1婚
hi鶴昼
昴
葉
靴I亀
ど
埋
重
iで
:低
:る
を導入し■場合)被宣を防ぐことができ、のとして社会的な観点から「
直接医療費」「
体
.「による遺失利益
業損失Jおよび早世
」の計算を行った。具体的には、①感染により各段
"、
階に病態が進行した際の'直接医療費 ②外来や入院に費やす時間に起因する1休業損失∵
、
"を
そして③期待寿命を待たずして死亡し￨“ 早世に事る遺失利益
社会的ョ挙卜として算
定した。
.
´
HBVにっいては急性肝炎のステージで病態が終息するとし、
HCVについては慢性肝炎、
へ
モ
デルをもとに算出し
た。
肝硬変、肝細胞がんの移行確率をMarkOv連鎖
Vに
らいて
こと
から
10年間においては死
軍
.(算定する今後
は予後が近年著しく向上した
亡がなく、定常的な状態にあるものとした。なお、これらウイルスの陽性血液を輸血され
た場合、必ず感染が成立するものとした。
また、2008年 8月より新 NATシステム (抽出・検出機器 cobas s401 試
薬TaqScreen
ルF HBv)HCVヽ HIVヤF関する構が行われていぅ:そ
MPX)IFI,707ニ
草
￨´ 1の
NバTの検出感度と現在のそれとの差を無視するが、2000年 ∼2010年 7月までの約 10年
ｍｍ出
端の技術で、しかも開発途上にあるため短期のサイクルで更新されていくものである。検
'
1. NATを行つているHBV、 HCVおよび Hrvについて
輸血用血液製斉Jの製造の際に感染性因子低減化工程を導入することはヽNATの検出感度
以下めHBVt iCVおよび HIvの混入による患者への感染を防ぎ得たことによる不必要な
０００＾ら１
﹁
００為．
＾鳥０
26oo年 ∼2010年 71月までの報告数
００ λ ん００
ズ猛
ウイ,′
０乃為０００
表 1 検体陽性数をもとに算定した年間感染件数
Й ２００００
Ｐ
￨
ん０００００
つた。これを年開発生数で表すと下記のようになる優=D。計算は、年間発生件数を用い
て行った。
〓
一
余の間に献血が原因と考えられる輸血後感染症は、HBV 95例、HCV 3例、HIV l例であ
1年間報告件数￨
HBV
898
HCV
HIV
1
(1)HCV感染の Mar■c7連鎖モデル
￨
HCV感染後の患者は、急性肝炎→ キャリア■■慢性肝炎→肝硬変→肝細胞癌という自然
推移をとることが多いが、必ずしもそのょうな推移をとるわけではなく、中には慢性肝炎
から肝硬変を経ずに肝細胸癌を罹患するという症例も見られる。また、肝硬変の症例は肝
細胞癌を合併する前に死亡する例も見られることから、この推移は一義的ではない。この
ような疾患の自然推移をモデリングするために HCV感染者の予後デ‐夕[1]、E2]、[3]、
:すi青目の本態から j番目の状普に推移する確率 (推移確 )を意味すぅ。
￨￨でヽp・
警
点に慢性肝炎を発症する確子を示していぅ。 ■の推移行
例えば、p23はキヤリアーが次の時′
チるもの治綺することはな:く角成分よりもヽ9攀確素が全て 0六
、患
￨の
`対
鷲
′IFは琴 1進行
を仮定して、ヽる。
各時点で林鶏が推移すぅ確率が時点によらず一定であぅことヽ
・
上記のァルコフ連鎖モデルによ 't時 `点iにおiするそれぞれの状態の人数は、現を初期
レ,7連鎖モデルにおけ
状撃の本数￨レたとき、 Li三ル,_lP=LOP′で表すことができ、マィ
のよ
る推移行列を下記
うに定めることができる[11。
たとえば、1年単位の推移行列を下記のように推定すると、
0:00052
0
0
0
0
0977
0023
0
0
Markov連鎖は別名 Markov過程とも呼ばれる確率過程のことである。すなわち、未来の
0
0
0957
挙動が現在の値だけで決定され、過去の挙動と無関係であるという性質を持つ確率過程で
0
0
0
0923
0
0
0
0
0697
0
.0
0
0
ある。例えば、ある慢性肝^例が肝硬変を発症する確率が、その症例がどのよラに (例え
ばどの時点で)HCVに感染したかと無関係であるとき、この確率過程は MarkOV性を有す
るという。
上記は数式により以下のように表すことができる。時点 iにおける集団の状態を、
003
0
0
¶ ｍ一
酬
99948
E4]をもとに Markov連鎖モデノ
ンを用いて、NAT後 10年間の遷移確率を計算1/、それぞれ
の状態において要する医療費を当てはめた。
0
0013
0
0,043
0,034
0303
1
'こあ推行列に対して、初
したとき、年次の条件
期ネ件をL。子0 0 0 0 0 0)と
移
の推移は表 9、 10の通りであぅ。ご?LIこ夕時′
態
、将来
の各病
の
数
￨で
本を代^すれ￨ゴ
における HCVの自然経過をモデル化できる。
l
S,=61,2■
3 ■4 ■5 ■6 ) . 、
2.輸血後副作用颯告があったその他の感染症
とする。ここでベクトルの要素は疾患の推移 (HCV非感染、キャリアー、慢十
日千炎、肝硬変、
肝細胞癌、死亡)にそれぞれ対応する。次に、時点 1におけるそれぞれの状態の人数を、
L′
=014243444546)
.
とする。時点の経過とともに、ベクトルの各要素である各状態の人数は変動する。マルコ
フ連鎖モデルでは、この変動を推移確率行列という行列で確率的に規定する。
,
`
日本赤十字社に報告があったその他の感染症として以下あヽのがある (表2)。
1についても年間肇生件数もとに、「
直接療費J「挙業堺本」ゃよび「
早世￨こ
年
￨￨:ら
「
i但し、「
レボウイルネB19」「
ヒトパィ
よる遺失利益」の計算を行らた。
細菌」「
HEV」による
感染は慢性化することなく、急性期で終息するものとした。
表 2 輸血後副作用報告があったその他の感染症
￨
(製
剤陽性例
1998∼ 20074F)
凛譜件数
糸田磋
百
感染者数/年
08(うち死亡が 02)
梅毒
0
HTLV・ 1
0
ヒトパルボウイルス B19
HEV
結果
:
1.直接医療費
ー
HBV、事CV、 HIVおよびζの■の感響症の医療費は「
?005年疾昼別医療費デタ」(津
谷、2007年 )により算定した。その結果を表 3(4、 5に示している。
平均在踪日数およゞ平均外本日数1ま
患煮調査をもとに算定ぃ `?結果1主麓ュL■ =旦
に示すとおりである。
さらにMarkリモデルによる耳cVの各病態今の遷移確率と予想される人夕を表 9、lo
に示している。
￨
とに計算すると
10年
後
直接医療費」it麦11に示すょうに
間の「
、今
￨れりをヽ
5
仮定としては、感染性因子低減化工程を取り入れた場合と取り入れなかった場合を比較
して、取り入れなかつた場合に 1年間に血液製斉Jを輸血され感染が成立した患者群を 10年
間追跡した場合の「
直接医療費」「
休業損失」および「
早世による遺失利益」の総コストを
1こ
算定し、れを使益とした。
また、計算の対象とした年齢は、わが国の標準的な動労者とした。当該年齢の平均賃金
の厚生労働省の「
社会辱療診療行為統計Jを用いて算定した。
￨
■者調査」、「
「
早世による遺失利益」については、死亡した時点から65歳 (収入が得られる何らかの
職業に従事している上限年齢を66歳に設定)までのFR5の
残奈年数を求め、昨今の経済情勢
をカロ
味して賃金上昇はこの期間ないものとして算定した。
表3 肝疾患の年間医療費 (津谷 2∞7年)
―
766,237
3,748.163
15,168,287
円
,￨り
4う【
17,310,343
慢性肝炎
2,952,795
ll■
破変
2,080,998
3,757,797
肝細胞がん
表4, HⅣ の年間医療費 (津谷 2007年 )
11‐11
賜
法を採用し、現在価値に置き換えた。ホ7● シ法については通常法定利.息(割引率)5%を
用いるところヽ昨今の情勢に鑑み 3%として計算した (注 :参照)。
狭
:円
14,900,000
表0 その他の感染症 (細菌、ヒトパルボウイルス B19おょびヨビリの年間医療費
)麟
2007年 )
.
注)ホフマン法
`
lやI入院:‐
Σ A/(1+nr)￨
n■ 1
円￨
6,770,602
細菌感染
X:現在価格 (手取額)
A:将来得ることが可能な利益
n :利益が生じるまでの期間
r:禾U率 (割引率)3% (法
4,276,679
急性肝炎
これら3うの因子の今後 10年間の値は、民事事件で損害額の算定に用いられるホフマン
X〒
円
魯性肝炎
慢性肝炎
肝硬変
肝細胞がん
`
‐
定利率である5%は昨今の経済状況から用いなかつた。)
具体bll)
X =2,945,00γ(1+OX0103)+2,945,000/(1+1ィ
o o3)
+2,945,000/(1+2X003)+ ・・・・・
ヒトパルボウイルス B19
1,4431080
HEV
4276679
=外来￨
細菌感染
ヒトパルボウイルスB19
HEV
1円￨
1,341,824
6,019,502
17310343
崎ｍ［
は、男女計 2945千円(平均年齢は 411歳 )であらた。
,
I
「
休業損失」については、入院の場合 1日、外菜通院の場合 05日の損失があらたものと
仮定した。
2005年疾患別医療費データ」(津容 2007年 )、平成 20年
.「直接医療費」につぃては、「
242,987,846円
となり、1年当た224,298,785円
となる。 .
細菌感染については、「
その他の感染症および寄生虫症」
、ヒトパルボウイルスB19に
ついては「
皮膚及び粘膜の病変を伴うその他のウイルス疾患」
童EvについてはHⅣ 、
、
HCVと同様に「
ウイルス肝炎」の金額を用いた。
￨
HEV感染については、重症化することなく急性肝炎で終焉したと仮定した。
表 6 肝疾患の平均在院日数および平均外来日数
鳩
日
急性肝炎
量性肝炎
355
肝硬変
224
肝細胞がん
外来
肝硬変
3617
500
440
″千糸田胞がん
380
急性肝炎
慢性肝炎
表 7 HIVの
平均在院日数および平均外来日数
∞
紡
日
細菌感染
ヒトパルボウイルス B19
HEV
`夕
￨151こ
細菌感染
ヒトノ'レボウイルス B19
233
．
．
∞崎ヾＨい∞ ”⇔ ︼
表 8 入院および外来期間
りＣ００黙製Ｄ
外
HEV
ゅ
m
H
卿
2.樹
失
今後 10年間の体業損失総計は、4,201,504円で 1年当たり420,150円となる。数が多い
HBVによる損失が、この過半 (2,751,410円)を占めていた。
下するものと思われる。一方、今回の計算では「
感染性因子低減化技術」を 1年間実施し
た場合のHCVの予後について 10年間のみしか考慮しなかった。HCVの自然史経過は全体
で30年間程度に及ぶことから、
厳密には30年間の経済計算を行う必要があうたと考える。
｀
しかし、30年間の計算を行ちたとしても、もともとの感染予想者の数値が小さし
ためその
増分は僅かであり、結果にはほとんど影響を及ぼさないことと思われる。
3。早世による遺失利益
‐
過去に死亡例があつたり、死亡を想定したものとして細菌感染とHCVがあるが、これら
の結果を表 12に示す。
図 1 都内の輸血状況
1
都
内の輸血状況
1年代別輸血状況(平成21年1月∼12月) ￨‐
HCVに
よる遺失利益総計
0∼0量
21ヽ
10∼ 10歳
￨
2 0 ∼2 9 歳
3 0 ∼3 9 歳
歳
９
４
”競
4.便益
´
:
以上より、不活化技術導入により得られる 1年当たりの「
直接医療費」「
休業損失」「早
世による遺失利益」を併せた便益は、25.852.698円となる￨ (表13)。
腱 13 .不
活イヒ技術導入によ
目
傾本 (円)
243488785
4201504
101886690
258.526.979
25.852.698
´
考察￨
わが国では HBV感染者が多いが、これは「
直接医療費」と「
体業損失」の大半が HBV
を原因としていることにも表れている。成人の HBV感染の場合、その約 98%が急性肝炎で
推移し、ほとんど慢性化しないことから 1年目の医療費等の出費が増大するが、以後ほと
んど影響を及ぼさない。但し、近年の海外に起源を持つ HBVは慢性化すると言われている
がここでは考慮しなかった。
￨
HCVについては、慢性化する害J合が高いものの、HBVに比人ると数が少ないことによ
り、同様に経済的影響は少ないものとなつている。￨
HIVについてもHBV及び HCVに比して感染者自体が少ないことから、経済的影響は同
様に少ないものと考えられる。
休業損失や遺失利益は就業者を対象にしたものであり、今回は勤労者の平均年齢を用い
て便蓋を算定した:東京都あ調査によると、輸血を受けている者の平均年齢は 646歳と推
計されることから、この平均年齢を用いると「
体業損失」と「
遺失利益」はほとんど生じ
ないことになる。加えて原疾患の予後が不明であるが、健常人の生存曲線より減衰率が高
いものと考えられる (図1)。したがつて、これらのことを却味すると実際の便益は算定し
たものより少ないものと思われる。力日えて今回の計算では、輸血によらない原疾患による
輸血後の死亡のデータがないため計算できなかったが、これらを考慮すれば,層便益は低
東京都輸血状況調査より
l」暑
TML翻
の
薇
懺酉肇
島雉五
鱚炉
馨
ぼ
雪
穏
馨
麗
燃
槽
。
級中央値に年齢が集中していると仮定して、輸血を受けた者の平均年齢を求めると
646歳と推計される。
1
1
まとめ
晨 1ゴ去、たっぃて111集糟で宗した便基11較しそ峯論する必墓:':;。 N鳥
はウイ′
レスを検出することに主眼を置いているが、ウイルス等の病原微生物そのものの不
餞こ
済
lど
fF'層
斎
了
翼
野
墨
轟
ξ
聾
電
昇
す写
蠍
欄
Lヾ
ア
錨
賃
ξ
また、本稿では新興。再興感染症の流行の問題を考慮していない`いかなる感染症まで
対象を広げて経済計算を行うべきか、そして血液の検査や製造ェ程にどの程度の経済資源
を投入す人さかについても議論￨｀
必要であろう。.
:
:
参考文献
: 、
11〕 KenJi I■eda、 SatOshi Saitoh、 Iも ad Koida、 LsuJi Arase、
Ak■ hito Tsub6ta、
Kaをutt Chayama、
o Kttwahishi A Muitivariate
Httomitsu Kumada and Masahむ
Analysぉゞ Risk FactOrs for Hepatocenular carcttOgencsis: A Prospect市
e
卜ｍＨ
爾
直接医療費総計
休業損失総計
遺失利益総計
総合計 (今後 10年間)
総合計 (1年当たり)
Observatlon of 795 Padents with VLal and Alc¨
ohC Cirr)。sis HepatO10g,こ
」uly:47‐
53
[2〕 Yuli Kato、Keisuke Nakata、不 attuhisa Omagari、 RyuJi Furukawa、 Yukio
Kusamoto、 Iwao MOri、 Heiichiro TaJha、 HaJme Tanlokat MichitamiYano and
s h i g e n O b u N a g a t a 1 0 R i s k o f H e p a t o c e n u l a r c a r c m O m a h r hP oa st i se n t s w i t h C む
in JapanI Cancё
r、 15(74112234‐
2 238、 1994:
:3〕KEN」 IIKEDA、 SATOSHI SAITOH、 ISAO KOIDA、 YASUJI ARASE、 ′口αHITO
TSUBOTA、 KAZUAKI CHAヽ LttVIA、
HIROMITSU KUIIADA AND 1/1ASAHIRO
Ъ
bξ
:[:規
漁講』
境ilttth犠
::l]::::l:l::優
mttlstilIII::[i驚
C士rhoSis:Hepatolbgyt July:47‐
53、19931
41 高瀬幸次郎、中野赳、為田靭彦、小坂義種.C型慢性肝炎の予後に関連する因子の解
〔
‐,析 :日本臨床、53:662・
666、 1995
,
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素熟、
lΨ熙就「猟勝獄∬
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standard plasma Transfuslon(
39:479・ 487、 1999
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表現上、不快の念を抱か,る部分が●るかもしれませんが、「
何卒c 4解のほどよろしくお願いいたします。
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献血した血液について、梅毒、HBV(B型
トTリンパ球向性ウイルスー1型 )等の検査が行われること
(エイズウイルス).HTLV-1(ヒ
を了解し、献血します。
署名
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年月日
品
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献血される方は、「はいい tヽえ」欄の該当する方に日■ また{よ=■ 印をご記入
願います。
それ以外の欄には、問診を行う者が、必要事項を記入いたします。
採血
センター
111 :占￨
まで i藪あCt拓ぶiこ該当することがありますか。
0イツフェルトヤコカ高くC」 D)または類縁疾患と診断さねた。
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この予ラシをよくお読みいただき、内容を了承されたうえで、献血受付にお進みください。
anttただく
前に、
ています。(結果は詢血御ケ月以内に親屁にてお届llし
書す)
検査結果通知のご希望の有無をおHttし
Mお願い:5
( 1 ) お知らせしている検査項目
●血液型検査、生イヒ学検査 0血
踪針蠍検査
C2)検査で異常を認めた場合にお知らせする項目
肝
￨:癬郡
献血していただいた血液は、輸血や分画製剤性して患者さんの治療に用いられます。
患者さんが安心して輸血を受けられるように安全な献血をお願いします。
￨￨
より安全な輸血医療のために
薫‐
Ⅲ 肝氣`=主“饉葉"により育い世“に感染が拡がっています
エイ
ズウィルス(HⅣ)ゃ肝炎ゥィルス(IIBV、
との性交渉や、
注射器を共用し
HCV)を
保有してい7.人
0渡航歴について
・海外から帰口 (入国)して相間以内の方
、
・昭和55年 (1980年)以降=ヨーロッパ・サウジアラビアに
一定期間滞在された方 (目名・期間等は受付におたずねくだきい)
エイズや肝炎のウイル不に聾染する恐れがあります。
麻藁などを使用した場合に、
献血いただけません。
下記はいずれもこれらの危険性が高い行為です。過去 6ヵ月以内に該当する場合 !よ
(a)不特定の具性または新たな興性との性的接触 (c)麻楽、
■せい相を使用した
(b)男性 ω方 :男性との性的機触
(`,C,∼ (c,饉当者との性的接傲
・‐
・
集饉・
ダい
‐
0この3日間に出血を伴う歯科治僚 (抜歯・歯石除去等)を受けられた方
工存Cイルスや肝炎ウイルスの感染初期には、強い感染力を持つにも力ヽわらず、最も鋭敏な検査方法
を用いても検出できない期間があり討。
￨
0輸血や臓器の移植を受けたことがある方
0ヒト出来プラセンタ注射薬を使用したことがある方
二七珀麟葦漁燿出た■■￨=■￨■ ￨■li‐
:
‐
0エイズ感葉が不安で,エイズ検査を豊けるための芳
エイズ検査をご希望の方は最寄りの保健所にお「
. 5 合せください課健所 0 まエイズ検査を鷹名、
‐ 「
(臨鰯I嶽席磐慇:1躍響 :麒
・…
1‐
・な
0この6ヵ月以内に下記に該当することがある方
・不特定の異性または新たな異性との性的接触があった
・男性どうしの性的接触があつた
。麻薬、=覚せい剤を使用した
いるとわからた■合はご連絡ください.
歓血後、健康診断や医療機関などで B型・C型肝炎の疑いがあると診断された場合等には、
嵐液センターまでご連絡くださしヽ (又は主治医に献彙した旨をお伝えください)
・
黎■1■
コけ￨●
11■
■ ■■ .￨
‐
￨
0梅毒,o型肝炎,マラリア・シヤーガス病詢にかかったことがぁる方
￨
D瀬
海驚鶴驚難器鑓群認そ
産裁警"°摯rす￨
・輸血を受けられた患者さんについて、感染症などの報告があつた場合、輸血医療の安全性向上と
献血された方ご自身の健康管理のため、検査用ュ液の採血を再度お願￨・
する場合がありまち
・献血された方に「
輸血を受けられる患者さんのために」という印刷物をお渡しします。
楽上記に腋当されない方でもヽ検診医の判断で像血を
ご選慮していただくことがあります。
これをよくお読みになって、思い当たる場合は、必ず献血当日中に血液センターヘお電話ください。
※ 医薬品を組用されている方1ま:必ず検診医にお申し出ください。
献血,F際して取得した皆様の個人情報は、血液センターにおいて厳重に管理されます。
+蟻
以下の内容をよくお読みになり、ご了承のうえ、献血申込書 (診療録)に _ E入ください。
:摯
n前に
￨
献血後は、
本分の補給と休憩 (少なくともlo分以上)をおとりくだoい。
電車でお帰りの際、
転落防正のため駅のホームでは線路の近くで電車を待たないでく
(気分不良、失神などはじうと立っていう時に発生しやすいといわれています)
‐
■ お名前、生年月日、CL所、電話番号等は正確にお書きください。
のため、運転免許証などの示をぉ願ルる
:■ ,とがあります。
甲 r本人 ,確認
警
。
ださ
●￨
「"参影質問にぃ正確にゃ奮えく
￨ :
,
￨
瑾一
献血後あ直ご砺￨
く献血当日は次のようなことをお願いいたします >
:
■プライ′,7■は巌守いたします.
■献血後に高所作業や激しいスポーツ、自動車の運転等をされる方は献血前にお知らせください。￨
以上)を取つていただく必要があります
特に乗り物の運転をされる方は、献血後に十分な休憩 (311分
■副作用予防のため、
献血前に水分(スポーツい,ンタ等)を補綸してください。
水術0補館1
1細颯ま :
かります。
H20∞ 工 4∞ mL献五では lo分から15分位、成分献血 Clよ“ 分から∞ 分位の採血時閣力勁ヽ
■ 血圧や ■色素量 (ベモグロピン濃 ■ )を事前に測定します。
ジュース(スポー'ドリンタ)、
お茶などで十分補給してください
■ 採血針は、一人ずつ使い 40てとなっています。
1聾
■■作用と注意
.
日採血に伴う副作用が生じることがあります。
採血中や採血後に、気分不良、吐き気、めましヽ
、失神などが約0.9%(1/100人 )の頻度で発症し、
ことによう皮下出lllが
まれに失神に伴う転●llが
発生することがあります。また、針をXllす
) の剣贅で発生します`:
)、神経損傷 (脱力や痛み)が細 01%(1/10,000人
約02%(1/5011人
口絆鳳針を刺した箇所 ■針跡力竣ることがあ 2ます。
口
」
と
塘詈
￨:猛
響
を
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島
拿
織
、
温
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直ち
断護
,捏
會た
Tに
露:警
日採血中に気分不良やめまいを起こした場合は、直ちに職員にお知らせください,また、採血後に
同様の症状を起こした場合は転例を防止するために、すぐl=しゃがむか横になってください。
・
入浴 … 2時間以内の入浴と当日のサウナは避けてください
・
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スボ ‐ ツ :水泳、マラシンなど激ししヽ
・
重労働一採血側の腕に強い力がかからないようにお願いします
日献血によって健康被告が生した場合に医療費等を補償する献血者健康被告救済制度が設けられています。
詳しくは血液センター職員にお尋ねください。
献=｀
しそいただぃた血液は
■ 献血血液は(医療機暉で血波を必要とする患者さんのもと、届けられ￨すが、以下のように
有効利用させていただくことがあります。
・la液型や輸血副作用の検査・研究のため、薫血球型t白血球型、血小板型及び血漿蛋百の
遺伝子検査を実施する場合があります.
￨なお、その他の遺伝子検査をご本人の承諾を行すに行うことはありません。
ヽ
緊張感の強し
場合やその日の体調にようでは、
採血の数時間後、まれに気分が悪0つたりめまいがすることが
あります。
そのような場合はすぐにしゃがむか、横になつてく
ださい。
通常は頭を低くしてЮ分程度安静にするだけで軽快します。
また、
採血後の腕の痛みなど何かご心配なとき￨ま、
すぐに菫液センタ=までご出肩ください。
・血液製剤の品質管理や綸血用の検査試藻製造のために使用することがあります。
・輸血の有用仏安全性及び検査サービスの向上を目的とした研究のために血液を使用することが
ありま丸
○○○赤十宇血液センター ()∝X‐Ю∝ =XЮ∝)
: 口次の検査を実施し、血液製剤の基率に適さないと判断した場合は総こに使用しません。
. 移
イ'森｀
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動採 Ⅲ 車の運行予定や献血ルームのご案内な出まホ■ ムベーラでもご覧いた● ナます。
wW“ QOOO OOO)
(http:〃
ます。
口血液の一部は少なくとも11年間冷凍保存し、輸血副作IH・感染症などの調査のために使jTlし
日献血血波が採血装置等の不具合・
不良により輸血に使用できなくなることがあります￨
140
OO赤十字献血センター m XXκ 継
004博
鰤センタ=―
XXX‐―
献血ルームのこ案内
‐oo献血ルこムメ
X滲 Ю∝ XЮ∝ ・OO献颯ル=ム Ю∝ XXX諄
ー…
ÒOmル
終 XXXX ・ 0鎌血ルームxXX〉Ⅸ淮継
厚生労働省
“輛￨￨●
イHrul,““瞑8お―
o
資料 871
Press Release
平成 22年 11月 12日
医薬食品局血液対策課
(担当・
内線)課長二宅 (2900)
企画官安日 (290コ)
( f t 表電話) 0 3 ( 5 2 5 3 ) 1 1 1 1
0 望通電話 0 3 ( 3 5 9 5 ) 2 3 9 5
(F A X)03(3507)9064
報道関係者各位
フィブリノゲン製剤納入先医療機関の追加調査について
平成 16年 12月 9日に公表したフィブリノゲン製剤納入先医療機関を対象として、
平成 19年 11月 7日付で実施した追加調査の結果11ついて、平成 22年 10月 1日ま
二に回収した医療機関からの回答を取りまとめた状況をお知らせいたします。
(1)追加調査実施期間
(1)投与の年月について回答があつた医療機関数と元患者数
医療機関数
元患者数
9125施設
￢3 , 7 3 8 人
( 投与年別は別表 )
( 2 ) 上記以外にt 過去に投与の事実をお知らせしたという記録が残されているが、現在
1 ´では投与の年月は特定できないとする回答があうた医療機関数と元患者数
医療機関数
元患者数
(3)(1)と
95施設
312人
.(2)の合計
医療機関数
元患者数
1,001施
設 (※2)
14, 050人
(※2)厚生労働省ホームベージ「C型肝炎ウイルス検査受診の呼びかけ (フィプリノゲン
について)」の公表:医
入先医療機関名の再/AN表
製lll納
療機関等リスト上の該当医療機
‐ 関の「
備考J欄に、「
フイプリノゲン製剤を投与されたことが判明した元患者の方が
いるとの報告あり。」と記載した。
平成 19年￢￢月7日ん 12月 5日 (※1'
(ただし、現在も回収中)
(4)元患者の方への投与の事実のお知らせの状況
「
(※1)・(1)の調査以降、平成20年 8月 25日及び平成2￢年1月 16日にも元患者の
方へのお知らせ状況等について再度調査を行つており、 ( 3 ) 回答施設数以降はそれ
らの結果を反映したものである。
￨
お知らせした
81 116人
(58%)(※
お知らせしていない
5, 934人
(42%)
( 2 ) 追加調査対象施設数
療機関 6 , 6 1 0 施
医
設
( 平成 1 6 年公表施設のうち、所在地等が不明であつた施設を除いた医療機関)
投与後に原疾患等により死亡
1, 974人
(140/6)
連絡先が不明文は連絡がつかない
21 755人
(20%)
肝炎ウイルス検査の結果が陰性
422人
(3%)
( 3 ) 回答施設数
・平成 1 6 年公表時に存続していた 5 , 3 9 7 施
設のうち、5 , 2 9 1 施
設 (98%)
から回答があつた。
・なお、このほか平成 1 6 年
公表時に廃院等していた 1 , 7 ￢ 3 施設のうち、5 0 7
今後お知らせする予定である
228人
(2%)
555人
(4%)
施設がら回答があった。
その他 (未記入含む)
14,05し
3)
0人
(※3)元患者の方に■人でも投与の事実をお知らせした医療機関は827施設であった。
Ｈ¶ Ｈ
1 回答状況
2 主な調査結果
( 別表)
投与の年月について回答があつた元患者数の投与年別の内訳
( 5 ) 診療録等の保管状況
平成 6 年以前の診療録等が次のいずれかにより保管されている施設数
手術記録あるいは分娩記録
1, 498施設 (23%)
設 (24%)
1, 576施
製剤使用簿
処方箋
輸液箋あるいは注射指示箋
崚セプトの写し
.
入
院サマリーあるいは退院サマリー
その他の書類
０７
2 , 0 4 ￢施設 ( 0 1/°
o)(※ 4)
( 内訳) ( ※ 5 )
診療録 ( カルテ)
人数
投与年
昭和 39年
135施
142施
277施
設 (2%)
設 (2%)
設 (40//o)
83施設 (1%)
291施
295施
設 (4%)
設 (5%)
8人
12人
42年
143年
￢6人
118人
44年
45年
19人
46年
22人
47年
25人
48年
34人
49年
48人
48人
1 50年
51年
6.7人
52年
88人
53年
128人
の設間であつたため、保管していると回答した施設の割合が異なつたものと思われる:
54年
198人
55年
3‐
22人
(※5)厚生労働省ホームベージ「C型肝炎ウイルス検査受診の呼びか￨チ(フィプリノゲン
製剤納入先医療機関名の再公表について)」の公表医療機関等リスト上の「
ヵルテ等
の有無」欄に、平成6年以前のカルテ等の記録が一部でも保管されている場合、△印
56年
431人
を付していたが、さらに保管されている記録の保管期間、保管状況等を記載した:‐
57年
564人
58年
963人
487人
59年
60年
1
716人
61年
2
379人
62年
2
913人
63年
1
686人
平成元年
206人
2年
157人
3年
91人
4年
43人
5年
219人
6年
13人
計
13, 738人
ＮヾＨ
(※4)平成 16年の調査では「
昭和 63年 6月 30日以前にフィプリノゲン製剤を投与し
対し、
た記録 (診療録、使用簿など)が保管されていますか,」￨の設間で■づたのI子
今回の調査では、「
干成6年以前のカルテ等の各種書類が保管されていますか。」と
40年
■ 41年
人人
(括弧内は調査対象施設数に対する割合)
●鱗撫
厚生労働省
資料 8-2
口' 露
町 J H ●l h i 轟
Press
“ W嚇
Press Release
平成22年 10月 27日
医薬食品局血液対策課
(担当・
内線)企画官安田 (2901)
課長補佐難波江 (2905)
(lt表 1雹:活)03(5253)コ￢11
(直通電話 )03(3595)2395
(F A X). 03(3507)9004
平成 2 2 年 1 0 月 2 5 日 ( 月)
医薬食品局総務課医薬品副作用被害対策室
室長補佐 : 信沢 ( 内線 ) 2 7 1 7
管理係長 : 内沼 ( 内線 ) 2 7 1 8
( 直通) 0 3 - 3 5 9 5 - 2 4 0 o
報道関係者各位
C型肝炎訴訟の和解につぃて
本日、名古屋地方裁判所において、下記のとおり和解が成立しましたのでtお知ら
せします:
ヽ
平成20年 1月以降、同地裁に係属している原告 (患者数 2人 )についての和解。
‐
「
製剤はフィブリノ￨ゲン製剤。
(参考)
.
1 趣旨 ‐
1
‐
7イラ'ノグ摯剤1納入が確認されをぃる厚年労働省岳管あ医療機茜及
び国立大学法人の医療機関1こ対し、
診療録等あ保管状況を確認するとともにこ
投与事実の確認作業の実態等をIE握するため、今年度は、然下の要領で訪問
調査を実施する。
1
、
■
2 調査対象施設
‐
‐
ラィブリィゲン製剤の納入実績等をPHkま
えて選定したo4医療機関
(別添参照) ￨
l
r
l
.
1 1606人
0和解等成立人数挙
O新規提訴等人数※2 1764人
‐
￨
(10月
22日現在)
,
※i「和解等成立人数」は:今回の和解成立者は含まず、これまでに和解が成立した人数 (患
者数)である。また、調停が成立した4人を含む。
※2「新規提訴等人数」はt救済法施行後に提訴等し、訴状等が国に送達された人数 (患者
数)である。このうち、1398人は既に和解等が成立している。
￨
3 調査のスヶジュニル
■
年度内を自途に訪間調査の結果をとりまとめt公表を各ら予定`
(参
考)
1
1 1
:
t
フィプリノゲン製剤の紳入が確認されている厚生労働省所管の医療機関人の訪問調査は、■成2o
年度に4o病院、平成21年度に 16病院実施済みである:
ｍヾ［
上記の症状の内訳は、肝がん 1人、無症候性キャリア 1人である。
‐
(別添 )
○調査対象施設
(4):l■
会堡険中琴総合病貯￨
‐
1.(独 )国立病院機構病院
(1)北海道がんセンター
(5)社
(6)社
(7)社
(8)佐
(9)社
(2)函館病院
(3)高崎総合医療センタニ
(4)西埼玉中央病院
￨
・
‐
‐
(5)名古屋医療センタ
(6)京都医療センター
￨
l
(7)神戸医療センター
(8)姫路医療センター
、
(11:)都城病院
21(独 )国立高度専門医療研究センター
(1)国立がん研究センタニ中央病院
(2)国立国際医療研究センター病院
:3.労災病院
(1)中部労災病院
￨● (2)神戸労災病院
:￨￨(3)中
国労災病院
(4)山口労災病院
:
t
会保険京都病院
会保険神戸中央病院
会保険下関厚生病院
■
賀社会保険病院
会保険宮崎江南病院
5.国立大学附属病院
(1)東京医科歯科木学医学部附属病院
(2)東京大学医学部附属病院
.(3):東京大学医科学研究所附属病院
(4)神戸大学医学部附属病院
.(5)山口大学医学部附属病院 :
(6)佐賀大学医学部附属病院
(7)宮崎大学医学部附属病院 ‐
(3)鹿児島大学病院
:
ヾヾ［
(9)兵庫青野原病院
(￢0)呉医療センタ=
4.社会保険病院
. :
(1).札幌社会保険総合病院
(2)北海道社会保険病院
(3:)社会保険船橋申央病院

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