From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
Pure
Red Cell Aplasia
(PRCA):
Response
of Three
Patients
to Cyclophosphamide
and/or
Anti
lymphocyte
Globulin
(ALG)
and Demonstration
of Two Types
of Serum
IgG Inhibitors
to Erythropoiesis
By A. Marmont,
Three cases of adult
(PRCA)
are reported.
refractory
to
pure
All
C. Peschle, M. Sanguineti,
red cell
patients
various
Additionally,
of
androgens
and corticosteroids.
The first
case, harboring
a thymoma,
showed
a
complete
clinical
remission
following
cyclophosphamide
therapy.
The second and
third responded
similarly
to either a combined
cyclophosphamide
+ antilymphocyte globulin
(ALG)
treatment
or to ALG
administration
preceded
by a small
dosage
of cyclophosphamide,
which
had
proved
ineffective
when
administered
alone. Serum lgG inhibitors
to erythropoiesis were
demonstrated
in all cases
by
means
of in vivo and/or
in vitro
techniques. The inhibitor(s),
although
directed
against
the erythroid
marrow
in both the
first and third patients
(PRCA type A), apparently
functioned
as an antibody
to circulating
erythropoietin
(Ep) in the second
A
LTHOUGH
scribed
half
ported
so
regarded
sponse
presence
to
nature
of the inhibitor(s)
strated
the
that
or
the
far,
PURE
RED
cell
a century
ago,”2
60 of whom
both
experimental
types
lished
of
is
an
peutic
human
in normal
ies support
agents
of
to
roids.
In
has
inhibitor(s)
been
activity
was
immunodepressive
not
detected
treatment.’9
PRCA
The
thera-
is confirmed.
ALG
may
tool
It is
represent
an
in
re-
cases
and/or
addition,
ste-
cyclophosphamide
proved effective
in a patient
harboring
a
thymoma
not amenable
to surgery.
Finally, it is postulated
that lgG serum autoantibodies,
directed
against
either
an
early erythroid
precursor (PRCA type A) or,
more
rarely,
play
a major
the
circulating
role
disputed,’5
IgG
several
serum
following
It has
in
Ep (PRCA
the
type
pathogenesis
B),
of
disease.
in the adult
was
150 cases
have
a thymoma.3’4
in the
stud-
adult
cyclophosphamide
PRCA
as an autoimmune
condition,5
characterized
thymectomy
or nonsteroidal
immunodepressive
of serum
inhibitor(s)
to erythropoiesis.6’7”4’9
inhibitory
patients
therapeutic
sistant
present
that
disease.
that
additional
for
estab-
cytotoxic-immunodepressive
in PRCA
emphasized
were
The
contention
autoimmune
role
models
PRCA
rodents.
the
aplasia
(PRCA)
little
more
than
harbored
M. Condorelli
case (PRCA type B). The inhibitor(s)
was
always
absent
in postremission
samples.
aplasia
proved
combinations
and
been
has
been
first
been
dere-
recently
by
both
a favorable
reagents5’3
and
the
Although
the immune
investigators
fraction.7”6’9
either
suggested
have
It is of
successful
that
demonrelevance
thymectomy
the
“
inhibitor(s)
From the Division of Hematology
and Internal
Medicine.
Ospedali Civili. Genova-Sampierdarena.
the Institute
of Medical
Pathology.
Second Faculty of Medicine and Surgery,
University
of Naples.
Naples. Italy. and the Division of Nuclear Medicine.
Ospedale Duchessa di Galliera, Genova, Italy.
Submitted
March 4. 1974; accepted July 31. 1974.
Supported in part by a Grant from the CNR, Italy.
Address for reprint requests: Cesare Peschle, M.D.. Istituto
Patologia
Medica, Nuovo Policlinico.
Via S. Pansini,
80131
Napoli,
Italy.
& Stratton.
Inc.
Blood, Vol. 45, No. 2 (February),
1975
© 1975
by Grune
247
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MARMONT
248
may
be directed
precursor,’8
against
or the
Three
cases
reported.
are
remission
the
stem
cell
erythroid
compartment,’5
now
therapy.
Of
over
12
further
mo
was
interest
induced
is that
by
a patient
CASE
male
anemia.
mass,
examination
skin lesions
1,250,000/cu
ential
count
platelets,
was
antilymphocyte
globulin
harboring
a thymoma
therapy:
erythroid
(Ep).
the first one
precursor,
not
treatdemon-
(patients
1
the second
REPORTS
the
Sampierdarena
examination
condition
negative,
was
except
for
Hospital
at the
age
20
had
in March
dullness
cell
The
paraprotein
and
of the
latex
speckled
and sucrose
tests
B. GIUSEPPE,
total
examinations
in October
of
first recognized
a mediastinal
and legs. Laboratory
mm.
no
LE
to
X-ray
and
1970
because
shown
the presence
1970. On admission,
multiple,
maculopapular
Hb, 3.5 g/I00
ml; Hct,
13%;
mm; MCV,
109 cu z; reticulocyte
count,
0.0%;
WBC, 6700/cu
mm. The differneutrophils,
67; eosinophils,
3; lymphocytes,
23; monocytes,
5; TUrk’s
cells,
2;
g globulins);
agglutinins,
admitted
the anemic
arms
400,000/cu
(++)
positivity
100 ml. Ham’s
was
a chest
was
on both
RBC,
3.05
patient
Although
of a mediastinal
physical
therapy
complete
a
1)
A 60-yr-old
of severe
erythroid
to cyclophosphamide
to erythropoiesis
were
strated
prior
to but not after immunodepressive
and 3) was apparently
directed
against
an early
one (patient
2) against
circulating
erythropoietin
(Fig.
early
to immunodepressive
case
(patient
3),
amenable
to surgery
showed
a favorable
response
ment (case
1 ). Two types of IgG serum
inhibitors
Case!
an
compartment.7
of adult
PRCA
who
responded
In a cyclophosphamide-resistant
lasting
(ALG)
either
differentiated
ET AL.
serum
peaks
tests
protein
were
were
was
observed.
negative.
type.
Total
were negative.
60 yrs:
level
showed
bilirubin
“PURE”
5.80
Direct
g/l00
and
Antinuclear
was
RED
0.40
CELL
ml
(2.75
indirect
antibodies
mg/100
APLASIA
g albumin
Coombs’
showed
ml,
serum
WITH
THYMOMA
Ht %
I
-I
days
20
10
t tt
TRANSFUS.
I-
t
CYCLOPHOSPH.
:pREDNlsoNE
Fig. 1.
Clinical
(400
(50
mg)
mg)
course of patient
1.
cold
moderate
iron
I
I’
and
test,
140 /Lg/
From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
PURE
RED
CELL
APLASIA
Bone marrow
marked
blasts
249
aspirates,
obtained
hypercellularity
were
of
absent.
Frequent
Radiographic
and
protruded
in the
surgical
excision
thymoma.
the
twice from the sternum
granulocytic
clusters
of mature,
tomographic
left
of the
line
with
tumor.
A
of
also
showed
was
anterior
character.
showed
lesion
the
mass
The
typical
consistent
Erythro-
observed.
a large
marginated
examination
a skin
showed
megakaryocytosis.
were
chest
smoothly
bioptic
examination
abundant
cells
of the
a
and once from each iliac crest,
and
lymphoid
examinations
hemithorax,
Hystologic
cell
whorls
with
the
which
patient
of
refused
spindle-cell
pattern
of
Kaposi’s
angiosarcoma.
The
patient,
cessfully
2 mo.
In
a second,
sociated
RBC
up
the
test
next
inhibitor
rising
and
drop
iron
Kaposi’s
skin
positive
(++).
sarcoma
6 mo
of
levels
demonstrated
The
patient
a
His
the
rapid
lineage.
serum.
In
of 2.8
This
of
mass
In
hematologic
of
was
May
in the
dismissed
values
his
dosage
increase
markedly.
deterioration
hematologic
unsuc-
approximately
in
a total
(WBC,
granulocytic
normal
treated
for
g)
1800/cu
mm).
of 15% was observed,
followed
examinations
showed
marked
mediastinal
was
a
initially
to
a progressive
diminished
showed
dismissal.
was
the
and
although
lesions
induced
after
prednisolone
(400 mg/day
up
of severe
leukopenia
depletion
serum
was
and
a reticulocyte
peak
40%. Bone
marrow
to
examinations
Kaposi’s
at home
up
transfusions,
erythropoiesis
Furthermore,
of
cell
propionate
to
significant
of
normality.
follow-up
of
died
red
of this treatment,
moderately
mo,
Case2(Fig.
his
same
asand
not
a Ham
month.
general
normal
Hct,
apparently
1972
condition.
were
was
Hb,
acid
During
Thereafter,
condition.
to the
The
end.
2)
A 70-yr-old
of severe
to
packed
testosterone
cyclophosphamide
at the appearance
peak
extension
was
3
progression
patient
completion
a distinct
values
modified,
the
IgG
repopulation
with
serum
an
ofintravenous
discontinued
impressive
erythroblastic
regular
of both
meantime
a course
and
days after
Twelve
on
mg/day
100
the
March
1971
was instituted
by
maintained
with
woman
anemia,
was
which
Serum
admitted
was
to
first
the
Sampierdarena
recognized
in
C. ANGELA,
RI
1966.
70yrs:
Hospital
Since
on
this
January
anemic
IDIOPATHIC
12,
1973
condition
PRCA
Ira
3.,,
I
II
days
Erythr.
10
20
t
conc.ttttt
CYCLOPHOSPH.
5.2 Gms (200/day)
t
30
t
40
50
t TRANSFUSIONS
f”
r
___________________
DEXAMETHASONE
8 mg/day
I__________
Fig.
2.
Clinical
60
course
of patient
2.
1 ALG
1(145 ml)
because
proved
re-
From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
250
MARMONT
fractory
to
which
lately
On
various
treatments,
she
induced
sensitization
reactions.
admission
amination
the
was
tracings
were
mm;
ential
was
count
monocytes,
(3.7
g albumin
265
mg/lOO
negative;
and
iron
A series
148
granulocytic
served
on any
Ham’s,
and
g/
The
patient
values
down
combined
and
was
not
instituted,
up
and
mm.
60,000/cu
On
the
The
mg ALG,
were
Two
and
and
received
insulin
UW%;
and
GPT,
tension
and
cardiac
values
to 37.5%.
of
this
1 mg
and
treatment,
130
went
bicarbonate,
and
and
hepatic
failure
UW%).
failure
Au
were
this
with
typical
145
the
woman
was
long-standing
not
ob-
the
Hct
5%
mg)
promptly
a low
mm,
and
to
bone
(Behringor 250
No
at
appearance
still
times
the
side-effects
good
of
She
days
was
after
vigorously
clinical
3 mg/l00
picture
ml;
negative.
10%
hematologic
alternate
the
of
peak
in
on
coma.
were
respectively,
9 days.
However,
tests
March
25%,
sustained
bilirubin,
antibody
on
a
diabetic
(serum
to
blood,
and
over
was
three
recovered.
supervened
fell
equine
ALG
from
5 mI/day,
to
who
into
WBC
a
mg/day)
138,000/cu
discontinued
patient,
of
Thereafter,
of
GOT,
Refractory
200
hypo-
19, 1973.
admitted
anemia.
to the
Splenectomy,
Sampierdarena
Hospital
performed
in
April
on
1972,
April
had
7,
not
1973
because
been
followed
ratio
for
initiated
count
of a
by
erythroid/
at
another
or Hct
values
observed.
On admittance
The
physical
for
mediastinal
5This
a very
findings
mm;
preparation
are
immunoglobulins
lins. Full informed
cases,
the
with
or near
Laboratory
consent
procedures
patient
normal
peripheral
ALG
proteins
pale
were
tumors.
2,480,000/cu
both
a hyper-
were
(200
the
improvement.
In January
1973 bone
marrow
smears
showed
a 1.25/100
myeloid
precursors.
A course
of cyclophosphamide
therapy
was therefore
institution
(total
dosage,
3 g); however,
no change
of either the reticulocyte
was
with
peripheral
to
progressed
suddenly
and
normal
erythroblastic-reticulocytic
up
ml (7250
however,
by death
the
fall
reached
in the
tetracosactrin
antigen
followed
in
marrow
point,
seen
rose
count
of repository
was
3)
A 58-yr-old
severe,
end
reticulocyte
dexamethasone,
hepatitis
Case 3 (Fig.
Hct
had
of
with
the
the
of
was,
The
was
a precipitous
meantime
gradually
amount
test
normal.
At this point
she was administered
intravenous
drip infusion
(starting
which
IgA,
erythrocyte
cyclophosphamide
At
the
were
values
LE
erythroblasts
and
hyperplasia
Hct
treatment,
itching.
after
discontinuation
progressive
and
fragility
ml
ml;
The
of red cell concentrates.
latter.
in
reticulocytes
up to a total
this
and
mm)
weeks
large
g/lOO
indirect
within
However,
mg/day)
had
5.9
present.
g of the
erythroblastic
count
during
hives
condition
treated
day
up to 20 mI/day)
(350,000/cu
which
any further
increase.
West
Germany)5
by
observed
moderate
of 5.2
differ-
mg/lOO
and
a hypercellular
5 days.
(8
dosage
showed
but did not show
werke,
Marburg,
first
RBC,
The
lymphocytes,
was
be detected.
were
cx-
25%;
mm.
1080
direct
Osmotic
of a series
platelets,
same
reticulocyte
the
dexamethasone
the
preparations
islands.
during
administration
Hct,
level
megakaryocytosis;
was
ml;
IgG,
could
data
showed
near-normal
infiltration
transfused
to a total
mm,
examinations
lymphoid
were
negative.
physical
metamyelocytes;
Both
biochemical
her
9000/cu
protein
peaks
transfusions,
electrocardiographic
g/l00
three
total
absent.
were
8
cell
otherwise
WBC,
values
were
all other
and
including
The
paraprotein
tests
ml;
crest
required
and
mm.
No
sucrose
Hb,
myelocyte
antibodies
100
iliac
Focal
to 12%
2100/cu
ml.
component
therapy
marrow
220
smear.
one
red
negative;
absent;
immunoglobulin
mg/lOO
but
was
virtually
85,000/cu
anti-IgG
was
of sternal
plastic
with
were
packed
fatigued,
showed
were
g globulin);
and
tests,
Serum
was
1gM,
antinuclear
range.
of
2.2
and
regular
examination
examinations
70,
platelets
on
pale
chest
reticulocytes
neutrophils,
ml;
extremely
Laboratory
peripheral
10;
antiglobulin
was
maintained
Fluoroscopic
normal.
2,270,000/cu
20;
patient
negative.
was
ET AL.
is a sterile
and
was
WBC,
pirogen-free
IgG
discoloration
and
obtained
from
Helsinki
convention
Hb,
8600/cu
patients
were
and
at
2 and
followed.
was observed.
examinations
6 g/100
mm,
5% solution
IgT,
of the skin
chest
showed
absent;
comprising
slaty
Fluoroscopic
examinations
reticulocytes,
of the
a grayish,
normal.
ml;
were
Hct,
of which
3 prior
90%
to
RBC,
neutrophils,
in saline. Virtually
least
negative
18%;
are
iS
its
administration.
68;
100%
of
immunoglobuIn
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PURE
RED
CELL
APLASIA
251
days
ft t
t
tTRANSFUSIONS
CYCLOPHOSPH.
/
Fig. 3.
Clinical
cyclophosphamide
eosinophils,
serum
was
paraprotein
peaks;
antiglobulin
tests,
biochemical
values
ig/l00
ml,
Sternal
with
some
collections
After
a 3-wk
a period
not
administered.
no immediate
was
fell
of
serum
from
The
smears
apparent.
of
iron
was
therapy.
are
also
the
145
ml
the
bone
levels.
value
of
were
serum
iron
g/
100 ml.
given
ALG
(7.25
g of globulin)
fever
rise
Hct
up
treatment
3030/cu
mm
to
to
these
absolute
a low
of
this
and
with
to
treatment,
and
instituted
supervened
(peak
massive
values,
erythromacro-
followed
by
a
lymphocyte
mm,
but
by
Although
modifications;
circulating
2 g
were
hives
A
were
390/cu
mega-
(up
therapy
peripheral
the
and
lymphocytes
normality.
changes
All
280-300
of 11 days.
ALG
no
normal.
myeloid
of
itching
total
indirect
were
thereafter
a period
some
erythrokinetic
ALG
end
of
with
Corticosteroids
was
after
values
preceded
These
with
developed
of
the
therapy
over
or
small
immunity.
at
and
cyclophosphamide
ALG
apparent
Direct
which
of
of
oral
ml)
negative
hyperplasia
were
moderate
all
The
g/l00
limits.
levels,
course
mm.
3.05
dissemination
marrow.
marrow
During
normal
fragility
was
reticulocytosis
apparent.
within
antiequine
a previous
460,000/cu
globulins,
bone
a sustained
platelets,
marked
patient
prevent
observed,
Brisk
readily
of this
patient
to
by
a pretreatment
discontinuation
tenance
up
were
was
to
with
and
for
A
reticulocytes
in
treatment.
repopulation
erythroblastosis
434
both
the
peripheral
followed
osmotic
erythroblasts.
aimed
observed
side-effects
which
drop
This
infusion
of this
of
were
TIBC,
obtained
4;
ml
except
showed
of observation,
No
drip
at the end
blastic
observed.
were
intravenous
16%)
was
period
and
ml and
absence
of 12 days).
no erythroblasts
tests,
been
g/l00
fractions
aspirations
near
had
monocytes,
3.15
normality,
134 g/100
and
25;
sucrose
within
crest
effect
ml (albumin,
and
were
iliac
No
immunoglobulin
Ham
series
over
g/I00
single
karyocytic
focal
ALG
1; lymphocytes,
6.2
UIBC,
and
1
course of patient
3.
(total dosage,
3 g).
2; basophils,
protein
( 2 Gms)
sharp
count
rebounded
after
therapy.
dismissed
Twelve
months
within
normal
in
excellent
later
limits.
condition
her
blood
However,
on
data
are
renewed
June
13,
still
1973.
She
completely
collections
was
normal.
of
small
given
Bone
lymphocytes
no
mainmarrow
are
From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
252
MARMONT
MATERIALS
Ferrokinetic
Measurements
Evaluation
90
mm,
iron
of radioiron
2,
3,
and
6
incorporation
reaching
after
values
a plateau.
during
a 9-day
for
period.
from
thawed
and
of the
to
and
3,
were
obtained
after
fluoresceinated
determinations),
fixed,
washed
2 and
again,
and
were
to and
after
full
erythroblastic
After
antihuman
gentle
30,
60,
and
radio-
determined
heart,
liver,
after
remission.
remission,
bone
washing
globulin
inspected
10,
Peripheral
when
and
spleen
were
gently
3)
until
intensely
at
citrate.
sacrum,
prior
-20’C
remission.
(FITC)
obtained
59Fe
over
performed
at
were
jCi
erythropoiesis
(Patients
the
13
determined
maintained
with
of
ineffective
examinations
at 37’C
donors,
exposed
ANF
2
incubated
original
were
of
was
Investigations
patients
samples
injection
evaluation
these
3)
Plasma
radioactivity
All
METHODS
1 and
clearance.
intravenous
Surface
Immunofluorescence
Sera
(Patients
plasma
hr
AND
ET AL.
sera
under
in
(the
both
marrow
preparations
buffered
same
saline,
currently
transmitted
they
used
and
for
incident
BV
illumination.
Studies
on Ep and Inhibitor(s)
Collection
patients
of serum.
both
maintained
prior
at
(anti-Ep)
Garcia.2’
One
All
and
was
Institute
sera
tography23
and
Medical
IgG
establish
its
oforiginal
purity.
The
sterile
blood
remission.
or IgG
3)
was
Serum
employed
to
thereby
employed,
of
the
and
or
125
12.5
DEAE-cellulose
IU
or
separated.
collected
from
plasma
all
samples
is always
sera.
Rabbit
reported
by
IU
of
of
human
were
either
mouse
quantitate
or
expressed
in
terms
sheep
of
IgG
the
Ep.22
chroma-
and
the
and
B Ep
column
immunodiffusion
to
antihuman
Schooley
standard
DEAE-Sephadex
Standard
respectively,
IgG
PRCA
method
neutralizes
London)
were
from
of
here
either
fraction
amount
fraction
a modification20
Research,
subjected
the
clinical
1 , 2, and
(Patients
nonheparinized
Ep serum
by
anti-Ep
techniques
Sera
utilized.
obtained
for
were
electrophoresis
until
of
or
complete
antihuman
milliliter
PRCA
after
-30’C
ofrabbit
Ep serum
(National
Heparinized
to
frozen
Preparation
in PRCA
immuno-
fraction
and
equivalent
volume
serum.
Preparation
patients
of
were
incubator
test
materials
incubated
with
constant
Inc.,
Davis,
conditions.
The
precipitate
was
In other
Ep (step
Calif.)
Research
plasma
Lab.,
Inc.,
Davis,
IgG
Ep,
with
means
ofa
two-step
with
graded
The
incubations
IgG
and
performed
then
known
from
goat
antihuman
(2) after
of
centrifugation,
2 was
(from
the
(GARGG,
under
the above
appropriate
similarly
amount
of
incubated
PRCA
was
Anti-
ascertained
1 or
This
Medical
(GAHGG,
previously
supernatant
with
Connaught
globulin
was
procedure.
to the above
all
bath
of anti-Ep.24
gamma
IgG
from
a water
globulin
15 mm
of protein;
of GAHGG
quantities
according
I or
lU/mg
in
gamma
The
sera
The
anti-Ep)
quantities
patient
of 0.5
amount
known
antirabbit
centrifugation.
against
with
of
for an additional
by
activity
appropriate
(I)
ofGAHGG;
were
and
Goat
added
ml
2) were
incubated
incubation
by
incubated
with
Ep.
(GAHGG
+
was repeated
as a control
together
with the experiment
involving
incubation of IgG + Ep and then + GAHGG.
Assay of test materials
in either normal
or exhypoxic
polycythemic
mice.
CF I female
mice
weighing
20-25 g were employed.
The animals
were maintained
on a diet of laboratory
pellets
and tap water ad libitum.
Normal
mice
received
test materials
either
intraperitoneally
or subcutaneously
on
days
0, 1, and
2. Radioiron
(0.5
zCi 59Fe citrate
in sterile
physiologic
saline)
cent
5%
then
The
incubation:
amounts
30 mm.
fraction
a specific
mice.24
serum/0.l
discarded
serum
polycythemic
PRCA
by testing
Canada)
Calif.).
exhypoxic
of
for
thereafter
the
Toronto,
bodies
ml
at 3i’C
ascertained
experiments,
I sheep
in
(I
was subsequently
was
previously
assay
anti-Ep
shaking
Antibodies
GARGG
for
with
was
Ep)
injected,
RBC-radioiron
of body
exhypoxic
weight.
hr.
respectively,
incorporation
Mice
with
polycythemic
intermittent
220
+
Test
hypoxia
materials,
mouse
(0.42
either
intravenously
values
a final
assay,25
atmospheres
incubated
or
thereafter
hembtocrit
value
the animals
ot
or
intraperitoneally
determined.
air)
not
fo
as
of
were
18
on
Blood
less
than
rendered
hr/day
described
up
above,
day
3,
volume
40%
were
discarded.
polycythemic
to
a
total
3were
and
24-hr
per
was assumed
to be
In
by exposure
of
injected
approximately
intraperito-
the
to
From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
PURE
RED
CELL
APLASIA
253
Table
1.
ron Turnover
Radioi
Studies in Patient
59Fe
Citrate
Injected
On
11/19/1970
Plasma iron clearance
Plasma
iron pool
Plasma
iron turnover
(t3, mm)
rate (mg/day)
RBC uptake
neally
mice
on
determined.
hematocrit
Rat
or human
bone
from
tap
of the
the
cells
were
passed
cell
pellet
was
20%
fetal
Rat
the
was
end
plasma
(0.5
and
Studies
count
Radioiron
incorporation
RBC-59FE
cell
suspensions
was
incubated
iCi/plate).
Ep
IgG
The
and
filter
and
U
plate
contained
5
x
with
rat
plasma
serum.
The
incubated
18-hr
cells
48
(59Fe
were
removed
incubation
with
and
lgG
chloride)
for
from
24
the
the
for
15
hr
a 60%
III
sheep
from
C02-95%
the
air
jCi/0.1
incubator
and
radioactive
the
NTC-l09,
(step
(0.5
mm).
and
subtracted
in a 5%
was
suspension,
taken
Ep
was
hr at 3i’C
iron,
of
Added
of
pellets
a slight
femora
rpm
was
in 2 ml
marrow
to
After
count
mixture.
volume
for
radioiron
plates
106
tibiae
(1200
cell
Bone
according
from
a final
laboratory
penicillin/mI.
in
thereafter
with
Ep.
of
fraction
centrifuged
nucleated
20%
with
as
were
Mice
a diet
marrow
100
A
calf
IgG
on
PRCA
et al.26
steel
were
an
and/or
administered
values
weight.
serum
maintained
NTC-l09.
the
After
PRCA
7590
was
of body
fresh
fetal
incubation,
7%
of
heparin/mI
and
the
be
rats,
stainless
in
from
48-hr
to
Krantz
U
(precolostrum),
The
of the
added
tracted
a
Each
subtracted
volume.
mixture.
through
resuspended
serum
was
by
200
accordingly.
calf
Ep)
NTC-109
At
5 posthypoxia.
cent
with
reported
2500
per
incubation
incubated
32-52
21.8
day
Sprague-Dawley
containing
The
plasma
was
method
in NTC-109
adjusted
cultures:
male
ad libitum,
modification
collected
marrow
150-200-g
water
volume
from
7. Forty-eight-hour
The blood
volume
was assumed
of less than 56% were discarded.
obtained
and
1.7
starting
day
2.4-4.0
979
(per cent 59Fe injected)
or subcutaneously
normal
80120
3.54
53.5
814
Range
Normal
66
6.15
19.2
TotolRBCiron(mg)
.
4/14/1971
320
(mg)
1
gas
ml).
radioiron
heme
was
cx-
counted.
on
human
of 2.5
marrow
x 106 cells
cultures
per
were
performed
similarly,’9
employing,
however,
a nucleated
plate.
RESULTS
Ferrokinetic.
Two
Measurements
cases
of PRCA
measurements
and 3 confirm
prior
to but
not
peak
values
for
inferior
molysis
have
prior
to and
the complete
after
be postulated.
been
previously
3)
studied
after remission.’2-27
absence
of 59Fe
therapy
incorporation
is also
immunosuppressive
during
in line
with
the
59Fe
4/17/1973
iron clearance
Plasma
iron pool
Plasma
Total
RBC
(ti,
mm)
iron turnover
uptake
855
(mg)
rate (mg/day)
RBC iron (mg)
(per cent Fe
-
injected)
means
(Tables
clinical
sharp
of
studies
by the
1 and
remission
ferrokinetic
in patients
bone
marrow
2).
Although
were
slightly
and/or
excessive
hedeposit
iron pool
should
drop
of
radioiron
plasma
therapy.
Table 2. Radioi ron Turnover
Plasma
by
The present
incorporation
range,
ineffective
erythropoiesis
out. Thus,
an expansion
of the
This
after
ts 1 and
immunosuppressive
radioiron
to the normal
may be ruled
clearance
(Patien
-
Studies in Patient
Citrate
Injected
3
On
5/28/1973
73
Range
Normal
80-120
7.98
5.3
2.4-4.0
9.32
72.4
32-52
1447
36
2500
75-90
1
From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
254
MARMONT
20
Fig. 4.
Ep levels in serum
of patients 1, 2, and 3
prior to immunosuppressive
therapy,
as evaluated
in
exhypoxic
polycythemic
mice on the basis of 48-hr
per
cent RBC-59F
incorporation
values
(mean
±
SEM).
(IU)
oib’#{176}Fe
E
.
080
T
1
:
I
PRCA I
‘
PRCA I
PRCA II
Immunofluorescence
In patients
the
Investigations
2 and
erythroblasts,
3 no
which
slight,
aspecific
homogenous
and
fluorescence
globulin
of
be
types,
erythroblasts.
Studies
on Ep and Inhibitor(s)
in Fig.
affecting
in PRCA
4, Ep
levels
at
the
level
preparation.
and,
of
the
Conversely,
to
a lesser
extent,
Incubation
of
strong
nuclear
PRCA
erythroblastic
fluorescence
of
the
all cells
bone
in-
Sera
were
on the
eosinophilic
could
be observed.
SLE
serum
showed
marginal
is
3)
demonstrated
holes”
both
in each mouse
and then goat antirabbit
(GARGG).
2 and
could
as “black
fluorescence
eluding
As indicated
per 0.1 ml of anti-Ep)
gamma
(Patients
appeared
neutrophilic
granules
marrow
with
active
serum
ALP1E
of serum injected
The serum was injected
either alone or after
with anti-Ep
serum (A-Ep)
(1 ml of PRCA
indicated.
incubation
#{149}
.
I
The total amount
020
!
ET AL.
of the
(Patients
elevated
marrow
1 , 2, and
in patients
and
3)
1 and
2 (Hct,
22%
and 18%, respectively),
or barely
detectable
in patient
2 (Hct,
21%).
Also
of
interest
is that the activity
was fully neutralized
following
incubation
of serum
with anti-Ep
and GARGG.
Although
not presented
here,
further
experiments
indicated
that
incubation
of PRCA
serum
Ep
(cases
1 and
3) with
neuramini-
dase
induced
complete
neutralization
of Ep. Additionally,
dose-response
gression
lines
following
injection
of purified
serum
PRCA
Ep were
parallel
to those of Ep standard
B. Thus,
it is apparent
that,
in all cases,
molecule
in serum
erties.
During
ALO
showed
therapy,
patient
2 (peak
values,
neutralized
following
Figure
5 shows
that,
normal
biologic,
immunologic,
however,
Ep activity
was
2.1 IU/ml;
incubation
in human
Hct value,
with anti-Ep
bone
and
elevated
chemical
propin the serum
of
26%).
This activity
and GARGG.
marrow
cultures,
the
restrictly
the Ep
was
IgG
also
fraction
fully
from
the serum
of patients
1, 2, and 3 exerted
a significant
inhibitory
effect
on the
erythropoietic
response
induced
by Ep. It is noteworthy
that
postremission
serum
IgG did not exert an inhibitory
action.
As indicated
in Fig. 6, the serum
Fig. 5.
Heme synthesis
(mean cpm ± SEM)
in cultures
of normal
human marrow
incubated
with Ep (0.4 IU Ep Step Ill per plate) and/or
lgG (amount
equivalent
to 0.1 ml of original
serum
per plate). The lgG were purified
from
the serum
of either a normal
subject
(NORM
lgG), or PRCA
patients
1. 2. or 3 (PRCA
lgG).
The latter sera were obtained
either prior to or
after (PRIOR
or AFTER)
immunosuppressive
therapy.
Although
not presented
in this figure.
comparable
results
were
observed
after
a
similar
incubation
with Ep of smaller
amounts
of normal or PRCA I. II. or Ill lgG (equivalent
to
0.02. 0.04. 0.06. or 0.08 ml of original
serum).”
line. #{149}
p <0.01
when compared
with third, fourth,
cpm
2.000
[
cpm
[CASE
1i1
I]
LI
i cii
ZCXX)J’
cpm 2000r-
[
I CAEi1
cor
.i
rc
19G
p < 0.01 when compared
and last bar on the same
:
(p
:
NORM
‘P
wit h first
line.
{
POR WIER
‘‘-‘
PRCA IgG+Ep
bar on the same
From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
PURE
RED
CELL
255
APLASIA
0*
SALINE
LE
NORMAL
lgG
A-Ep
PACA
SERUM
FRACTION
Fig. 6.
Effect in normal
mice of the lgG fraction
purified
from the serum
of either
a normal
sub( NORMAL),
a patient
with
systemic lupus erythematosus
(LE) without anemic PRCA patient 1
(PRCA), or a rabbit producing antihuman
Ep (A-Ep) on 24-hr per cent RBC-5
Fe incorporation
values
( mean ± SEM) . The amount of lgG injected in each mouse was equivalent
to 0.2 ml of
original
serum
per day x 3. 1p < 0.01 when compared
with other groups.
ject
lgG
fraction
from
patient
I also
induced
poietic
activity
in normal
mice. Similar
tion
from
patient
2: saline-injected
RBC-59Fe
7. 1 1 ±
jected
from
incorporation
0.90.
with
patient
inhibitor
tion
±
SEM),
inhibitory
PRCA
effect
appropriate
amounts
(0.1-0.3
3. It is therefore
postulated
7 indicates
1 and
poiesis
no
decrease
of the
were obtained
with the
23.14
±
1.71 (24-hr
II serum
was
IgG
apparent
(0.1
in normal
mI/day)
of the IgG
that,
in some
PRCA
serum
cases,
erythroIgG
per
fraccent
ml/day),
mice
in-
fraction
the IgG
is species-specific.
Figure
patients
values
However,
a significant
results
controls,
elicited
of PRCA
that
2 exerted
in exhypoxic
polycythemic
a significant
inhibitory
by a simultaneous
I IgG
with
Ep
injection
and
mice
effect
of
subsequently
Ep.
the
on
IgG
the
wave
Furthermore,
with
GARGG
fraction
from
of erythroprior
led
incuba-
to full
%Fe
resto-
Ep(JJ)
15
020
in exhypoxic
polycythemic
mice of Step I
or not with
(A)
anti-Ep
rabbit
(0.1 ml serum per 0.2 IU Ep) and then goat
antirabbit
gamma
globulin
(GARGG),
(B) serum lgG from
patient 1 (amount equivalent
to 0.1 ml of original
serum
Fig. 7.
Effect
Ep (0.2 IU),
serum (A-Ep)
incubated
per 0.2 IU Ep) and then goat antihuman
(GAHGG),
or (C) serum
lgG from patient
gamma
globulin
2 (amount
as for
patient
1) and then GAHGG,
as evaluated
on the basis
of 48-hr per cent RBC-59 Fe incorporation
values
(mean
±
SEM).
SALINE
C
‘
+A-(p
+96
(PRCAI)
(p
(PRcA)
From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
256
MARMONT
::
-‘:-----
i:
-.-------
----
trohonof
original
.
:
:
!
0
8
g
_,
0L
‘::
_-;--
0
5
-
15
#{149}1
ration
ofthe
Ep
the Ep molecule
stitute,
therefore,
it is concluded
that
and
a similar,
GAHGG
are
identical
and
with
port
for
Since
this
it interacts
that
to those
this
the
observed
contention
0.05
day),
from
a sustained
either
when
compared
with
a normal
acts
at the
following
subject
incubation
the
near
during
of the
indicates
that
does
not conbeen
described
in marrow
cultures,
organs.
By implica-
marrow
level.
of Ep
It is noteworthy
with
rabbit
autoantibody
molecule.
absence
of
anti-Ep
interacted
Further
sup-
Ep
activity
in
therapy,
in the
for human
PRCA.
of serum
IgG from
In the
patient
immunosuppressive
two experimental
models
injection
of microdoses
inhibition
values.
serum
IgG from
patient
2 with Ep
of the Ep activity.
These
results
that
this IgG
as an anti-Ep
from
to but not
values.
control
clearly
which
have
inhibitor
is also effective
with the Ep-generating
suggested
functioning
derives
Figures
8 and 9 show
one (Fig. 8), prolonged
1 induced
<
inhibitor
It is therefore
Ep, thereby
serum
of this patient
prior
presence
of low hematocrit
first
‘p
days
two-step
incubation
of PRCA
led to complete
neutralization
GARGG.
circulating
per
activity,
as evaluated
in these
mice.
This
did not interact
with the IgG fraction,
an antibody
to Ep. Comparable
results
in previous
reports.’6”8
it can be excluded
that
tion,
serum
(NORM lgG) or PRCA patient
1 (PRCA
lgG),
on moan
values of 24-hr per cent RBC-59F. incorporation,
Hct,
and serum Ep levels (evaluated
on the basis of 48-hr
RBC-39Fe incorporation
values in polycythemic
mice
receiving
a total amount
of 1 ml of donor mouse serum).
I
‘n.-
ET AL.
erythropoietic
activity,
associated
the
with
both
a progressive
drop
of the hematocrit
values
and
an inverse
rise of Ep
serum
levels.
Thus,
at the end of the experiment,
an experimental
model
for the
PRCA
condition
of patients
1 and 3 was established.
As shown
in Fig. 9, a
rabbit
ogous
lowing
pearance
immunized
with
and heterologous
a booster
of erythroid
human
urinary
Ep,
Ep, showed
a sharp
injection
precursors
of
human
producing
anti-Ep
to
drop
of the hematocrit
Ep.
in bone
This
was
correlated
both
homolvalues
folwith
marrow
disap-
smears.
No Ep was detected
in the serum.
It is postulated
that
this
experimental
PRCA
was mediated
by
production
of anti-Ep
neutralizing
endogenous
rabbit
Ep. Further
support
for
this contention
derives
from
a subsequent
increase
of the Ep serum
levels,
corEp
Fig. 9.
Effect
of two
booster
Inlections
urinary
Ep (2 x 25 lU) in a rabbit producing
Ep cross-reacting
with
rabbit
endogenous
serum
titers (per cent of peak
values),
Hct
reticulocyte
count are indicated.
of human
antihuman
Ep. Anti-Ep
values,
and
0
E
i4.
0
3)
From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
PURE
RED
CELL
257
APLASIA
+k4I-(p/
________________________
O/o’e
Fig.
10.
Effect
in exhypoxic
polycythemic
mice
of
020
Step I Ep (0.2 IU), administ.red
either alone or with
anti-Ep serum (0.2 ml), or serum lgG from patient 1
(amount
evaluated
equivalent
to 0.2 ml of original
serum),
on the basis of 48-hr per cent RBC-59Fe
values (mean
istered
either simultaneously,
anti-Ep serum or lgG. *p
corporation
with
corresponding
related
and
patient
0.01
when
values.
to a drop
ofanti-Ep
ofthe
2 was
Figure
hematocrit
10 shows
the
<
:V-H.
-
compared
titers
values.
and
Thus,
0.05
an
(p
0
o.2u
WTL
directly
i
Tfl4
to both
experimental
(p
1)
a reticulocytosis
model
for
PRCA
of
established.
from
PRCA
poiesis
evoked
regard,
inEp was adminor 12 or 24 hr before
Ep + anti-Ep
inversely
a rise
serumi
as
SEM).
±
Ep(IU)
that
in exhypoxic
1 exerted
by Ep
half-life
polycythemic
mice
a significant
inhibitory
injected
simultaneously,
ofheterologous
the
effect
on
or 12 or
gamma
globulin
IgG
serum
the wave
of
24 hr earlier.
in the
mouse
fraction
erythroIn this
is 5 days.29
DISCUSSION
All three
a spindle-cell
patients
showed
a typical
PRCA
condition,
thymoma
lasting
for at least 40 yr. Similar
demonstration
previously.3’4
secreted
ofthe
Although
by the
thymic
tumor
it has been
thymoma,
doubt
and onset
suggested
has
been
ofthe
anemia
that a humoral
cast
on this
of immunologic
homeostasis,
perhaps
tions
of T lymphocytes,
as postulated
mediated
by
by Allison,30
association
ofthymoma
sarcoma
of primary
tumors,3’
with
Kaposi’s
again
perhaps
as
sented
due
against
hematopoietic
cytes have
indication
variety,4#{176}’4’ and
identification
of human
more
generally
mediated
Serum
IgG
in vivo and/or
immunodepressive
cultures),
erythropoiesis.
stem cells.36 On the
been
observed
in chronic
of an immunoproliferative
immunologically
rodents,
to impeded
both
yielded
bone
(normal
negative
recorded
might
be
A disruption
controlling
more
likely.
ofthe
of
funcThe
coexistence
defective
of small,
mature
scattered
reports,33-34
germinal
centers
immuno-
lymphocytes
has been
have
been
in
obob-
This bone
marrow
lymphothan
one interpretation.
The
cells,35
which
are present
in
However,
marrow
evidence
has
lymphocytes
been
pre-
as committed
other
hand,
similar
collections
of lymphocold
agglutinin
anemia,3738
as a possible
disease,39
in the idiopathic
warm
antibody
in organs
(thyroid,
muscle,
liver)
affected
by
diseases.42
inhibitors
to erythropoiesis
in vitro
techniques
in all
therapy.
In case
3,
in vivo
a loss of
appears
is an example
served
on histologic
sections
in idiopathic
PRCA.12
cytosis
in PRCA
marrows
is susceptible
to more
lymphocytes
may be regarded
as committed
stem
number
have been
inhibitor
hypothesis.’7
a consequence
surveillance.3”32
A focal and/or
disseminated
infiltration
PRCA marrow,
previously
mentioned
in
served
in all cases
reported
here.
Furthermore,
large
associated
in case 1 with
long intervals
between
were
demonstrated
three
patients
prior
however,
assay
of
or polycythemic
results.
Thus,
mice)
it is apparent
and
that
by means
of
to but not after
the
inhibitor
in
in vitro
consistent
(rat
marrow
demon-
From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
258
MARMONT
stration
of the
human
bone
Although
parently
this
inhibitory
constitutes
last
serum
adult
activity
in the
marrow
cultures.
the inhibitor
is usually
regard,
an
an
antibody
anti-Ep
of only one out
PRCA
have been
is characterized
IgG
serum
directed
to
molecule
against
circulating
has
been
elevated
levels
requires
the
Ep
bone
in rare
Ep
of
by our
so
The
of serum
studies
marrow,
cases
demonstrated
of five patients
examined
apparently
demonstrated.
by both
fraction
far.’6
first,
and
ET AL.
in
it
ap-
in
the
PRCA.
group
In
Thus,
two types
of
and most usual,
one
an
IgG
serum
inhibitor
against
the erythroid
marrow
(type A), the second
one by barely
detectable
1evels of circulating
Ep and an anti-Ep
serum
IgG (type
B). In regard
to PRCA
type A, the mechanism
ofaction
ofthe
inhibitor
is not yet elucidated.
Since
the
IgG serum
fraction
of case I exerted
an inhibitory
effect
on the wave of erythropoiesis
lective
evoked
in polycythemic
action
of the inhibitor
unlikely.
patient
Therefore,
in view
3, the possibility
should
at
of
mice
the
by Ep injected
level
of the
the negative
be considered
12 or 24 hr earlier,
Ep-responsive
cells
immunofluorescence
that the inhibitor
a seseems
studies
in
interacted
with
an early
erythroid
precursor.
This postulate
is in line with the complete
absence
of recognizable
erythroid
precursors
in marrow
smears
of these
patients.
However, it is of relevance
that an additional
inhibitory
effect of PRCA
IgG on the
differentiated
erythroid
compartment
(“erythroblast
cytotoxicity”)
has
been
demonstrated
by Krantz
et #{149}19.43
Strong
evidence
supports
the contention
A or B, are autoantibodies
playing
a major
Thus,
the
inhibitory
more,
it can
munosuppressive
human
PRCA
quired
to assess
The
ALG
activity
of
steroid
phamide
the
this
ALG
reactivity
to this
the
enhancing
ALG
ALG
therapy
when
therapy
serum
inhibitors
the
more
these
patients
myeloid
bone
marrow
agent
in case
3, and
role
of
ALG
latter
based
effect
in
in patient
3: the
of cyclophosphamide
administration
are
ofthese
of the
of a lower
by 7.25 g of ALG.
The chief objections
diseases
IgG
fraction.
are
obtained
by means
of an
to an autoimmune
mechanism
therapeutic
demonstrated
former
course
quential
the
but not after
remission
experimental
models
in rodents.
Thus,
the
Further-
induced
by imfor both
types
of
basic
criteria
resatisfied.t
alkylating
in PRCA
conventional
has failed.
In addition,
according
be administered
in PRCA
cases
of
of response
though
role
the inhibitors,
whether
of type
in the pathogenesis
of PRCA.
agent
and
and/or
militate
androgen-cortico-
to our
associated
results,
with
cyclophosa thymoma
to surgery.
Initiation
dictable
of
to
before
In addition,
established
pathogenetic
type
treatment
should
amenable
is confined
demonstrated
therapy.
have
been
striking
remissions
lend further
support
in favor
not
be
that
role
to the
on
its
on oncogenesis,
is fundamentally
could
be detected
a former
was
uncertain
on
its “toxic”
the
trial
in
by
case
2,
serum,
no
B lymphocyte
lack
Krantz)#{176} Alit was
clearly
resistant
to a
to the se(2 g) followed
in humoral
autoimmune
T lymphocytes,45’46
side-effects.
unpre-
the
proved
fully
dramatically
of ALG
effect
an antithymocyte
between
T and
by
of cyclophosphamide
administration
and
suggested
clinical
patient,
who
(3 g), responded
amount
fundamental
was
to cyclophosphamide,
However,
difference
in
populations,47
its
rumored
although
uptake
so
of
that
From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
PURE
RED
CELL
259
APLASIA
differentiated
immunofluorescent
absorptions.48
mediated
In addition,
autoimmune
splenectomy.#{176}
reactions
Although
the
greatly
patients
fewer malignancies
have been reported
for autoimmune
diseases.-55
Nevertheless,
does not play a greater
and/or
different
immune
mechanisms
against
neoplasia
ALG
toxicity,
eliminated
In conclusion,
is a humorally
whether
bodies,
lating
cyclophosphamide
only
risk
of
is well
after
de
novo
oncogenesis
established,5153
in
considerably
in patients
similarly
immunosuppressed
it has been demonstrated
that ALG
role in the breakdown
of hypothetic
than
conventional
cytotoxic
agents.51’56
due to the
refined
recent
liberation
of
preparations.58
kinins,57
support
the contention
that
disease.
Immunosuppressive
alone
specific
effect
in humorally
ITP
relapsing
after
or
in combination
has
adult
PRCA
treatment,
with
ALG,
induced
remission
in two corticoid-refractory
cases
and in one patient
with
not amenable
to surgery.
It is proposed
that
IgG serum
autoanti-
usually
directed
Ep (PRCA
type
genesis
apparently
in the more
the present
studies
mediated
autoimmune
with
a complete
a thymoma
be obtained
therapeutic
refractory
increased
immunosuppressed-transplanted
Finally,
early
been successfully
could
ALG
exerts
a strong
diseases,49
including
of this
against
the erythroid
A or B, respectively),
marrow
or rarely
play
a major
role
against
in the
circupatho-
disease.
ACKNOWLEDGMENT
We
for
wish
to express
his kind
advice
our
gratitude
in the
to
preparation
Dr.
Albert
of an early
S. Gordon,
draft
New
of this
York
University,
New
York,
manuscript.
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Blood
cells
4 1:417,
Ramirez-Matcos
H:
Medical
1973
JG,
uses
of
anti-
57.
Bradley
Kinin
i, Cuscheni
liberation
globulin.
during
Lancet
A,
Mason
therapy
2:578,
K,
with
Mason
anti-
1972
From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
1975 45: 247-261
Pure red cell aplasia (PRCA): Response of three patients of
cyclophosphamide and/or antilymphocyte globulin (ALG) and
demonstration of two types of serum IgG inhibitors to erythropoiesis
A Marmont, C Peschle, M Sanguineti and M Condorelli
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