From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
A New
By
Inherited
Interaction
EUGENE
Abnormality
with
Sickle
M.D.,
KAPLAN,
HIS
REPORT
hemolytic
syndrome
clinical,
cell
nor
the
hemoglobin
unusual
has
studies,
a new
component
cell
features
and
abnormality
their
J.-U-lES
of hemoglobin
pattern
families
In the
wit-h
this
sickling
fitted
PaulilIg’
electrophoretic
in detail
hemoglobin.
erythrocytic
was
subject-ed
in a separate
clearly
present
to
the
of patients
neither
typical
sickle
from
analysis.
disclosed
the
from
clinical,
existence
both
of
normal
hematologic
abnormality
(‘elI
sickle
these
that.
electt-ophoretic
report,2
recognized
to light
sickling
in whom
of
distinguishable
paper
newly
that
en-
came
the
auid his associates
mobility,
blood
by
of hemoglobin
associated
bed.
For the
genetic
demonstration
described
These
with
a characteristic
individuals
sickle
inherited
associated
hematologic,
Following
anemia.
a new
.XD
Its
PH.D.
in
ill
the course
pheuiomenon.
the
with
M.D.
ZUELZER,
M.D.,
and
American
Negroes.
The existence
of this traitof extensive
clinical
and
genetic
studies
u’egarding
Among
the individuals
examined
thei’e were a- number
countered
‘it-h a
deals
%V.
WOLF
V. NEEL,
T
of Hemoglobin
Cell
Hemoglobin
an(l
auid
genetic
of hemoglobin
ai’e
(lescri
III,
time
since
being
it is the
this
third
iew
type
hemoglobin
component
of adult-
human
is designated
hemoglobin
trophoretic
methods,
the other
two being
normal
In the individuals
thus far studied
the combination
cell
hemoglobin
sickling
is
and
globin
III
is associated
The
sickling.
beeui
wit-h
associated
with
homozygous
a mild
condition
wit-h
identified
and sickle
of hemoglobin
hemolytic
In coml)inat-ion
an asymptomatic
splenomegaly.
as hemoglobin
to be
normal
st-ate
by
dcc-
hemoglobin.*
III with sickle
syndrome,
w’ith
carrier
respect
cell
ervthrocvtic
hemoglobin,
without-
hemoerythuocytic
to hemoglobin
III
has
not- yet
recognized.
METHODS
Sickling
& Co.)
preparations
as
a reducing
Siderocyte
The
his
in
agent
preparations
mechanical
associates.7
ysis
were
oxygen
in
this
of
laboratory,
atmosphere,
with
sealed
an(1
sodium
cover
was
from
controls
6 to 13 per
(kindly
films of capillary
method
erythrocytes
normal
metabisulfite
glass
by the
made
were
fragility
In
macic
of MacFadzean
determined
have
cent
and
by
ranged
supplied
the
from
hemolysis
Lilly
by
blood.5
1)avis.6
method
in
of
10 per
4 to
carbon
Sheis
cent
and
hemol-
dioxide
atmos-
phere.
From
Read
This
Children’s
before
the
study
Submitted
*
The
realization
‘as
May
Hospital
Society
supporte
of Michigan,
for Pediatric
I in
16, 1951;
part-
Detroit-;
Research,
by
accepted
a grant
and Heredity
Clinic,
Ann
Atlantic
City,
N. J. May
from
for pihlicttion
the
tentatively
in
namely,
adult
and
remairss
to be
explored.
ol)servat
ions of our own
that-
abnormal
an
The
Recent
studies
group
(Baylor)
hemoglobin
component-
relationship
of Singer4
utilizing
is tlso
1240
of
with
Already
hemoglobin.3
Fund
and
advances
can
hemoglobin
with
to fetal
his associates,
as
well
of alkali
in
t halassemua.
full
knowledge.
l)e distinguished,
III
present
Michigan.
our
of hemoglobin
the met-hod
Mich.
3, 1951.
July
17, 1951.
is advanced
very
system
of nomenclature
here
l)roposed
that- drastic revision ma’
become
necessary
it is apparent that
at least two variants
of normal
fetal
Children’S
Arbor,
deu,atur:s-t
as
hemoglobin
UnpUl)lished
ion,
suggest-
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
E.
‘I’he saline
II,
our
Fecal
the
limit
average
is .33
urobilinogen
of Watson,5
Miller,
and
Singer
and
cent-
per
the
results
the
to
for
.28 per
were
Family
an(l
fecal
The
The
1241
NEEL
by a method
adapted
from Ponder.3
is .45 per cent
to .49 per cent saline,
saline.
poole(I
four day specimens
“Hemolytic
Index,”
using
urohilinogen
excretion
hemoglobin
in
in
by the method
the formula
of
mg.
Gm./l00
estimated
at 7 .6 per cent of the
bY the method
of Powell.”
measured
by a modification
of the
was
based
on
cc.
X
l)Ody
00
weight-.
the
method
of
Young,
Platzer
Ashby
and
technic
of differential
Rafferty.’3
HISTORIES
IV
W.
was
studied
because
were found
to have erythrocytic
sickling
born
American
Negroes
whose
physical
of Caucasian
stock.
The mother
has the sickling
trait
of a mixture
of normal
and sickle cell components.
The father’s
but contain
a mixture
of normal
hemoglobin
and hemoglobin
2 older children,
who have a mild hemolytic
anemia
and eryth-
anemia.
The parents
suggests
some admixture
an(I her hemoglobin
consists
do not sickle,
III.
as
V.
measured
erythrocytes
rocvt-ic
on
J.
was
was
survival
hemolytic
appearance
cent
expressed
CASE
I l”arnily
hemolysis
determined
circulating
1)100(1 volume
Erythrocyte
AND
Dameshek’#{176}
bilirubin
hemagglutination,’2
ZUELZER
limit
was
Daily
Serum
W.
was determined
upper
excretion
Total
where
W.
of erythrocytes
fragility
experience
the lower
and
KAPLAN,
hemoglobin
sickling,
Ilenloglobin
of the
consists
of
a mixture
2 of 3 children
are
of
native
sickle
cell
hemoglobin
and
the
new
component.
of thcyoungest
child is of the normal
type.
Case
1. Rosetta
W., is a 12 year old Negro
girl who has attended
the Out-Patient
Clinic
of Children’s
Hospital
since infancy
for an occasional
mild respiratory,
intestinal
or skin
infectioui.
There
have
been
no episodes
of pallor,
icterus
or I)ain.
Hepatosplenomegaly
has been
noticed
since she was 2 years
old. The spleen
has gradually
increased
in size and
now
exten(is
6 cm. below
the costal
margin,
being smooth,
firm and nontender.
The liver
edge
has
remained
at approximately
2 cm. below
the costal
margin.
A functional
cardiac
murmur
has been present
since infancy
in the absence
of cardiac
enlargement
or abnormal
electrocardiographic
tracings.
Erythrocytic
sickling
was
first demonstrated
when the patient
was 4 years
old during
an attack
of lobar
pneumonia.
The hemoglobin
level at that
time was 10.8 Gm. per cent. Since that illness
she has remained
in apparently
good health,
and
is now
an alertadolescent
girl
of normal
height,
weight- and development.
Roentgenograms
of the
skull and extremities
have
shown
nothing
unusual.
During
the two year jeriod
of our observations,
there has been a very mild normochromic
anemia
wit-h minimal
reticulocvtosis
and no elevation
of leukocvt-es
or serum
bilirubin
(table
I). Target
cells
are
frequent
in fixed periiheral
blood
films,
but
crescentic
sickle
forms
and
iron-staining
erythrocyte
granules
usually
present
in sickle
cell
anemia
are
virtually
absent.
In sealed
moist blood films the erythrocytes
sickle rapidly
with formation
of long filaments.
There
is a moderate
increase
in
the fecal
urobilinogen
excretion.
Bone
marrow
examination
reveals
a moderate
erythroid
hyperplasia
(table
2). The patient’s
eryt-hrocytes
are rapidly
eliminated
after
transfusion
into
a normal
recipient-,
(fig.
1)
whereas
normal
ervthrocvtes
transfused
into the l)atient
are eliminated
at a normal
rate
(fig. 2). Electrophoretic
study
of the patient’s
hemoglobin
revealed
both the component
characteristic
for sickle
cell hemoglobin
and a new component
which
moves
as a more
positive
ion than either
normal
or sickle
cell hemoglobin
(fig.
3).
Case 2. Terry
W., a 10 year old Negro
boy, brother
of Rosetta.
has been free of any complaintfor the last- eight
years,
and is now an active,
alert
child of normal
height,
weight
and development-.
During
his infancy
no abdominal
visceral
enlargement
or other
abnormalit-y
noted at repeated
visits to the Well-Baby
Clinic.
At age 24 years he had an acute
febrile
illness
with coryza
and back
pain
followed
two days later
by marked
pallor.
On
entry
to this hospital
the following
day he was acutely
ill, temperature
102 F., not icteric,
but very pale with signs
of nasopharyngitis
and enlargement
of both
liver and spleen
3
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1242
NEW
INHERITED
ABNORMALITY
1.-Summary
TABLE
OF
of
HEMOGLOBIN
Hernatologic
Data
(2d
.e
E
.
.c3
cd
U
L
z
R. W.
T. W.
E. W.
Mrs.
Mr.
12
10
8
32
34
W.
W.
.Ji
OMCDe
BMCDe
OMcDE
OMcDE
BMCDe
0
0
10.4_12.Ohl.2_2.833
75007726
9.2-10.8
1.0-4.02895007326
12.0
1.6
41740079’25
13.0
0.2
4383009029
0
14.6
5.4
P. C.
7 Pr. C.
8
R.C.
9Mrs.C.
10 Mr. C.
4
I
ANcDe
7 ANcDe
5 ANcDe
29ONcDe
30 ANcDe
+
0
0
-
1.0
45 730082
22
.42-18
.45-25
.42-30
+4.2
0 15.2
30 +
33 0
1
ii
.45-30
.45-30
2.-Bone
1.4
0.8
3782008826
4874009230
Marrow
Differentials;
in carbon
8,43
7,24
0.3-0.7
0.5
8,8
-0.3
Cent
10,58
4,8
04-0.6
0.5
6,8
1.4
-
dioxide atmosphere.
Distribution
Case
P.C.
Case 7
6
0.4
0.2
16.8
38
Pr. C.
1.8
34
0.6
1.0
0.2
4.2
41.0
10.2
0.4
1.0
23.0
6.0
0.2
0.6
0.8
1.8
1.0
1.2
6.0
17.4
0.4
0.4
0.6
6
21
0.6
2.8
Cells
Pronormoblast
Basophilic
normoblast
Polychromatophilic
normoblast
Orthochromatic
normoblast
CO2
Per
cells
Myeloid
Cells
Promyelocytes
Myelocytes-Neutrophilic
Eosinophilic
Metamyelocytes
Bands and segmented
Eosinophils
Basophils
Megakaryocytes
Myeloid:
Erythroid
Ratio
70
2
0
45
4
1
Lymphocytes
Monocytes
Erythroid
31- 0
.45-. 18
.37-. 18
45-. 28
49-. 33
.40-. 18
50
28 +
31 0
30 0
Case 1
R. W.
Reticulum
Stem cells
26
+
+
0
+
24
C.
Key for table
1.
Hg. III, abnormal
hemoglobin
component
by electrophoresis.
Sickle Hb., abnormal
hemoglobin
component
by electrophoresis.
R.B.C.,
red blood
cells, millions
per cubic
millimeter.
Hg., hemoglobin,
grams
per cent.
Retic., reticulocytes,
per cent.
Ht., hematocrit,
venous
blood.
W.B.C., white
blood
cells, thousands
per cubic millimeter
MCV,
mean corpuscular volume.
MCH,
mean corpuscular hemoglobin.
MCC,
mean corpuscular hemoglobin
concentration.
Sickling, in moist blood films.
Target %, per cent target
cells in dry blood films.
Sal. Frag., osmotic fragility, per cent saline.
M. Frag., mechanical
fragility; per cent 02 in oxygen atmosphere,
S. Bil., serum
bilirubin, milligrams per cent.
Hem.
Index,
hemolytic
index
(fecal urobilinogen
excretion).
TABLE
33
36
31
30
+ 3.2-3.8 8.0-10.03.6-6.02975009025
0 4.0
11.5
0.8
3766009329
0 4.3
12.0
1.2
4078009328
11.0
15.9
IH
W.
+4.3-5.3
+ 3.7-4.3
0 5.2
+14.8
Family
6
-
ii’,.d
H
Family
2
3
4
5
-
Normal
1:2
Normal
1:1
0.2
14
2.8
2.2
12
26
0.8
0.2
Normal
3:1
19
2
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
E.
KAPLAN,
W.
W.
ZUELZER
J(JRVIVAL
AND
J.
V.
1243
NEEL
UiRvrs
/00
01
f0
DeTK5
Ho
IVot1
/N
FIG.
1-The
hemoglobin
(Cases
dividual
broken
cent
survival
(Case
were
line approximates
survival
of donor
,efc/P/ENTJ
of ervthrocvtes
1 and
6)
J’iaczr /
.
6)
from
transfused
transfused
the
on
individuals
into
normal
separate
cells; clays-days
occasions
normal
theoretical
with
curve
following
hemoglobin
recipients.
into
III and
Erythrocytes
2 different
of erythrocyte
sickle
from
1 in-
The
recipients.
survival.
%-per
transfusion.
ceJiev1fJ
JtJ’V/V’1L
/00
/0
De9YJ
Naeiwv
/fo
FIG.
globin
2.-The
III
and
survival
sickle
of normal
hemoglobin
CEL&.r
/c/czc
/7
ervthrocytes
(Cases
1 and
INTO
,e(c/p,rNTJ
transfused
6).
into
individuals
with
hemo-
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1244
NEW
cm. below
hemoglobin
the costal
3.5 Cm.
(uncorrected!)
50,000
INHERITED
margin.
per cent,
per
OF
Study
of his blood!
red cells 1,260.000,
mm3.,
revealed
no abnormalities.
rapid
convalescence
with
ABNORMALITY
and
He
the
(the first recorded
many
nucleated
erythrocyte
received
diagnosis
HEMOGLOBIN
sickling.
several
of sickle
for this pat ient)
revealed
red! cells, white cell count
of the chest- and ske!eton
X-rays
transfusions
cell anemia.
and
discharged
was
after
a
Noe/T’9L
5/cA2rQzL
29/T
A
5fc’-Lr
2zz
t’IVEt1I’9
/7tf7TC6ZO43’4’
Z’e’wr
.&#{149}
HP
HcNo5/w’ht/1o&ow
3.-Longsworth
FIG.
ent
types
of
Since
that
icterus
The
or
liver
and
encv
The
those
scanning
individuals,
illness
pain.
extends
nontender.
hematologic
At
diagrams
after
he
has
present
5 cm.
and
Itano
of the
and
Neel
carbonmonoxvhemoglobins
ins excellent
remained
his
heart
is
the
spleen
normal
3 cm.
health,
size,
in
below
free
of
have
heems
virtuall-
with
little
ret iculocytosis
skull
and
extremities
during
the
last
two
is a mild anemia,
reveal
no
hot
l)h’sical
years
of the
margin,
of
attacks
and
costal
X-rays
1). Noteworthy
entirely
configuration
the
findings
in his sister (table
of five
differ-
(1950).
Is
of
firm
p:illor,
signs.
consist--
abnormalities.
identical
with
or leuko-
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
E.
cytosis
in, the
1)100(1
pat
lreserlce
films,
tern
of
(‘axe
3.
chronic
hi’t
forms
W’., mother
Iser
gives
hemoglohi,i
sickle
cell
\Sorhl
II.
concent
are very
in
ionis
of
hpot
or
l,ist
to
for t lie
tern
and
rophoret
in
cell
from
(table
st at us
variety.
excellent
health.
ic study
revealed
rophoret
ic
apart
who,
of t he normal
old and
sickle
peripheral
elect
hematologic
be entirely
Elect
normal.
in fixed
The
absent.
clinical
is 32 years
irelv
1245
NEEL
that of his sister.
an
8 year
01(1 boy
is
to his
dleveloped
illness,
and
and
of
anemia
and
his
orv
of indlividual
hemoglobin,
red!
trait-a
nourished
who
mixture
in
Negro,
served
l,is
ins the
Except
that
normal
of
hlood
is
hemoglobin
:34
aged
Pacific
Physical
parents.
peripheral
with
ranging
st ud
ret
iculocyt
numerous
wit
years,
who
Theater
exanunat
liormal
III t rait (Case
from
but-
absent.
The
red
fragility
ii
(luring
ion
of I his
respect
to
5). Note
1 ol i rul)i
1(n)!
of
of the
and
t he
niunier-
normal.
an
\\‘hel,
content.
to hemolinto
transfused!
rate
the
types,
1).
shape
cell 1)opUlat.ion.
rapid
of two
cell
resistant
abnormally
a mixture
n (t tI lIe
target
hemoglobin
are unusually
is
at
revealed
Rosetta
shape
cells
ehiminate(!
were
both
es
ervthrocvtes
limits of size,
t lie niechanical
in
leukocyt
18 per cent- to 25 per cent
hemogloloni
of his
present
es,
occasions
are wit hini normal
er’throc’tes
his
ic
on
is consistently
saline,
nine
cells,
taken
films
(fig. 4),
componem,t
a
(fig. 6).
normal,
and
Terry.
and!
(‘
Family
(‘.
was
studied
I Iccause
:tnitl
hemolyt
ic anemia.
wit Ii I he physical
appearance
sickling
hennoglohi
ii.
hiennoglol
of normal
no
blood
sickling
cvt i sickling
ala!
is a well
ervt hrocvtes
II Family
I he
is
prominent
Elect rophoret
has
is cot
abnormalities
blood
recipient,
the new
with
hemoglol)in
pat
complaint
no
stained
Erythrocvtic
normal
blood
father,
There
remaining
ysis
isis
virtually
Terry,
children,,
V.
cells.
rat
fixed
The
the
4.-Peripheral
target
Ons
W.,
revealed
FIG.
and
characteristic
significant
War
suhject
ous
no
the
are
i(lentical
J.
cells are prominent
Target
siderocytes
of these
her
.ND
hemoglobin.
5. Mr.
hall
sickling.
and
showed
ic analysis
4. Mrs.
sickling
has
ZUELZER
hot Is wit Ii respect
is normal
for eryt lrocyte
(‘u.s-c
W.
the patient’s
hemoglobin
was
Eric \V., brother
of Rosetta
1). Elect rophoret
and
\V.
of ervthrocvte
sickled
asthma,
(‘axe
K.PLAN,
trait
The
0 n
and
and!
fat her’s
III
-
The
hiennoglohin
I lie
youngest
The
suggestive
her
ervt
of
liemoglohini
hrocvtes
hemoglohini
III. The
IUiXt
consists
sickle,
tlie oldest
hienioglohini
3 chil(lren
are
sonic
(10 not
of
of
parents
(if
both
was
native
ure with
Caucasian
of a mixture
but
conit
am
child, like that
t lie seconal
found
horn
child
to have
stock.
of normal
hot
eryt
American
Ii niormal
The
and
hro-
Negroes
mot
sickle
hemogloho
her
cell
n
of tlie fat her, is a niixt tire
is ent
in’ely
of t lie tiorinal
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1246
NEW
type.
The
hemoglobin
sickling
consists
III
a small
and
Case
seen
INHERITED
of the
of
a
fraction
6. Pearl
C.,
anemic,
slightly
subsided
and
old
icteric and
the
anemia
has
child
no further
with
no
the
two
period
year
associated
cyte
anc! no
hyperbilirubinemia
count-,
peripheral
blood
In vitro sickling
blood
is moderately
increased.
(fig.
The patient’s
1). Normal
red cells
erythrocytes
(fig.
2).
The
hemoglobin,
sickle
hemoglobin
Case 7. Prime
had
no
examination
count
blood
From
and serum
films, the
3 to 5 per
in
abnormal
(table
erythrocytes
t-rophoretic
hemoglobin
pallor
I)uring
transfusion.
on physical
observation
there
ervthrocvte
sickling,
1).
individual
There
severely
she
has
remained
is an
save
a moderate
are
w-as
the icterus
she
active
well
for moderate
margin.
norinochromic
ret iculocytosis,
cells
normal
of the
erythrocyte
granules
are
in type. Fecal
urobilinogen
absenit
excre
III
frequent
leuko-
films
of sickle
is a moderate
she
was
2 cm. below
the costal
on x-ray examination.
hemoglobin
absence
thens
examinationi
been
Target
when
she
convalescence
Since
mild
iron-staining
filament-ous
wit-h
cells and
has
that
At- present
or icterus.
ago
2 years
found
It was
and
in
sickle
cell
hemoglobin
forms.
erythroid
hyperplasia
of the bone
mar-
are rapidly
eliminated
when transfused
into a normal
recipient
have
normal
survival
when
transfused
into
the
patient
on electrophoretic
analysis,
was
found
to be a mixture
of three
hemoglobin,
C., Pearl’s
serious
hemoglobin
6 year
illness
his
III
and
a very
chest
and
and
old
brother,
no
is a we!!
significant
sma!!
skeleton
developed
complaints.
reveal
no
proportion
saline.
2),
and
the
The
fecal
are rapidly
eliminated
of the
hemoglobin
mechanical
fragility
urobilinogen
when
of
normal
revealed
a mixture
in
excellent-
sickling
is
not
of normal
an!
peripheral
The
bone
increased.
recipient
hemoglobin
x-
blood
is absent.
hemoglobin
and
There
is increased
into a normal
health,
examination
The
is normal.
excretion
transfused
child
Physical
abnormalities.
bilirubin
are normal
(table
1). Erythrocytic
erythrocytes
are round,
well filled with
cent of the erythrocytes
are target
cells.
hvpotonic
study
III.
erythrocytic
hemoglobin,
3).
of
hemolysis
globin
cell
(table
and
anemia
cell
ill until
been
of the spleen.
(table
target
row.
components:
with
of
numerous
tion
ray
not
infection.
(fig.5), but sickled forms and
is rapid! and predominantly
5.-Peripheral
6). Note
has
had
abnormalities
of our
anemia
who
a hemolyt-ic
sickle
w-ithout
improved
normocytic
Fic;.
girl,
enlargement-
had
has
of both the liver and spleen, each
extendling
cardiac enlargement-,
and the skeleton
is normal
enlargement
There
is no
(Case
who
HEMOGLOBIN
hemoglobin.
Negro
had
OF
components,
of a respiratory
rapidly
and
child,
three
of norma!
because
preschool
For
of
a 4 year
free of complaints
developed
youngest
mixture
the dispensary
in
ABNORMALITY
On
norma!
fixed
in
size.
resistance
marrow
The
to
is not
patient’s
(fig. 6). Elecanc!
hemo-
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
E.
KAPLAN,
W.
W.
ZUELZER
AND
J.
V.
1247
NEEL
Cii’vrs
5.5&ev/wcL
Nb
7T/T
CfLLJ
IN N01ftL
,pf/P/4y75
6.-The
FI(;.
5, 7 and
of eryt-hrocytes
survival
10) transfusec!
10) were
on
transfused
into
separate
mn(!ividuals
recipients.
occasions
3.-Percentile
TABLE
from
normal
with
Erythrocytes
into
tw-o
Distribution
(lifferent
of
hemoglobin
from
III trait- (Cases
one
individual
(Case
recipients.
Hemoglobin
Coin
ponents*
Per Cent Distribution
Normal
Hemoglobin
I
Sickle
Hemoglobin
-
Hemoglobin
III
100
Normal
Sickle
cell
Anemia
Sickle
cell
Trait
Family
100
24-45
55-76
W.
Case 1 R. \V
Case2T.W
I
53
50
50
100
Case3E.W.
Case
47
4 Mrs.
W
68.9
31.1
69.8
Case5Mr.W
30.5
I
48
Family
C.
Case
6 P.
Case
7 Pr.
Case
S R.
Case
9 Mrs.
C
66.5
Case
10 Mr.
C
64.7
*
Table
Case
and
the
C.
13
C
33.6
100
adapted
8. Rohert
hematologic
normal
39
66.4
C
from
C.,
status.
variety.
Pearl’s
Itano,
H.
5 year
Electrophoret-ic
and
old
Neel,
brother
analysis
J.
V.
33.5
Proc.
is entirely
showed
35.3
Nat.
normal
his
Acad.
with
hemoglobin
Sc.
36:
respect
613,
1950.
to his
to
be
clinical
entirely
of
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1248
NEW
Case 9. Mrs.
for erythrocytic
typical
(‘use
family
mother
of these
sickling
her blood
for
the
10.
Mr.
sickle
C., the
hist
ory
is
were
and!
8 to
and
the
is
well
a
noncontributory
levels
of red cells,
target
study
eliminated
at
the erythrocytes
(fig. 6).
a very
were
and
The
of his
The
osmotic
Negro
found
rate.
transfused
and
hemoglobin
were
Several
into
Except
pattern
SPECIAL
and
leukocytes
occasions.
a mixture
of
into
later
the
are
wit-bin
blood
ttre
two
the
recil)ient.
was
with
normal
types,
a niormal
sul)ject
recil)ient
His
Peripheral
fragility
transfused!
niormal
health.
examinations.
l)hsical
mechanical
mouths
a second!
excellent
iii
on
revealed
erythrocytes
rapid
old
are
hemoglobin,
reticulocytes
was present
on two
cells.
component.
30 year
abnormalities
hyperbilirubinemia
12 penS cent
new’
HEMOGLOBIN
is 29 years old and in excellent
health.
normal
and gave the electrophoretic
developed
No
.
1). Electrophoretic
normal
children,
is entirely
OF
trait.
father,
A slight
contain
(table
cell
blood
limits.
films
ABNORMALITY
C.,
The peripheral
norma!
INHERITED
h)led
again
idenitical
results
INVESTIGATIONS
1 Elecirophoresis
.
The
new
positive
type
ion
This
behavior
structure,
normal
and
of hemoglobin
than
yet
elsewhere.2
small
fraction
of
hemoglobin
component-s
The
with
is given
in table
3.
III
the
to
in individuals
with
the
sickle
component,
cell
in
trait,
as
hemoglobin
6;
1 and
and
iii
percentile
demonstrated
Thus
far, hemoglobin
III has been
types
of hemoglobin.
As yet,
the analogous
sickle
cell anemia,
in which
the hemoglobin
al)normal
variant,
has not been
recognized
encoun-
an
the mixture
produced
by
of normal
and
these
matings
mixture
of hemoglobin
family
had only the
These
facts
indicate
hemoglobin,
simple
sponsible
transmitted
addi-
with
of these
combination
distril)ution
in the same individual
and normal
hemoglobin
by
found
only
sit-nation
is uniformly
wit-h respect
was
2, wit-h
Pauling
and
admixture
to the usual
his
asso-
with
other
pattern
of
ill
composed
of
to hemoglobin
a single
III.
sickle
(fig.
had the new component
parenthad the typical
cell
7).
hemoglobin.
Two
Three
children
in
admixture
cell trait
iii
sickle
types
Family
of offspring
W. (Cases
afl(l 2) had a combination
of sickle
cell hemoglobin
and hemoglobin
III,
child
in Family
C. (Case
6) had the same
mixture
with
an additional
fraction
of normal
hemoglobin.
Secondly,
one child in Family
C. (Case
cell
3).
Studies
In each of the two families
one parent
with normal
hemoglobin,
while
the other
with
were
of
III,
Cases
Case
10. The
ciates.’
2. Genetic
a more
(fig.
hemoglobin
in
and normal
hemoglobin
presence
of sickle
cell
simultaneous
as
hemoglol)m
abnormality
hemoglobin
5, 7 and
in Cases
cell
identified
types
of hemoglobin,
the
details
of the electrophoretie
analysis
hemoglobin
of hemoglobin
is comparable
cell
normal
only,
presence
new’
sickle
appal’attls
sickle
molecular
given
in combination
Tiselius
or
another
from
the two previously
sickle
cell variant.
The
been
rrh
in the
hemoglobin
distinct
the
tered
normal
migrates
normal
characterizes
have
t-ional
either
is determined
Mendelian
for
III
normal
that
dominant.
the
sickling
independently
and
normal
hemoglobin.
hemoglobin.
the presence
by
The
a gene
of each
child
like
that-
III,
which
to be transmit-te(l
appears
relationship
is not
other,
one
of hemoglobin
precise
phenomenon
Lastly,
they
clear
may
of
as yet.
he linked
this
The
genie
two
on the
to
and
1
one
small
7) had a
each
iii
of
sickle
as
a
that
re-
genes
may
be
same
chromo-
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
E.
or they
some,
for
KAPLAN,
pi’ove
mtty
(lifferelitiatilig
The
any
the
modifying
effect
expressed.
( )i’dinarily,
cell
one
each
of the
associated
with
parents
cOtlI(l
cationi
J.
of a series
the
The
(lepends
pa1ents)i
.
V.
of the
from
sicklinig
development-
of
sickling
the
the
was
genie
the
even
method
elsewhere.14
now
availal)le.
appears
to exert
a hemolytic
genies,
syndrome
only
one
that
hemoglobin
the
syn(lrome,
of sickling
though
is
only
hemolytic
a pair
a
sickling
produces
It is apparent
for
The
erythrocyte
however,
genie.
of the
for
of
founid
a sickling
presence
III
genie
presence
patients,
alleles.
presented
limited
(lat-a
been
a single
on
1249
NEEL
of multiple
has
i)asis
Iii mm
16
transmitte(l
have
of
trait.
en’vthrocvte
resulted
on
presence
cell
anemia,
sickle
sickle
AND
possibilities
possible
the
classical
ZUELZER
presence
of the genie for hemoglobin
the manner
in which
a single
gene
011
asymptomatic
from
these
is not
e’eiit
W.
to be meml)ers
between
differentiation
Iii
W.
this
III.
of
the
modifi-
mieach
Since
lIU11111111
P
I3
C
/9t7/zv
FIG.
the
inherited
a (letailed
Since
the
the
in
all
combination
sole
various
present
as
hemoglobin
his
refer
Numbers
sickling
1)100(1 groups
either
supports
ill
initrafamily
in
of the
ill
in it-self
appears
pec!igrees.
7.-Family
analysis
of impaternity
as
I/o.
cases,
to
table
mothei’
(ont1’ibuted
the sickling
gene, the possibility
that
in the children
was
actually
the
result
of an additional
from
a fat-her
other
thani the legal parentwas considered.
svnidrome
globini
4’t*91
3
/
family
IIIJII1
I
4
the
component,
fractions.
family.
the
1) did
Moreover,
evidenice
the
for
true
niot
indicate
distribution
studied
with
wit-h
determinied
by
in a child with
the
to
sickle
the
percentage
so
cell
hemolytic
sickling
The
of
gene
result-
of
possibility
new
the
hemo-
paternity.
or
electrophoresis
the
the
each
other
respect
1.
any
of the
two abnormal
with normal
hemoglobin,
it is of interestto note
the quantitative
Unpublished
studies’7
suggest
that
there
individuals
corn’elat-ions
parent.
(table
.‘
trait
that-
tends
of sickle
the
hemoglobins
rather
than
relationship
of
are significant
cell
proportioni
to
resemble
hemoglobin
of
the
abnormal
proportion
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1250
NEW
In the
enhance
of such
case
of sickle
each
other
subjects
of the
sickling
may
whose
govern
In
the
only
these
their
consist
of 100
seem
per
cent
to
he
individuals
sickle
variety
even
within
new
the
In
the
variety
limits
proved
may
hemoglobin
though
III.
of the
genes
the
each
in
less than
50 per cent
that
similar
condi-
of hemoglobin
a mixture
sickling
to
only
with
child
normal
of technical
consist-
error,
of hemoglobin
was
or apwere
at-,
values
30 per cent.
These
figures
suggest
that- the two different
genies present
in
subjects
may potentiate
each
other
much
as the two similar
genes
of the
trait
quired
to
potentiate
show
each
whether
Hematologic
other
this
Hemoglobin
both
the
cell
the
6)
sickling
phenomenon
(Cases
1 , 2,
no sickled
forms
could
in the
great
majority
there
morphology
has
is at
present
no
sickling
phenomenon
our
experience
is distinctly
filamentous
predominate.
with sodium
all the
In dry,
presence
invariably
ably
masia.
Nucleated
rocyte
The
in
general
and
cells
stained
assume
blood
the filamentous
films the only
target
cell population.
is marked.
There
cells are
range
red
inclusions
number
which
In this respect,
In other
respects
is no
appreciable
normochromic
for children.
cells
cells
are
There
extremely
are seen.
of siderocytes
and
is only
rare.
(erythrocytes
trait
and
erythrocytic
quickly
results
shape.
striking
sickling
in
from
Al-
to their
cell anethat
trait.
the
rate
cell
anemi&9
in
and
cell
sickle
formation
conditions,
when
sealed
a very
short
feature
comprise
in
sickle
the
in
vitro.
resembling
sickle
differences
the
forms.14
In the trait,
under
comparable
The erythrocytes
from
our patients
metabisulfite
show complete
sickling
normal.
The
normal
rapid
in
(in contrast
with sickle
in a manner
the uncomplicated
concerning
between
In the patient-s
new component
present
in fixed blood
films
films from subjects
agreement
that
more
of numerous
of the red
cell anemia
is re-
phenomenon.
Cell Hemoglobin.
and that- for the
was
be found
of blood
of the
been
anemia
experience
is a consistent
mia)’8
sickling
in sealed
wet preparations
occurred
of sickle
cell anemia,
and distinctly
different
from
While
A larger
anemia.
potentiation
III
and Sickle
gene for sickling
though
presence
in sickle
mutual
Observations
_4 . Subjects
with
y#{231}ho
had! inherited
ally
two
so that
sickle
hemoglobin
the value
for each of the two fractions
50 per cent, even though
in the parents
the corresponding
sickle
it
the
effect
in considerably
in table
3 indicate
distribution
‘as,
father.
whose
hemoglobin
of his
HEMOGLOBIN
that
additive
aspects
found
percentage
that
three
it would
simple
quantitative
was
exactly
III and
proached
anemia
the
the
almost
cell
OF
particular
gene resulted
The dat-a presented
hemoglobin
hemoglobin
ABNORMALITY
beyond
may
parents
the
hemoglobin.
tions
3.
INHERITED
of
holly
leaf
in a moist
time and
of the
erythrocytes
45 per
cenit
long
forms
drop
virtuis the
to 75 per
cent
too, the resemblance
to classical
sickle
the erythrocyte
morphology
is remarkanisocytosis,
the corpuscular
slight
elevation
In ordinary
with
poikilocyt-osis
constant-s
of the
Romanovsky
iron-staining
or
are
ret-iculocyte
polychrowithin
the
count.
stains
no eryth-
inclusions
by
the
Prussian-blue
technic)6
was not
increased
as compared
wit-h normal
controls.
This
finding
stands
in contrast
to the increased
frequency
of siderocytes
in the
majority
of sickle
cell anemia
patients.
A systematic
st.udy
of siderocytes
mi
sickle
cell disease
now in progress
in our laboratory
indicates
that
siderocyt-osis
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
E.
is a fairly
SiCkle
constant
W.
feature
W.
ZUELZER
in sickle
cell
AND
J.
but
anemia,
V.
1251
NEEL
is not
present-
the
in
simple
trait.
The
The
cytes
resistance
figures
are
have
tion
carbon
i)ehavior
our
of the eryt-hrocytes
within
the range
a normal
with
This
ill
KAPLAN,
mechanical
dioxide
would
own
to hypotoniic
saline
encountered
in sickle
fragility
gas,
seem
experience
their
in an
oxygen
mechanical
upon
the
characteristic
trait-.
As judged
by the usual
criteria
for in
rul)inemia
and
increased
fecal
urobilinsogens
increased.
erythro-
The
anemia.
atmosphere.
fragility
to he dependent
it is equally
is significantly
cell
After
satura-
is significantly
sickling
of sickle
increased.
phenomenon
cell
since
anemia
and
sickle
cell
disturbance
ret-iculocvte
upper
limits
mi our
demonstrable
serum
was
The
bilirubin
and
of
normal.
Fecal
of 2 to
7 in childreni.2’
a metabolic
possil)iht-y
not- excluded
was
a metal:)ohc
hyperplasia
t-ion.
was
as
5h1.lIit
explains
suggests
cases
either
with
a half-life
On
patient
separate
behavior
in fecal
cell
transfused
of twelve
occasions
indicates
days
measured
The
above
uroi)ilinogen
hemolytic
in 2 of
hemolytic
the iiormal
excretion
mi sickle
the
indexes
range
might-
cell
might
he due to such
to us. It- is unlikely,
re-
anemia.22
‘
23
a mechanism
however,
that
increase,
since
there
is marrow
erythroid
activity
for increased
red cell destrucbone marrow
normal
range,
of the 2 patients
studied
although
not as extreme
anemia.
were carried
hot-h patients
out
into
recipients
1 , and
normal
intracorpuscular
in Patients
six
1 and 6. The
The survival
normal.
was
normal
in Case
in 2 different
an
bili-
mild
a
perio(I
of our study.
elevated,
or at the
was
demonstrated
ratio
in the
beyond
the
studies
into
during
the
only slightly
excretion
been
all of the
compensatory
of sickle
reticulocytosis,
only
moderately
increased.
which
lie definitely
increase
as has
well
Erythrocyt-e
survival
of normal
cells transfused
from
patient-s
levels ‘ere
that
part
of this increment
wit-h the methods
available
which
usual
The
such
The myeloid-eryt-hroid
1 : 1 and 1 : 2, values
in the
22
‘
shunt
hemolysis,
excretion,
urol)ilinogeni
3 patients
and was found
to be only
were
I 9 and 24 respectively,
figures
fleet
The
vivo
was
and
markedly
eighteen
recipients
defect
shortened,
days
respectively
6 (figs.
1, 2).
This
comparable
to
that
in Case
erythrocyte
survival
of cells
of sickle
cell anemia.
Shortened
erythrocyte
survival
is not- ol)served
in the
sickle
cell trait-.’9
24 J is therefore
noteworthy
that
it could
be demonstrated
in these
patients
who had inherited
only a single
sickling
gene and who in this respect
,
are comparable
hemoglobin
the
evident
the
that
to individuals
erythrocyt-es
shortened
wit-h the sickle
of our patients
survival
results
cell trait.
contain
either
from
Since in addition
to sickle
the new component
it is
the
interaction
of the
al)normal
hemoglobins
or is related
to the presence
of hemoglobin
The data
to be presented
in the following
section
tend to support
the
B. Subjects
with Hemoglobin
III
and Normal
Hemoglobin.
These
(Cases
5, 7, 10)
had
no symptoms
related
to
anemia
and
exhibited
two
III per se.
latter
view.
individuals
no
unusual
physical
findings.
The red blood
cell and hemoglobin
values
were in the optimal
range
for their age and sex. In one instance,
Case 10, slight
elevation
of the serum
bilirubin
‘as present
oni two
occasions
due to an increase
in the “indirect”
fraction;
dence
a fecal
the reason
for
of a hemolyt-ic
urohilinogeni
this finding
was not apparent-.
process.
In 1 individual
both
determination
were
performed,
In general
there
was
no evia hone
marrow
puncture
and
with
entirely
normal
results.
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1252
NEW
Repeated!
test-s
inclusions,
The
of numerous
cells
cent
anemic
the
were
subject-s
occasionally
the
we
white
normal
subjects,
or at- least-
In
experience
up
the
of targetupper
2 of his
third
target
cells
cells
in Case
of anemia,
is less
in one
from
the
5 pe1 cent
7, 3 to
of normal
than
1 per
cells
in
nioii-
in apparently
nor-
prol)ably
studies
dlat-e disclosed!
of the brothers
hut
cent,
apparently
7 is therefore
Further
at a later
appeared
rangecl
betweeii
10. These
figures
number
cent- target
target
cells
of normal.
described
neither
deviation
Case
a large
uniformly
was the pI’esenice
were seen amidst
themselves
subject,
2 to
limits
Family
W. w-hich will be fully
of target
cells, in the absence
were
consistently
cent- in Case
3 per
to 3 to 4 per cent
to
Erythrocyte
cells
noticeable
wit-h
of
up
and
at
the
frequency
incidlence
and
any
target
cells
8 to 12 per
our
observed
l)loOd
of the erythrocytes
(fig. 4). These
cells
show
range.
In
usual
have
The
Negroes.
cant,
normal
present-.
negative.
red
population
they
couiits
between
In
beyond!
cells
did
HEMOGLOBIN
uniformly
nucleated
cell
red
nor
repeated!
in Case
5, and
diameter.
well
were
a.iid
abnormality
in fixed blood
films
hypochromic
target-
sickling
bodies,
normochromic
16 to 25 per
OF
morphologic
target
appreciably
normal
ABNORMALITY
eryt-hrocytic
only
a normocytic
mal
for
Howell-.Jolly
absent-.
are
INHERITED
on
signifi-
relatives
of
a high incidence
of Mr. W. and in
children.
The
resistance
subjects
correlation
and
of the
normal
between
erythrocytes
had
erythrocytes
in one
osmotic
normal
to
hypotonic
subject.
Iii
resistance
mechanical
saline
this small
and
the
fragility
was
group
number
in both
increased!
there
was
of
in
no
target
oxygen
anid
two
apparent
cells.
The
dioxide
carbon
atmosphere.
Erythrocyte
survival
studies
subjects
in normal
individuals.
consistently
shortened
in a second!
normal
half-life
ranged
indlividluals
that
the
one
six
eighteen
to
rapid
instance,
Case
the
days.
made
the
of these
incompatibility
in
unique
erythrocytes
each
was
the
uniderlying
seems
from
was
The
repeated
of erythrocyt-es
our experienice.
from
AcThe
was
the
result-
by
the
fact
3
and
erythl.ocyte
mechanism.
excluded!
of the
markedly
study
results.
behavior
is
to elucidate
10,
same
This
hemolysis
elimination
group
out with
cells
their
survival
essentially
demonstrable
were
blood
In
wit-h
from
attempts
detected
6).
recipient-
without
cordingly
hility
(fig.
were carried
Unexpectedly
possi-
of an
that-
tin-
they
behaved
in the same way in 4 different
recipients,
none of vlsn-i ha-d previously
been
transfused.
Moreover,
the presence
of unusual
antibodies
of ani immune
nature
in the sera of the recipient-s
active
againstthe eryt-hrocytes
of these
subject-s
the
was
excluded
serum
gave
direct
dependent
cubation
tients’
plasma
indirect
acid
produced
test.
test--
The
cells.
The
hemolysis
patients’
Coombs
donor
Coomhs
on
of the
fragility
a negative
trypsin-modified
a negative
defect
ical
by
wit-h
possibility
was
ruled
aiid
subjects’
by
cross
own
of an undetected
out-
l)y
the
matching
cells
of
invariably
erythrocyt-e
appropriate
test.
In-
cells
no
as compared
in normal
plasma,
and of normal
cells in the paincrease
in either
spontaneous
hemolysis
or mechall-
with
normal
controls.
DISCUSSION
1. The
The
sickle
Combination
combination
cell
disease
of Hemoglobin
of hemoglobin
that
has
not
III
III
been
and
with
Sickle
sickle
previously
Hemoglobin
hemoglobin
defined.
produces
This
syndrome
a form
vould
of
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
E.
seem
to
and
genetic,
tive
sickle
megaly,
present
anid
anemia
were
AND
between
clinical
considered!
time.
hemolytic
grounds.
benign
course,
the
would
cell
anemia
more
severe
hilinogeni
tal
anemia
excretion
symptoms
patients,
their
in childlhoo(l
and
the
made.
Their
over a l)eriO(l
to
2 and
of the
greatly
leadls
6,
in(licat-es
In fact,
recur
with
the
011CC
at that-
normal
r#{231}i
has
wit-h
is usually
sickle
has
beeni
of sickle
cell
respect
progressively
behavior
enlarged
associated
experience
severe,
produces
variable,
fecal
history
a
uro-
of 2 of our
episodes
of sickle
occurred
cell
completely
anemia
manifest.
to growth
en-
evaluation
musculoskele-
The
crisis-like
cell
of our
progressive
manifestationis,
ntntritioni.
become
spleen
1)eeame
not the expected
spleen
is inconstantly
the
more
a diagnosis
however,
childreni
and
though
severe
time
the
splenomegaly
and
to that.
disease
anemia
tentaspleno-
features
to find a (‘Omprehenisive
mi children.
In our own
to cardliac
that.
l)e only
sickling,
1)e considered!
increased,
in growth
subsequenit
course,
of years
in contrast
the 2 older l)atients
tomatic
cotllse.
ith this disease
the
Marked
hy
can
dlistiniguishinig
to I)e eonsideral)ly
apt
commonly
cliildhoo(l.
early
are apt
favorably
attended
impairment
and!
Cases
is
trait
these
entities
on
genetic
and chemical
syndrome
ordinarily
largemenitof the spleen.
\Ve have been tiniable
of the manifestations
of sickle
cell anemia
sickle
sickle
both
of erythrocytic
grounuls
mildness
asymptomatic
section.
consisting
clinical
1253
NEEL
from
The
of the
anemia
On
V.
the
in a previous
A syndrome
sense.
J.
It is distinguishable
characterization
usual
the
ZUELZER
and
been
chronic
in the
cases
anemia.
hematologic
have already
clinical-hemat-ologic
at the
W.
intermediate
cell
chemical,
aspects
The
W.
a position
OCCUpy
classic-al
KAPLAN,
andl
was
asymptomat-ic
in which
Our
in
anemia
symptoms
patient-s
compared
development-.
In
enlarged
despite
the asympof sickle cell anemia.
In children
and tends
to become
smaller.
with
severe
anemia
afl(l
other
maui-
fest at ions.
Most
experienced
which
hematologists
it is difficult
have
to classify
the
seen
cases
condition
of
as either
mild
sickle
sickle
cell
cell
disease
anemia
or
in
the
trait.
It is probable
that- some of these
eases represent
examples
of the hemoglol)ini 111-sickle
cell coml)ination.*
So far it would
seem that
the syndrome
resulting from the combiniat-ion
of hemoglobin
III and sickle
hemoglobin
is relatively
benign
as compared
firms
these
import
2.
of
The
and
Combination
state
are
*
this
globini.
trait
this
point-.
elect
III
1w
target
Interest
rophoret
stis
inglv
the
enough
ic pat
cells
Normal
Hemoglobin
t cmi
process
and
cell
also
of
shortened
erythrocyte
idenit
ic:sl
to
anemia,26
in
conipletioii
t he hemoglobin
niot
and
hemoglobini
consist-s
is an asymptomatic
survival.
in a wide
variety
of circumstances.
mi the blood smears of normal individuals.
in sickle
28
in
and
occurs
the
increased
p;tper
anemia.
If further
experience
conof this condition
would
seem to have
implications.
target
cell
he found
occasionally
that
cell
as seen in the indlividluals
whose
III and
normal
hemoglobin
hemopathies’
\Vhile
abniornial
III
markedly
Mediterranean
eugenic
hemoglohin
may
cells
are
diagnosis
characterized
aware
Target
They
sickle
precise
of the hemoglobin
The hemoglobin
a mixture
of
carrier
typical
the
anit- prognostic
We
to
with
impressions
the
a lesser
hypochromic
Greeni
of their
wit Ii the
and!
Conley25
mi the
degree
anemia
of
called
first patientis said
abnormality
of sickle
iron
attention
to
cell
have
an
hemo-
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1254
NEW
deficiency.
They
following
may
or
in the
splenic
can
III
trait.
in the
only
be
Target
child.
by
Lubitz33
wit-h
may
well
Target
an
with
of Mr.
incidence
increased
to hemolytic
with
only
by
the
study
sera.35
the hemoglobin
a slight
increase
resistance
to
presence
or absence
an unsuspected
Elucidation
uals
problem
hemoglobin
fest
are
hemolytic
survive
also
cells.
cells
await
studlies
trait
who
rapidly
in their
It
reported
Negro
invariably,
chemical
lysins34
in 2 of the individluals
cells and a child
with
other
hand,
in 1 adult
‘
contains
‘
but
reference
pertinent
in part
on the
several
without
is now
account-
no
target
case
trait.
but not
to
and
of
is of interest
in a nonaniemic
for
ilicidence
of erythrocytes
exhibited!
vitro
though
nonfeature
of
The
III
question
may
in
numerous
childlren.
saline,29
The
trait
must
III
phenomena.
normally
W.,
cells. The literature36
in normal
Negroes,
III
(luires
comment
. Shortened
survival
ily bespeaks
an intrinsic
erythrocyte
erythrocytes
cases.
hypotonic
III in the Negro
population.
elimination
in normal
recipients
the
with
of target
hemoglobin
of this
for hemoglobin
The rapid
of more
of Family
target
#{176}
and
‘
produced
in the 2 adults
a constant.
feature
The osmotic
resistance
is increasedi
III trait,
1 adult
wit-h many
target
in target
cells. It is normal,
on the
to
ings.
increased
cells are
in 2 of his
cent
he
of the hemoglobin
thin,
are commonly,
blood
also contains
many
target
of increased
osmotic
resistance
the
and
jaundice,29
may
media.32
Even
to he a significant
study
of 67 per
whose
report-s
whether
and
of relatives
W.,
HEMOGLOBIN
of obstructive
‘
‘
to hypertonic
cells appears
representanother
example
cells which
are abnormally
associated
afldl
presence
cells are greatly
Whether
target
established
to note that,
in a preliminary
cells were found
in a brother
OF
atrophy
of normal
erythrocytes
presence
of many
target
the hemoglobin
slightly
increased
trait
ABNORMALITY
develop
splenectomy
by exposure
specific,
the
the
INHERITED
from
evidlence
of er’vt-hrocvtes
in normal
defect
and it. is presumedl
as
to
these
find-
of the
gene
the
3 inidivid-
of hemolysis
reci pient
that such
re-
s ordinar-
defective
destroyed
in their
original
host as showni
by mauiThe
observation
that
erythrocytes
which
seem
to
host. are destroyed
rapidlly
in normal
inidlividuals
ap-
pears
to be unique.
No immune
mechanism
could
he demonstrated!
to accountfor the
survival
curves.
The possibility
of a technical
error
accounting
for the survival
curves
of the eryt-hrocytes
of individuals
with the hemoglobin
III trait appears
remote.
Erythrocyte
survival
studies
using
the met-hod
of differential
hemagglutination
have
been
performed
Control
cipients,
survival
yielded
present
investigation.
in our
on
normal
normal
Erythrocytes
fused
on
identical
two separate
results,
and
from
other
the
laboratory
studies,
with
the expected
from
occasions
into
similar
survival
2 individuals
were
a very
wide
scale
eryt-hrocytes
transfused
survival
curves
during
one
different
curves
of these
for
several
years.
inito normal
rethe period
of the
individuals
were
tranis-
normal
recipienits
with
virtually
were obtained
when
erythrocytes
transfused
into
normal
recipients.
Similarly
shortened
survival
times
were
mixture
of hemoglobin
III and
to the inheritance
of a single
which,
by itself,
is not associated
obtained
with erythrocytes
from
patients
with
a
sickle hemoglobin.
These
individuals,
with respect
sickling
gene,
are comparable
to the sickle
trait
with shortened
erythrocyte
survival.
The rapid
elimination
be
or
to
of their
interaction
cells
between
may
the
two
ascribed
either
hemoglobins.
to the
hemoglobin
III
per
se,
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
E.
The
conclusion
containing
corpuscular
seems
this
‘ere
incubated
nificaiit-
3.
with
serum
the
cell
syndromes
Negro,38’4’
and
been
identified.
hemoglobin
I I I to
The coml)ination
of Italian
and
this
sickle
cell
from
by
In
are
and
nw
in
At
to Mediterranean
‘sIediterranean
disease
has
vice
intraexists
present
the
revealed
no
Rodart-e,
no sigthis phe-
the
chiefly
-
Although
disease
gene
and
‘
distinguished
of
in families
more
clinically
sickling,
rehas
relationship
described
was
Bianco,43
be
described
in Caucasians,
genes
to
been
of sickle
cell
the t-halassemia
to examine
from
parents
of the
yielded
elucidlate
have
report-ed
Ned.’4
apart
to
Disease
been
appears
presence,
versa,
anemia
and!
and!
erythrocytes
occurrence.
Moreover,
a new variantof the sickling
gene and
by Silvestroni
5,
normal
progress
it is of constant
coniditioni
the
of erythrocytes
Case
in which
individuals,
these
families
those
identifiable
as carriers
clearly
1 individual,
III
Powell,
the
entity
survival
individuals.
It- is therefore
pertinent
Mediterranean
dhsease.
of the sickling
and thalassemia
anemia
that
microcytosis.
genie were
by
of
resembling
ancestry
1255
NEEL
shortened
experiment-s
whether
cell
V.
in normal
blood
studies
sickle
Sicilian
country
the
of these
ancestry.42
interaction
the
the
J.
obscure.
vitro
of Hemoglobin
of Mediterranean
sult-ing
from
already
of
In
Further
to establish
Relationship
pH
normal.
and
rrarget
in
the
totally
AND
hemoglobin
reflects
a hereditary
in the affected
individuals
there
is lacking
is
the
information.
nomenoni
in
of
from
ZUELZER
that
which
mechanism
Measurements
deviation
W.
III and normal
defect
and that
mechanism
of
W.
inescapable
hemoglobin
erythrocyt-e
a protective
nature
KAPLAN,
recently
resembling
hemat-ologically
of hypochromasia
who contributed
Mediterranean
the
trait.
and
thalassemia
by their
hema-
tologic
features.
Some of the siblings,
and, in one instance,
children
of the affected
individuals
likewise
presente(l
the picture
of the Mediterranean
trait.
In view of the similarity
of the initeraction
between
the t.halassemia
and sickle
cell genes,
and the hemoglobin
III and sickle
cell genes,
the possibility
must
be
considered
globini
ent
thatfound
genetic
because
of the
This
recent
III
by
possibility
discovery
from
by
between
deserves
Singer
our
of our
and
and
who
had
1, 2 and
the
method!
thalassemia
not
show
carriers
grounds
of the Mediterranean
since each represent
examination
independent
and
that
by
preliminary
ani
the
hemoglobin.
of hemoglobin
the
abnormal
method
studies
of
indlicat-e
As
of hemoglobin
niot appear
that
blood
picture
emphasized!
h)y Silvest-roni
and
Bianco
thalassemia
and sickle
cell trait-.
Even
more
clear-cut
when
the subjects
with
a mixture
of hemoglobin
III
are compared
with
paral)le
on genetic
differ-
in thalassemia
combination
6) did
hemo-
careful
(Baylor)
the electrophoretic
patterni
oni hiematologic
grounids
it does
hemoglobin
are identical.
(Cases
more
abnormal
a somewhat
his associates4
on
patients
hemoglobin
the
into
all the
laboratory
III
hemoglobin
is actually
it-s introductioni
component.
may
be demonstrated
alkaline
dleniat-uration.
With
this
have
no information
ranean
disease,
but
III anid Mediterranean
Those
hemoglobin
modified
observationis
a similarity
cell
so-called
background.
unipublished!
hemoglobin
fractional
the
in thalassemia,
yet
we
in Mediterhemoglobin
III
hypochromic,
and
sickle
microcytic
for the combination
differences
are apparent
and normal
hemoglobin
trait.
The
heterozygotes
two
groups
carrying
of
are
corn-
one
gene
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1256
for
NEW
the
cells
abnormal
there
INHERITED
trait.
are
no
ABNORMALITY
and
its
similarities
normal
OF
allele.
between
the
HEMOGLOBIN
Except
two
for
groups.
the
The
presence
of target
III
hemoglobin
the microcytosis,
ovalocyt-osis,
and
polycyt-hemia
characteristic
Niediterranean
carrier
state.
Moreover,
the strikinigly
rapid
eliminiation
fused
erythrocytes
from
patients
with
the hemoglobin
III trait
is in
contrast
to the essentially
normal
mode
of elimination
cells.45’ 46
While
the available
evidence
seems
to indicate
that
by us is not identical
with the Mediterranean
syndromes
that
were
conversely
actually
Schwartz
some
related
the
typical
us.
In
picture
several
target
Mediterranean
of Mediterranean
of the families,
memlers
cells
ranean
in far
trait.
greater
They
individuals
number
reported
whereas
to
to
per
cent-
found
target-
1 to
8 per
only
trait,27
figures
which
of target
cells in
are
the
be
in our
Mediterranean
III
Further
in the
hemopathies
hemoglobin
trait.,
or even
experience
trait
well
may
show
the
will
Mediterranean
rest upon
with
the
a larger
munochemical
hemopat-hies.
identification
Negro
study
and
Pre-
From
the
conformed
deto
to that
dlescribed
by
and Mason
ol)served
of the
Medliter-
in several
in inidividlilalS
cells
(P1st
with our
of Schwartz
own
of these
with
experience.
and! ‘i-Iason’s
is comparal)le
to the findings
that- some of the cases reported
were,
in
unrecognized
number
disclose
a wider
spectrum
some degree
of overlapping
the
Negro
as yet
described!
remains
4 Negroes
families.
the cases
characteristic
in keeping
relatives
in the absence
of eryt.hrocyt-e
sickling,
cases.
The possibility
cannot
be excluded
patients,
in
their
that
seem
100
markedl
dhsease
in the
In an exhaustive
anemia
the
trans-
trait
the condition
the possibility
anemia,
rather
t-hani
however,
Schwartz
than
50
Dameshek
the Mediterranean
The
high
incidence
as
report-ed
considerable
supportive
evidence
covering
of the patients
themselves
it would
seem
of
of Mediterraniean
of the cases reported
as Mediterraneani
to the presence
of hemoglobin
III.
Mason38
and
sented
scription
trait
of
lacks
reality,
of cases
exhibiting
of
the
st-ate.
the
of clinical
or hematologic
in the manifestations
The
ultimate
of hemoglobin
examples
homozygous
hemoglobin
III
features
and
of this syn(lrome
separation
of
III by chemical,
may
and
these
syndromes
or perhaps
im-
means.
SUMMARY
Through
clinical,
normality
hemoglobin,
normal
of the
Mendehan
distinct
cell
hemoglobin
cell
called
cell
studies
recognized
in
hemoglobin
hemoglobin
hemoglobin
by
molecule
III,
a
American
can
niew
inherited
Negroes.
l)e
electrophoretic
from
The
by a gene
ab-
new
The
separated
analysis.
is determined
hemolyt-ic
syndrome
which
trait
and
sickle
cell anemia
wit-h sickle
cell hemoglobin.
is presented.
disease
splenomegaly
vitro,
the
shows
physicochemical
been
both
structural
iniherited
a-s a simple
between
the
dominant-.
sickle
drome
anid
has
provisionally
sickle
and
anomaly
A
genetic
hemoglobin
of
In contrast-
is characterized
in the
eryt-hrocytes
erythroid
absence
sickle
hyperplasia,
to
intermediate
from
the
A tentative
classical
by a mild
of cardiac
like those
fecal
is
results
sickle
hemolytic
combiniation
characterizatioii
cell
aniemia
anemia
or musculo-skeletal
of sickle
cell anemia.
urohihinogen
excretion
this
with
of
the synof
sickle
progressive
manifestations.
The hone
is increased,
new
the
form
slowly
beniign
of
In
marrow
audi
the
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
E.
KAPLAN,
survival
time
patients
pressed.
the red! cell
Ileticulocytosis
cell
of the
anemia
of
1)0th
these
the
III.
gene.
The
presence
globini
is expressed!
but
have
and!
new
J.
recipients
is not
to have
while
the
synidrome
does
is shortened,
but
are
slightly
when
coml)ine(l
with
carrier
state.
asymptomatic
genie
are
eliminated
with
abnormal
with
and! the
structurally
The
normal
hemodlO niot
increased
resistance
in such
rapidity
that
thalassemia
eryt-hrocyt-es
a high incidence
of target
cell deformity
and
Although
there is no evidlence
of hemolysis
ervt-hrocyt-es
desickle
in
to be identical
sickling
saline.
normal
in the
trait,
only one parent
parent
is a carrier
of
appear
of the
only
Whereas
the sickle
nonsickling
not
1257
NEEL
observed.
Presence
III
V.
concentration
icterus
expected!
simultaneous
as an
AND
hemoglobin
sickling,
of hemoglobin
to hypotoniic
of
are
The
the
from
ZUELZER
in normal
and
is slight
shows
hemoglobin
their
count
parents
resultinig
W.
erythrocytes
ilidividhlalS
sickle
W.
from
individuals
the
circulation
recipients.
The homozygous
identified
but niav
hemolvtic
anemia.
are
Studies
state
vell
iiow
abnormality
in
wit-li respect
to this new hemoglobin
1)e some
alread!v
recognized
atypical
progress
to
the
determine
inci(lence
has not yet- been
form
of chronic
of this
new
molecular
of hemoglobin.
Rlwl:Rl-:NCI-:s
1
L.,
PAuLns;,
disease.
11. A.
AN!)
Sc.
3
t-rophoretic
SINGER,
534,
1949.
J. V.
NEEL,
613,
36:
M. A.,
ANDERSCII,
H. A.,
110:
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ACtt(l.
2 ITANO,
Nat.
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S. J. ANI)
: New
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abniormahit-v
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1951 6: 1240-1259
A New Inherited Abnormality of Hemoglobin and Its Interaction with Sickle
Cell Hemoglobin
EUGENE KAPLAN, WOLF W. ZUELZER and JAMES V. NEEL
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