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1980 56: 329-343

Autoimmune thrombocytopenic purpura

S Karpatkin

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The Journal of
B L 0 OD The American Society of Hematology

VOL. 56, NO. 3 SEPTEMBER 1980


Autoimmune Thrombocytopenic Purpura

By Simon Karpatkin

SUMMARY platelet count to normal. This can generally be accom-

Adult autoimmune throbocytopenic purpura (ATP) plished with a platelet count of >40,000/cu mm with
is a platelet disorder that develops in certain individu- patients having this disorder. Approximately 50% of
als with a genetic as well as sex (female) predisposition patients respond to steroids by a significant elevation
following an environment event (?viral). This results of platelet count and improvement of purpura.
in the production of an IgG antiplatelet antibody However, cessation of therapy results in eventual
capable of reacting with the host’s platelets, as well as relapse if the disease is of the chronic variety. Splenec-
crossing the placenta. This leads to the rapid clearance tomy is successful in approximately 659’o-7S% of
and destruction of opsonized platelets by the reticu- patients, resulting in a restoration of the platelet count
loendothelial system, particularly the spleen, by to normal or safe levels by removing a major source of
greater than tenfold the normal rate. Bound platelet platelet destruction as well as antibody production;
lgG correlates with disease severity, whereas serum platelet survival improves. At least 50% of patients “in
antiplatelet IgG does not. It has not been rigorously remission” following steroids or splenectomy generally
established whether bound platelet IgG is directed have a compensated thrombocytolytic state in which
against a platelet antigen or represents an immune increased platelet production keeps up with increased
complex bound to the platelet Fc receptor. Neverthe- platelet destruction. Antiplatelet IgG can often be
less, several lines of evidence suggest that antiplatelet found in the serum of these patients.
IgG binds directly to a platelet antigen(s). Patients refractory to steroids and/or splenectomy
Megakaryocyte number, volume, and mass are present with a serious therapeutic problem. Immuno-
increased commensurate with increased platelet turn- suppressive therapy is effective in approximately one-
over. Platelets of i ncreased size, megathrombocytes, third of refractory patients, but often relapses occur,
are noted on peripheral smear or via platelet volume requiring maintenance therapy with potentially
distribution analysis. Megathrombocyte number is mutagenic drugs. The use of ymca alkaloids has
proportionate to megakaryocyte number and to plate- recently been proposed. Its efficacy has yet to be
let turnover. Megathrombocyte diameter is inversely established and its use should be confined to research
proportional to platelet survival. centers.
Antiplatelet antibody is also associated with quali-
tative platelet functional defects, which are indistin-
guishable from those noted with thrombopathia (i.e., In the 1950’s, the term idiopathic thrombocytopenic
apparent platelet release defect). Antibody-induced purpura (ITP) referred to a clinical disorder of
functional defects are probably more common than unknown etiology associated with thrombocytopenia
quantitative thrombocytopenic defects and may repre-
sent a significant portion of those women with the From the New York University Medical School, New York, N.Y.
“easy bruising” syndrome and normal platelet count. Submitted November 28, 1979; accepted February 19. 1980.
Address reprint requests to Simon Karpatkin, M.D., New York
Adults who develop ATP generally develop the
University Medical School, Department of Medicine, 550 First
chronic variety, which remains premanently with the
Avenue, New York, N.Y. 10016.
patient. Treatment should be directed towards main- © 1980 by Grune & Stratton, Inc.
taming the patient free of purpura, not restoring the 0006-4971/80/5603--000J$02.o%

Blood, Vol. 56, No. 3 (September), 1980 329

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and purpura. The disorder could be acute and often capable of inducing thrombocytopenia when infused
transient, as in the case of childhood ITP, recurrent into volunteer recipients.
with episodes of “remission,” or chronic, as in adult
ITP. It was noted that mothers with ITP (with active SERUM ANTIBODY

disease or in remission) often gave birth to children Harrington then developed a simple platelet agglu-
who developed transient ITP, suggesting the transfer tinin test that consisted of the addition of heat-
of a humoral factor. It was also noted that patients inactivated “test” sera to an aliquot of normal plate-
with Coomb’s positive (autoimmune) hemolytic let-rich plasma followed by incubation overnight at
anemia often had episodes of ITP (Evan’s syndrome) 5#{176}C.3
The sera of patients with ITP were positive in
both transient and recurrent, suggesting an autoim- approximately 65% of cases.6 This antiplatelet factor
mune etiology.5 Furthermore, the favorable response was shown to be present in the gamma globulin frac-
to steroids (antilymphocytic) and/or splenectomy tion of sera. In 1965, Shulman et al.,7 employing the
(antireticuloendothelial) encouraged the thought that same in vivo test as Harrington,3 demonstrated that
this disease might be mediated by the production of the antiplatelet factor was in the 75 gamma globulin
anti-platelet antibody. fraction of serum, was adsorbed by human platelets,
In 1951, Harrington clearly established the humoral was species specific, and affected autologous as well as
nature of such an antiplatelet factor and provided the homologous platelets.
strongest evidence that this disease was antibody- The platelet agglutinin test3’714 as well as other
mediated.3 He infused the plasma equivalent of a unit tests’#{176}”5 for antiplatelet antibody, particularly the
of blood from a patient with ITP intravenously into antiglobulin consumption test,7’8”6’8 although repro-
himself, and promptly developed thrombocytopenic ducible in som&4”618 laboratories, was not reproduc-
purpura (Fig. 1). A drop in platelet count occurred ible in others7’8’”3”9 Indeed, some workers claimed
immediately, reaching its nadir in 1-3 hr and return- that the antiplatelet factor of serum was no more than
ing to normal in 4-6 days. Of interest was the observa- thrombin,’3 a potent platelet agglutinin. It was argued
tion that only 63% of patients with the diagnosis of that the absence of platelets and their phospholipid
ITP contained a factor in their plasma that was platelet factor 3 (PF-3) in these patients prevented
adequate utilization of prothrombin, leading to a high
residual prothrombin in their sera. This could then be
converted to thrombin by the addition of platelets to
the test system.’3
In 1968, Karpatkin and Siskind2#{176} employed an
ammonium sulfate globulin fraction of sera to develop
a PF-3 immunoinjury technique for measuring anti-
platelet antibody that circumvented the problem of
residual prothrombin or thrombin. This technique was
capable of detecting an antiplatelet factor in approxi-
0 mately 60%65%421 of patients with ITP, confirming
Harrington’s original work with platelet agglutinins,
as well as the work of Steffen,’6 Dausset,’7 and Van
deWiel et al.’ with the antiglobulin consumption test.
I- The PF-3 immunoinjury technique takes advantage of
a- the requirement of platelet phospolipid to act as a
catalytic surface for the coagulation cascade and is
measured by the acceleration of the clotting of plate-
let-rich plasma following addition of a factor capable
of injuring platelets.420’2’ The PF-3 immunoinjury
I 23 I 2 3 4 5 6 ‘7 8 9 technique has been recently modified so that it can be
HOURS DAYS employed as a rapid, routine laboratory test employing
Fig. 1 . Thrombocytopenic effect produced by transfusing 500
frozen platelets and requiring 4 hr for its perfor-
cc of citrated blood or its plasma equivalent from 1 7 patients with mance.2’ Positive results have been found in 60% of
thrombocytopenic purpura. Transfusions were given at “0” time. patients with ITP. Results are also positive in systemic
Recipients were healthy laboratory workers or patients with
inoperable carcinoma. The mean effect is represented by the
lupus erythematosus (SLE), rheumatoid arthritis,
heavy line.(Reproduced by permission.3) lymphoma, autoimmune hemolytic anemia, chronic
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hepatitis, and following numerous blood transfusions. (tests are positive in >92% of thrombocytopenic
This antiplatelet factor has the characteristics of an patients).
IgG immunoglobulin in that it is stable at 56#{176}C;20”6its The immunofluorescent technique is relatively
activity can be neutralized with a globulin fraction of insensitive. The complement lysis-inhibition technique
rabbit anti-human IgG antisera;4’2#{176} but not anti-IgM, is complicated, detects IgG at the 10-25-ng level, and
IgA, or IgD;2#{176} its activity can be adsorbed to plate- can be employed with as little as 106 platelets. The
the adsorbed activity can be eluted and the Fab-anti-Fab technique is also relatively complicated,
eluted4”6 activity neutralized with rabbit anti-human requires 3 days to perform, is sensitive at the I 5-20-ng
IgG but not with normal rabbit globulin;4’20 the eluted level, and can be performed on approximately 2 x 10
material has a molecular weight of 1 50,00020 and 520 platelets. The radioactive IgG Coomb’s test can be
value of 77#{149}5,16 similar to that of human IgG; and it applied to routine use but has a complicated method of
can be transferred across the pIacenta.’’2’ The heavy standardization (IgG fixed to red blood cells), is sensi-
chain subclass of the IgG immunoglobulin appears to tive at the 5-10-ng level, and requires approximately
be ‘yG3, and the IgG contains both kappa and lambda iO freshly collected platelets. The solid-phase
light chains.22 Some degree of platelet specificity does radioimmune assay can be performed with commer-
exist, since the anti-platelet antibody of 3 of 5 patients cial reagents and is relatively simple, except for the
studied reacts more intensely with their own platelets iodination of protein A. It is I 0-50-fold more sensitive
than with platelets from unrelated donors.22 The than other techniques, can be performed with as little
serum antibody is useful for diagnostic purposes only, as 2 x I 0 platelets, and can be employed with frozen
since its titer does not correlate with severity of platelet extracts (samples can be stored at - 20#{176}C
diseases.4 Results confirming the reliability of the the presence of protein inhibitors for future assay).
PF-3 immunoinjury technique2326’7’ and indicating the The inverse relationship between platelet count and
presence of antiplatelet antibody in ITP patients have platelet IgG is best expressed by a log-log equation
been published by a number of workers employing a with a correlation coefficient, r = -0.71, p < 0.001,
variety of different techniques.233’ Because of the rather than an arithmetic plot, r = 0.56, p < 0.001.
immunologic nature of this disorder, in which the This indicates considerably more antibody bound to
host’s immune system destroys the host’s platelets, it platelets from patients with low platelet counts than
was recommended that the term idiopathic be changed would be expected from a simple inverse arithmetic
to autoimmune and the disorder designated ATP or relationship. This could represent more antiplatelet
autoimmune thrombocytopenic purpura.32 This desig- antibody bound to larger younger platelets, mega-
nation has been accepted by other investigators.26’33 thrombocytes,”#{176} which are increased in number in this
disorder. However, a recent study suggests other-
wise.4’ It is conceivable that younger platelets may be
In I 975, Rosse and coworkers34 made a major more resistant to destruction and clearance by the
contribution to this field by developing a complement- reticuloendothelial (RE) system.
mediated red blood cell lysis-inhibition technique for Platelet-bound IgG has also been recently reported
the quantitative detection of bound antiplatelet anti- in 46% of patients following gram-positive or -negative
body, wherein 1 7 of I 7 patients tested were positive. septicemias,42 where positive test results are thought to
Bound platelet IgG was found to correlate with sever- represent nonspecific binding of bacterial antigen-
ity of disease. Treatment of patients with steroids or antibody complexes to platelets. Accordingly, positive
splenectomy lowered platelet IgG; and patients with results associated with septicemias should be inter-
considerably elevated platelet IgG were refractory to preted with caution, before making the diagnosis of
corticosteroids or splenectomy. This work was quickly ATP.
confirmed by several laboratories employing similar35
as well as different techniques, which include immuno-
fluorescence,36 Fab-anti-Fab IgG assay,37 radioac- Serum complement levels are generally normal, and
tive 251 Coomb’s test.3’ and a solid-phase radioimmu- attempts to measure serum complement-dependent
noassay for IgG, employing rabbit anti-human IgG antibody have been negative.7 Nevertheless, C3 has
“sandwiched” to radioactive ‘ 25I staphylococcal recently been reported to be bound to platelets in the
protein A, which binds to the Fc domain of IgG.39 The presence of bound IgG (9 of 14 patients with elevated
various techniques described measure 1-1 1 ng of platelet IgG; 9 of 16 total patients tested). The C3
nonspecific IgG on 106 normal platelets and 5-13 bound was proportional to the IgG bound. In another
times this amount on platelets from ATP patients study3’ employing a radioactive 1251 Coomb’s test, 12
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of 21 patients had elevated C3 in the absence of coated latex particles by rheumatoid factor or Clq.
elevated IgG levels. The pathophysiologic significance The sera of 48 of 72 patients with ATP (58%)
of fixation of C3 to platelets in 58% of the 36 patients displayed a significant inhibitory effect toward both
(from both studies) remains to be determined. agglutinating agents. A negative correlation was
obtained between the platelet count and the titer of the
inhibitory factors. When the sera were subjected to
In 1971, Karpatkin et al.4 demonstrated decreased Sephadex G-200 gel filtration, IgG and DNA could be
circulating antiplatelet antibody postsplenectomy in 7 detected in “heavy factions” corresponding to Ag-Ab
of 8 patients studied. In 1972 both Karpatkin et al.43 complexes in 6 different patients. However, DNA was
and McMillan et al.44 independently demonstrated not necessarily eluted with “heavy IgG” or fractions
synthesis of specific IgG antiplatelet antibody by the with inhibitory activity for agglutination of IgG-
spleen, which reflected approximately 0.6%-5% of coated latex particles. Dissociation and association of
total IgG produced. Both laboratories also noted a “immune complex” inhibitory activity could be
considerable increase in the synthesis of nonspecific obtained with sera from 2 patients. These authors also
IgG by splenic tissue from these patients that was found hepatitis HbsAg in 20 sera, Epstein-Barr virus
5-55 times that produced by control spleens;43’44 an (EBV) antigen in 5 sera, and adenovirus antigens in 6.
observation that remains unexplained. This very interesting report remains to be confirmed.
However, confirmation of the presence of immune
complexes would still not rule out the presence of
Present technology for the detection of antiplatelet specific IgG against platelet antigens. These com-
antibody in the serum or on the platelet does not plexes could represent an epi-phenomenon, wherein
distinguish between IgG and lgG complexed to an immune complexes are developed against platelet or
antigen, i.e., an Ag-Ab complex bound to the platelet other cellular antigens produced during cell destruc-
Fc receptor. It is conceivable that ATP is an immune tion by “specific” platelet antibodies. In order to
complex disease wherein the IgG antibody reacts with conclusively demonstrate the presence of specific anti-
a foreign (?viral) antigen or a (nonplatelet) circulat- body against platelet antigens, it will be necessary to
ing host antigen, to form an immune complex that demonstrate that Fab fragments of eluted platelet IgG
then binds to the platelet; or a foreign antigen binds to or serum antiplatelet IgG specifically binds to plate-
the platelet and then reacts with an antiforeign antibo- lets. Experiments designed to answer this question
dy. Six lines of evidence suggest that this may not be have as yet not been reported.
the case: (1) Antiplatelet factor classically crosses the
placenta in this disease, resulting in the passive trans- ROLE OF CELL-MEDIATED IMMUNITY
fer of neonatal thrombocytopenia. IgG is known to In 1970, Piessens et al.46 demonstrated increased
cross the placenta, whereas immune complexes are less lymphocyte transformation (incorporation of tritiated
likely to do so. (2) The in vivo infusion experiments thymidine into DNA) with autologous platelets from a
had demonstrated the thrombocytopenic factor to be patient with ATP as well as homologous platelets plus
in the 75 gamma globulin fraction of sera.6’7 (3) The the pateint’s lymphocytes, suggesting a role for cell-
serum factor demonstrates greater specificity for the mediated toxicity. Wybran and Fudenberg47 per-
patient’s platelets.22 (4) Lymphocytes from cultured formed similar studies on a group of patients with this
spleens are capable of synthesizing IgG, which specifi- disorder and noted positive lymphocyte stimulation
cally binds to washed platelets.43’44 (5) The eluate from with autologous platelets in 7 of 8 patients with severe
bound antiplatelet IgG migrates in the 75 (IgG) disease and 3 of 6 patients with mild disease; 10
region of a sucrose gradient39 (although it is conceiva- normal subjects and 6 patients with nonimmune
ble that the complex may have disassociated with the thrombocytopenic disorders gave negative results.
extraction procedure, or that the Ag may be too small Similar observations were made by Clancy4t in 6 of 7
to appreciably affect the IgG sedimentation value). patients with the disorder. He also noted inhibition of
(6) Antibody activity, as defined by IgG platelet leukocyte migration by autologous platelets in 9 of 10
adsorbtion, is eluted from Sephadex G200 and DEAE patients tested. This technique is based on the fact that
cellulose at the area where IgG is found.33 when antigen is incubated with sensitized lympho-
Nevertheless, circulating immune complexes have cytes, a number of soluble factors are released, includ-
been recently reported in this disorder by Lurhuma et ing a migration inhibition factor that inhibits the
al.45 These workers employed two methods for the migration of macrophages, polymorphs, and lympho-
detection of circulating immune complexes based on cytes. However, it now appears likely that the results
their inhibitory effect on the agglutination of IgG- reported in their studies actually represented nonspe-
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cific lymphocyte stimulation by platelet-antibody (compared to normal subjects) parallels the increase
complexes, which have been shown to stimulate in platelet turnover (compared to normal subjects).
lymphocyte transformation.49 Platelets have recently Although the older literature refers to “abnormal
been shown to be coated by antiplatelet antibody (see megakaryocytes,” reflecting decreased platelet pro-
Bound Platelet Antibody). In 1979, Quagliata and duction secondary to splenic inhibition of the bone
Karpatkin5#{176} reported impaired lymphocyte transfor- marrow via a humoral antogonist,6’64 the kinetic
mation in whole blood with mitogenic agents (phyto- evidence of Harker56 as well as Garg et al.#{176}
hemagglutinin and concanavalin A) in patients with otherwise. Nevertheless, common antigens for the
ATP (but not with washed lymphocytes). The number megakaryocyte and platelet have been demonstrated
of T cells, B cells, and null cells were normal. An with heterologous antiplatelet sera,6567 and more
inverse relationship was found for the number of T recently, with radioactive homologous splenic anti-
cells and platelet count in 31 ATP patients, with body synthesized in vitro.68 It is conceivable that
r = -0.55, p < 0.001. However, “killer” cells could impaired megakaryocytopoiesis69 may obtain in some
not be demonstrated employing lymphocytes from 7 situations; however, this has not been demonstrated as
ATP patients incubated with 51Cr-labeled allogeneic yet.
or syngeneic platelets. Lymphocyte capping with
rabbit antihuman lymphocyte IgG was impaired in 7
of 7 patients with ATP. Large platelets or megathromobocytes are routinely
The apparent disappearance of impaired lympho- noted in this disorder on EDTA smear or by volume
cyte transformation with washed lymphocytes and the determination in a Coulter Counter with EDTA
abnormal lymphocyte capping suggests the presence employed as anticoagulant#{176} (Fig. 2). Megathrombo-
of a blocking factor(s) or cell or humoral antibody(s) cytes generally correlate with megakaryocyte number
that could be responsible for the observed qualitative in most acquired platelet disorders of increased
abnormalities of cell-mediated immunity. destruction or decreased production, r = 0.7, p <

0.00l.#{176} Mean platelet diameter is 1.6-fold greater

than normal in ATP. The megathrombocytes in this
It is generally accepted that thrombocytopenia is disorder are probably “stress” platelets, which are
secondary to increased platelet destruction of anti- released during conditions of increased megakaryocyte
body-coated platelets by particularly turnover. The increase in megathrombocytes parallels
in the spleen. Platelet survival is markedly shortened the increase in megakaryocytes noted and can be in
to less than 10% of the normal 10-day survival.5559 the order of 3-4-fold.4#{176} There is generally a shift in the
Megakaryocytes are increased in number, volume, and platelet volume distribution curve to the right towards
immaturity.4056’57 Platelets are decreased in number larger platelets. Approximately 50% of patients in
but generally increased in volume (see Platelet Size).
More specifically, Branehog et al.6#{176}
have demon-
strated that platelet survival is proportional to the
circulating platelet count (at a platelet survival of 0-3
days). Harker 56 and Branehog et al.57 have both z
studied a total of 49 patients with comparable platelet I-
counts, mean 30,000/cumm. The mean platelet LU
survival was 0.3456 and 0.67 days, respectively. The
mean platelet turnover was increased to 4956 and 2.3
times normal,” respectively. Megakaryocyte mass has LU
been quantified by Harker et al. who studied 14
patients. Megakaryocyte number averaged 3 times the 4
control value, and megakaryocyte volume averaged LU

I .6-fold. Thus, the increase in total megakaryocyte

4060 P100
mass averaged 4.8-fold, indicating that under suitable
stress, the bone marrow can increase platelet produc- WINDOW SIZE
tion by approximately fivefold. The ratio of platelet Fig. 2. Coulter platelet volume distribution curves in 20
turnover to megakaryocyte mass in ATP patients was normal subjects ± 2 SD (grey area). (A) A patient with a normal
platelet count (1 60,000/cu mm) in “remission” from ATP (with
the same as that found in normal subjects. This
elevated platelet lgG. 25 ng lg/10 platelets). (B) A patient with
implies that thrombopoiesis is effective. Thus, the ATP and a platelet count of 55,000/cu mm. Calibration: 1 win-
increase in megakaryocyte mass in ATP patients dow = 0.25/cu p.
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“apparent” clinical remission have increased mega- patients with the “easy bruising syndrome” and
thrombocytes7#{176} (as well as bound platelet IgG39), mdi- normal platelet count. Platelet function was abnormal
cating increased platelet turnover despite a normal in 31 patients (29 were female) and was indistinguish-
platelet count. This is known as a “compensated able from the “aspirin-like” platelet aggregation
thrombocytolytic state.” There is a significant inverse defect reported in patients with ATP,7’ SLE,72 and
relationship between platelet diameter and platelet thrombopathiaY79 Of particular interest was the
mean life-span, r = -0.8, p < 0.001 .“ There also is a presence of antiplatelet antibody in 38% of these
significant relationship between platelet diameter and patients. Increased number of megathrombocytes was
platelet production rate, r = 0.7, p 0.001 and < also noted in 71% of these patients, suggesting
between platelet size and percent young megakaryo- increased platelet turnover despite a normal platelet
cytes, P = 0.6, p < 0.005.” count.
Patients with particularly severe disease also have In 1967, five independent groups779 described an
evidence for intravascular thrombocytolysis, as noted apparently new qualitative platelet disorder in which
by the presence of small fragments that can be the prolonged bleeding time, impaired collagen-
detected with the Coulter Counter by a shift of the induced platelet aggregation, and impaired epineph-
platelet volume distribution curve to the left or by a rine-induced secondary wave of aggregation were
separate small particle peak. These have been shown attributed to defective release of platelet adenosine
to contain platelet fragments as well as red blood cell diphosphate (ADP). The disorder was termed throm-
fragments by electron microscopy. The red blood cell bopathia and is indistinguishable from the acquired
fragments are associated with weak complement sensi- aspirin defect in normal subjects with respect to plate-
tization of red blood cells in 7 of I 2 patients, suggest- let aggregation. Most of the patients described have
ing that autoantibody might also be directed (subclini- been females. Three of six patients studied had
cally) against red blood cells.54 i ncreased megathrombocytes. Four patients had
histories that included ankylosing spondylitis, inter-
mittent arthritis, arthralgia, and myositis. Upon
In 1972, Clancy, Jenkins, and Firkin7’ reported the further study, two subgroups were documented: one in
presence of qualitative (functional) platelet defects in which the storage pool of adenine nucleotide and
I I patients in “remission” (normal platelet counts). serotonin associated with platelet dense granules was
Although no correlation was found between the diminished, termed “storage pool” disease,79 and the
presence of antiplatelet antibody (PF-3 technique) other in which the storage pool was normal, but the
and abnormal platelet function, an antiplatelet func- release from this pool with initiation of irreversible
tion factor could be isolated from the globulin fraction platelet aggregation was impaired, termed “release
of the patient’s serum that could inhibit platelet func- defect.”74
tion when mixed with normal platelet-rich plasma. The patients with thrombopathia (both varieties)
The antiplatelet function factor could be specifically are indistinguishable from the 31 easy bruising
adsorbed to washed human platelets and specifically patients described by Lackner and Karpatkin73 with
neutralized with anti-human lgG, suggesting that it respect to sex, clinical history (a mild bleeding disor-
was an immunoglobuin. However, a similar antiplate- der), and platelet function. The presence of antiplate-
let function factor was also found in 3 patients with let antibody in 38% of these patients, as well as the
mild intermittent disease in whom platelet function finding of similar platelet function abnormalities in
was normal. such autoimmune disorders as compensated ATP in
In 1974, Regan, Lackner, and Karpatkin72 remission and SLE, strongly suggests an autoimmune
described abnormal platelet function in 1 2 of 2 1 con- etiology or association for many of the patients with
secutive patients with SLE that correlated with clini- thrombopathia and/or the easy bruising syndrome.
cal severity of disease. No correlation was found This is supported by the disappearance of abnormal
between the presence of serum PF-3 antiplatelet anti- platelet function in at least 3 of the 3 1 patients
body and abnormal platelet function in the “nonre- studied, as well as the description of an acquired
sponder” group. However, an antiplatelet function storage pool disorder associated with antiplatelet anti-
factor could be isolated from the serum globulin frac- body that responded to prednisone therapy in a patient
tion of 3 of the 7 nonresponder patients, which could with nephritis, polyarthralgia, chondritis, thrombo-
inhibit platelet function of normal platelet-rich plas- phlebitis, Raynaud’s phenomenon, and a thrombotic
ma, whereas no such factor could be isolated from the tendency.8#{176} It is intriguing that 2 of the nonresponder
serum of 4 of 4 “responder” patients with SLE who SLE patients, 3 of the easy bruising patients, 2 of the
had normal platelet function. thrombopathia patients, and the patient with the
In 1975, Lackner and Karpatkin73 studied 75 acquired storage pool disorder had transient episodes
From by on October 7, 2010. For personal use only.


of thrombocytopenia. It is therefore likely that anti- now available that have specificities closely “related”
platelet antibody can contribute to or be responsible to alleles of the D locus and are therefore called DR or
for both quantitative as well as qualitative platelet DRw for D-related workshop designation. The DRw2
disorders. This can explain those patients with autoim- alloantigen has been found in 75% of 20 consecutive
mune thrombocytopenic purpura with so-called “safe” AlP patients in the New York City area, compared to
platelet counts of >50,000/cumm who have purpura 23% (<0.001) in an ethnically matched control popu-
and bruise easily. It is further proposed that some lation.’5 This provides a genetic predisposition with a
patients with thrombopathia and/or the easy bruising relative risk of 10. (A relative risk of I would indicate
syndrome may have a forme fruste of ATP, wherein no association between the presence of the antigen and
the antiplatelet antibody damage is insufficient to the disease.) Of particular interest was the apparent
result in thrombocytopenia, but sufficient to elicit typing of a single allele, DRw2, in I 0 of the 20 patients
functional platelet defects.73’8’ Perhaps two varieties of tested. Also noted were a high association of the
antiplatelet antibody are present: one capable of apparent haplotypes A3-B7 and A26-Bw38 of the
destroying platelets (? high-affinity antibody), and the HLA-A and B loci, which appear to be in linkage
other capable of altering platelet function (? low- disequilibrium with DRw2 in the population studied.
affinity antibody). It is suggested that thrombopathia These data indicate a genetic predisposition to ATP
and/or the easy bruising syndrome may be the bottom that is inherited with a DRw2 gene of the major
of the ATP iceberg. The incidence of this qualitative histocompatibility system. It is of interest that SLE
disorder(s) is considerably more common than classic has recently been shown to be associated with DRw2
84 and DRw3, with relative risks of 3.9 and 6.5, respec-
tively 66.87


It should be emphasized that thrombocytopenic DIAGNOSIS

purpura is merely the top of the iceberg, and that The term autoimmune thrombocytopenic purpura
probably many thousands of individuals have platelet should be applied to those patients fulfilling the
counts below 1 50,000/cu mm without purpura (95% following criteria.
probability of being abnormal”). These individuals (I) Increased platelet destruction as manifested by
are unaware of their illness, since symptoms of thrombocytopenia or shortened platelet survival i.e.,
purpura or bleeding do not occur until the platelet compensated thrombocytolytic states.40’57’82 Both con-
count reaches dangerous levels, i.e., <30-50,000/cu ditions are associated with an increased percent or
mm. There are still other individuals with a compen- number of megathrombocytes (young platelets).’#{176}’57’82
sated thrombocytolytic state, i.e., normal platelet (2) Increased number of megakaryocytes in the
count but decreased platelet survival and increased bone marrow. In the older literature,60 emphasis has
megathrombocytes.82 These individuals probably have been placed on abnormal megakaryocyte morphology:
subclinical compensated autoimmune thrombocytoly- i.e., absence of platelet budding, lack of granularity,
sis, wherein increased bone marrow production of vacuolization, cytoplasmic and nuclear degenerative
megakaryocytes keeps up with increased peripheral changes. These observations are probably a reflection
platelet destruction. These individuals are in precar- of megakaryocyte turnover and maturation. Any
ious balance, and any stress on the productive capacity disorder with increased megakaryocyte turnover is
of the bone marrow, such as nutritional (folate or B,,), likely to contain an increased number of young mega-
drugs, toxic substances (alcohol), or viral or bacterial karyocytes, which in turn would probably reflect most
infections as well as stress on platelet survival such as of the above findings.
alcohol, infection, etc., can precipitate thrombocytope- (3) Presence of bound antiplatelet antibody in the
nia. These individuals may possibly include the absence of septicemia42 or hypergammaglobaline-
numerous women with normal platelet counts and easy mia’57.
bruising syndrome and/or thrombopathia, some of (4) Exclusion of other primary clinical disorders
whom have antiplatelet antibody and defective platelet that are capable of giving all of the above criteria or
function. some of the above criteria: systemic lupus erythemato-
sus, lymphoma, disseminated intravascular coagula-
tion, hypersplenism, drug-induced thrombocytopenic
purpura, sepsis, etc. The distinction between ATP and
Recent studies on the genetic predisposition to ATP drug-induced immunologic thrombocytopenia is often
have revealed a high association with an alloantigen of crucial. All drugs should be withheld and the platelet
the HLA-D locus, which is responsible for the mixed count closely observed. Failure to return to a normal
lymphocyte stimulation reaction. Specific antisera are platelet count in 7-10 days (in the absence of serious
From by on October 7, 2010. For personal use only.


hepatic or renal disease) rules out the diagnosis of normal tourniquet test, and absent to normal clot
drug-induced immunologic thrombocytopenia. retraction, depending on the platelet count. There are
(5) Absence of splenomegaly in 97% of patients. Its diminished platelets and increased megathrombocytes
presence usually,88 but not always (as might be the on peripheral smear. Platelet and red blood cell frag-
case with children8991), excludes the diagnosis of mentation may be detectable via Coulter Counter if
ATP. the thrombocytopenia is severe enough. Anemia
The term ITP should be reserved for those 5%-I 0% secondary to blood loss may be present. The white
of patients without demonstrable bound antiplatelet blood cell count is generally normal or slightly
antibody but who fulfill the remaining criteria. increased. There is often a relative lymphocytosis with
atypical lymphocytes (particularly in children) and
eosinophilia. The bone marrow contains increased
The signs and symptoms of this disorder are directly numbers of young megakaryocytes and often an
related to the platelet count and are not specific for increase in eosinophiles.89’96 The myeloid: erythrocyte
ATP or ITP but will be present in any quantitative (M:E) ratio may be decreased if blood loss is a
platelet disorder. When the platelet level is insufficient prominent feature.
to support hemostasis, generally <30-50,000/cu mm,
capillary bleeding or purpura ensue. The degree of
thrombocytopenia required for hemorrhage can be
quite variable, 10-50,000/cu mm, and is probably Autoimmune thrombocytopenic purpura may be
dependent on such factors as platelet age (greater temporally classified into three categories: acute,
functional capacity of young platelets,9294 or mega- intermittent, and chronic.
thrombocytes95) antiplatelet antibody binding leading The acute variety most often occurs in children,
to functional defects,8’ and capillary vessel integrity. particularly following a seasonal (winter-spring) viral
The type of bleeding is predominantly dermal and illness96 in 50% of patients (or, rarely, following a
mucosal. Bleeding into the skin with pin-point hemor- vaccination against a viral illness.’33) These include
rhage (pctechiae), particularly in dependent areas typical childhood infections and upper respiratory
where there is increased capillary pressure (i.e., lower infections. The average interval between purpura and
extremities), is often the rule. Petechiae are viola- preceding infection is 2 wk.9#{176}Of interest is the recent
ceous, flat, round, intradermal, and submucous report of high levels of bound platelet IgG in this
hemorrhages that later turn blue and yellow. The disease, which the authors postulate represents Ag-Ab
petechial purpura may become confluent and present complexes.98 The disease has an average duration of
as ecchymoses. Common areas of hemorrhage are in 1-2 mo (usually less than 6 mo). The male:female
the nasal, buccal, gastrointestinal, and vaginal muco- ratio is I 3.89.90,96.97 Although the acute disease is
sa. Examination of the mouth often reveals violaceous usually considered a milder disorder with a better
hemorrhagic blebs, 0.25-0.5 cm in diameter, on the prognosis than the chronic disorder, 27 deaths have
buccal and glossal mucosa with bleeding gums. been reported out of a total of 709 cases not treated
Conjunctival and retinal hemorrhages may be noted. with steroids.89#{176}’9699 Approximately 7%-28% of chil-
In chronic ATP or ITP, there is often a history of easy dren go on to develop the chronic variety.8990’96
bruising in the absence of trauma, frequent epistaxes, The chronic form most often occurs in adults, is
and prolonged menses. If the thrombocytopenia is persistent, lasting years to indefinitely, and has a
chronic, gastrointestinal blood loss may ensue, and female:male ratio of 2_4:l.388971b01 The so-called
iron deficiency anemia with microcytic hypochromic remissions of the chronic form are remissions of
red blood cells may be evident on peripheral smear. purpura only. The platelet count usually remains at
The most serious complication and one which is one-third to one-half the normal value.97 Some
rarely seen (particularly when steroids are employed) patients have been followed with the chronic disease
is hemorrhage into the central nervous system. This for 30 yr.97
can be fatal89 and must be rapidly and vigorously The intermittent variety may occur in childhood or
prevented by suitable therapy when there is purpura adulthood and may by spaced by intervals free from
and signs or symptoms of CNS bleeding, such as disease, wherein both the platelet count and platelet
retinal hemorrhages, convulsions, meningismus, head- survival are normal.’#{176}2 The usual pattern is for the
ache, change in personality, or more specific neuro- platelet count to return to normal in less than 6 mo,
logic signs. and remain normal for at least 3 mo prior to the next
Laboratory findings reveal a prolongation of the episode.#{176} As many as 5 recurrences have been
bleeding time, a positive tourniquet test, an absent to reported over a 4-1 8-yr interval.’02
From by on October 7, 2010. For personal use only.


POSSIBLE INTERRELATIONSHIP BETWEEN phagocytes to digest intracellular particles and destroy

ATP AND SLE bacteria,’#{176} Steroids inhibit erythrophagocytosis by
ATP may be an early manifestation of SLE in 07 adherence of antibody-coated plate-
3%-16% of patients.88”#{176}3104 In a series of 34 patients, lets to granulocytes,’#{176}8 and phagocytosis of platelets by
the median time for the development of SLE post- granulocytes. ‘#{176} Steroids inhibit chemotaxis of mono-
splenectomy was 2.5 yr. with a range of 3 mo to I 0 cytes”#{176} as well as monocyte receptors for lgG and
yr.’#{176}5Data supporting the similarity of these two C3.” There is indirect evidence that steroids inhibit
autoimmune disorders (chronic ATP and SLE) can be binding of autoimmune antibody to red blood cells”2
obtained from the young female preponderance, the as well as platelets.3#{176} There is controversial evidence in
presence of antiplatelet antibody, and the high mci- man as to whether steroids in the dosages currently

dence of DRw28587 in both disorders. Indeed, the employed significantly inhibit antibody production to
claim has been made that splenectomy for ATP accel- a previously recognized antigen. ‘#{176}“ ‘ 2 4 However,
erates the expression of SLE or activates a “dormant” steroids have been shown to decrease the levels of free
form of the disease.’#{176}4This claim has been challenged, and cell-bound autoimmune anti-red blood cell anti-
however,88”05 and is not accepted by most workers in body in man following 4-90 days of treatment with 60
the field. mg/day ofprednisone.”2 And, with high-dose methyl-
prednisolone, 96 mg for 3-5 days, a significant 22%
TREATMENT AND DIAGNOSIS decrease in serum lgG has been reported in 86% of
The classical treatment for autoimmune thrombo- volunteers 2-4 wk later.”6 Steroids however, do
cytopenic purpura is palliative, not curative, and is increase the catabolic rate ofcirculating IgG.”4 16

directed toward blockage or removal of a major site of Prednisone at 40 mg/day can inhibit the response to
platelet destruction, the spleen. delayed hypersensitivity.”7 118 Steroids can enhance
capillary resistance.”9’22 The effect of steroids is
Treatment With Steroids usually noted within the first 24-48 hr7”23 if sufficient
Administration of steroids is usually successful in steroids are employed, i.e., prednisone, I mg/kg.
either raising the platelet count to safe levels or normal However, a delay of 3-4 days may sometimes be
levels and is often dose-dependent. It is equivalent to a required to effectively inhibit splenic sequestration.7
“medical splenectomy” in that it prevents sequestra- In some situations, a “response to steroids” may not be
tion of damaged or antibody-coated platelets by the noted until I or more weeks of therapy. An effective
spleen (Fig. 3). Steroid administration to normal mdi- response to steroids (i.e., platelet count rising to
viduals has no effect on platelet survival or platelet > 100,000/cu mm) occurs in 36%_44%I659l124I25126
count.7 Steroids are known to reduce the ability of of all patients treated. Raising the steroid dosage to
I .5-2 mg/kg’27”#{176}’ will have some effect on the platelet
count (although not necessarily to an effective level) in
70%-80% of patients. The sole purpose of steroid
implementation is to maintain the platelet count at a
safe level, i.e., >50,000/cu mm. There is little value in
Lu attempting to bring the platelet count to normal levels.
C- This is often associated with prohibitive levels of
steroids, which lead to the well known deleterious side
effects of hypercorticism. There is no available
evidence that long-term steroid therapy has any effect
z on the natural history of the disease (following cessa-
tion of therapy).#{176}’96 On the contrary, there is evidence
that long-term large doses of prednisone can occasion-
ally cause thrombocytopenia.’28

Indicationsfor Splenectomy
Fig. 3. Comparison of response of normal and splenectomized
persons to ITP factor. The graph on the left shows the effects of A favorable response to moderate steroid dosage, I
ITP plasma in a normal individual. The graph on the right shows
the effects of the same ITP plasma in a splenectomized person.
mg/kg, is probably an indication that the spleen is the
Note that the ITP plasma dose that did not produce thrombocyto- major site for platelet destruction and that the patient
penia in the splenectomized person was greater than the dose will benefit from splenectomy. Harrington et al. have
that produced marked thrombocytopenia in the normal individual.
(Reproduced by permission of Transactions of the Association of
reported a success rate of I 00% in such steroid-
American Physicians.) responsive splenectomized patients.6 However, the
From by on October 7, 2010. For personal use only.


duration of follow-up has not been reported. Further- that the quantity of antiplatelet factor determines the
more, Doan et al.88 have noted a 79% response to site of sequestration. Splenic sequestration was
splenectomy in patients who failed to respond to extremely sensitive to low concentrations of antiplate-
steroids. Splenectomy removes the potential site of let factor following in vivo infusion of “ITP” plasma
destruction of damaged platelets,3”29 as well as a into volunteer recipients,’29”32 as was platelet survival
significant source of antiplatelet antibody produc- in nonsplenectomized, isoimmunized dogs.’27 Higher
tion.4’43’’54 After splenectomy, platelet survival may concentrations of antiplatelet antibody infused in vivo
return towards normal within 65 hr to 5-8 days.’27 The into volunteer recipients resulted in hepatic sequestra-
antiplatelet antibody, however, is still present in the tion.’32
plasma3’4’9’2’ of patients with ATP, despite an apparent The above observations indicate that splenectomy is
clinical remission, as well as on the platelets of some in order for all chronic cases of ATP, i.e., >6 mo
individuals.38’39 The antiplatelet antibody can be duration, regardless of the site of sequestration or
demonstrated in vivo by passive transfer to normal response to steroids (if they cannot be maintained free
recipients3 and by the classical occurrence of neonatal of purpura on 5-15 mg prednisone/day). This is
thrombocytopenia in infants of mothers with splenec- further supported by the clinical observations that
tomy-induced remission from ATP. It is of interest unsuccessfully splenectomized patients sometimes
that splenectomy in a normal individual or animal has respond better to steroids’27 and/or immunosuppres-
no effect on platelet survival.7’””30 The response of the sive therapy,’27’35’3’ and that splenectomy makes
platelet count to splenectomy is usually immediate available to the active platelet pool the 40% of plate-
with a peak obtained between the first and second lets normally sequestered in the spleen.’39 These plate-
week, In one study, all 15 of 22 patients who lets are enriched with megathrombocytes,’4#{176} which
responded to splenectomy had a peak platelet count aggregate better in vitro than other platelets.95
>500,000/cu mm, while those who did not have a
remission had a peak below this level.96 Approximately Risk ofinfection and Death Postsplenectomy

109o-l2% of patients will relapse following initially The hazard of severe infection (particularly pneu-
successful splenectomy,88”24 the majority within the mococcal) and rapid death in splenectomized infants
first year, but some as long as 5 yr later.’8 and children has been recognized for the past 20
Shulman et al.’29 have shown that six times more yr.’4’ “ This has been associated with disseminated
antiplatelet factor (obtained from a patient with ITP intravascular coagulation and Waterhouse- Frider-
and infused into a volunteer recipient) is required to ichsen syndrome. It has been argued that only children
significantly lower the platelet count in a splenecto- with associated primary disease, such as thalassemia
mized recipient compared to a nonsplenectomized major, Wiskott-Aldrich syndrome, histiocytosis, portal
recipient (Fig. 3). This indicates that other reticuloen- hypertension, etc., are at greater risk to infection and
dothelial organs, such as the liver, although less sensi- death.’43 What has not been fully appreciated is the
tive as a “sieve,”
sponse to
still capable

of destroying

3 ‘ “ 32

with severe
of similar

reported 3988900024,1 33 However, Aster has (meningitis or bacteremia). Eight of these patients
suggested that hepatic and splenic sequestration can ( I 0%) had absent splenic function (seven had splenec-
vary in individual patients with the course and severity tomies and one had splenic atrophy). Six patients died.
of the disease’32.’34 Hepatic sequestration was found in Reasons for splenectomy varied from trauma (2
patients who were more severely affected, e.g., lower patients), incidental to surgery (2 patients), acquired
platelet counts and shorter platelet survivals.’34 There hemolytic anemia, spherocytic hemolytic anemia,
is some experimental evidence in animals that a autoimmune thrombocytopenic purpura, and thalas-
compensatory hepatic sequestration follows splenecto- semia major. The onset of pneumococcal sepsis post-
my,’3’ reaching its maximum 6-8 wk postsplenectomy. splenectomy varied from I .5 to I 4 yr and averaged 5
This was associated with increased erythrophagocyto- yr. Hemostatic defects were observed in 7 patients,
sis by Kupffer cells following treatment with damaged and in 4, the diagnosis of disseminated intravascular
red blood cells.’3’ Indeed, patients who relapse follow- coagulation could be confirmed at autopsy: hemor-
ing “successful” steroid response can be shown to have rhagic diathesis, fibrin thrombosis of renal glomerular
developed hepatic Nevertheless, Na- capillaries and adrenal sinusoids, focal ischemic and
jean et al.59 have reported a 30% response to splenec- hemorrhagic lesions of the adrenal cortex, kidneys,
tomy in patients with exclusively or predominantly liver, gastrointestinal mucosa, ovary, choroid plexus,
hepatic sequestration. Shulman,’29 Baldini,’27 and and myocardium, including 2 patients with the Water-
Aster and Jandl’32 have presented evidence suggesting house-Friderichsen syndrome. It is of interest that 14
From by on October 7, 2010. For personal use only.


of 1 9 cases of Waterhouse-Friderichsen syndrome refractory to steroids and/or steroids and splenectomy

reported in the literature and associated with pneumo- is less enthusiastic. We have experienced the rare
coccal sepsis had absent spleens or splenic atrophy.’ patient with prompt and dramatic recovery; as well as
In contrast, of 523 patients with nonpneumococcal the more common situation where there is a small rise
infection, only 1 patient had an absent spleen.’44 The in the platelet count of 10-40,000/cu mm, with usual
findings strongly suggest that the spleen is a main line relapse several days later. Side-effects of peripheral
of defense in the handling of pneumococcal sepsis as neuropathy and intense bone (particularly jaw) pain
well as disseminated intravascular coagulation. The are not uncommon. Ahn and coworkers have recently
former may operate via the ability of the spleen to introduced a new approach for the delivery of ymca
produce antipneumococcal opson i ns ‘ 50. S as well as act alkaloids to those patients.’55 This consists of the in
as a filter; the latter presumably acts via the clearance vitro incubation of the patient’s platelets (or donor
of activated coagulation factor products, since reticu- platelets) with ymca alkaloids, prior to the infusion of
loendothelial blockade or splenectomy enhances the I U of ymca alkaloid (vinblastine)-loaded platelets
hypercoagulable state.’52 into the patient. The patient’s circulating platelet
The splenectomized patient should be carefully antibody presumably reacts with these platelets and
scrutinized when developing any fever or infection thereby serves to deliver vinblastine-loaded platelets to
because of the rapidly fulminant nature of pneumo- the RE system. The RE cells that ingest the vinblas-
coccal sepsis and death in these patients. tine-loaded platelets are presumably “killed” by the
vinblastine. They have treated I I patients who were
refractory to intravenous vincristine, as well as sple-
Treatment ofPatients Refractory to Steroids
nectomy, steroids, and other immunosuppressive
and Splenectomy agents, with 1-4 such infusions over a 2-wk period
The role of extended immunosuppressive therapy (each containing 2-5 mg of vinblastine). Six patients
for the treatment of ATP (particularly azathioprine), have gone into remission; 3 of these relapsed and 3
although theoretically sound, has not proved over- patients have remained in remission for 5-10 mo. Of
whelmingly successful in the few patients stud- the remaining 5 patients, 3 were partial responders
ied.’26”27”35 38 Its use should be reserved for those and 2 failed to respond. Side effects included alopecia,
patients who are refractory to steroids and splenecto- mild confusion, and intense jaw pain. Similar studies
my. A controlled study in this regard is lacking. have recently been reported by another group’56 who
Twelve of 36 documented cases have had an excellent noted a complete remission in 2 of 10 patients (7-mo
response to immunosuppressive therapy. ‘ 2b. 35 Cytoxan duration). There were 6 transient responses (2-3 wk
has also been used for the treatment of refractory duration) and 2 complete failures. Of interest was
patients with possibly better success than azathio- their observation that bound antiplatelet antibody
prine.’36”53 The disadvantage of cytoxan as well as disappeared from the two patients who went into
azathioprine is the approximately 2-mo duration remission, with a T’/2 of 15 days, whereas it did not
required to obtain an effect. Cytoxan also has the disappear from the treatment failures. It should be
undesirable side-effect of hemorrhagic cystitis. The stressed that this interesting approach is still experi-
alkaloid, vincristine, has recently been employed for mental. The long-term side-effects of continued ymca
the treatment of such refractory patients by Ahn and alkaloid treatment, as well as RE damage has as of yet
coworkers,’54 with benefit in 6 of 7 patients refractory not been evaluated.
to steroids with intact spleens, 9 of I 3 patients refrac- It cannot be overemphasized that the goal of ther-
tory to both steroids and splenectomy, and I 0 of I 0 apy should not necessarily be directed toward restora-
patients with SLE and thrombocytopenia. Follow-up tion of a normal platelet count, but toward the restora-
studies have revealed that 4 of the original I 3 patients tion of a sufficient number of functioning platelets to
are in prolonged remission (>6 yr). Five patients maintain hemostasis for normal daily activity. This
require the continued use of ymca alkaloids, and four can generally be achieved with a platelet count of
patients are treatment failures. The drug is unique in 50-80,000/cumm. It is rare for patients to develop
that it is both immunosuppressive and thrombocytotic, purpura in this range if the defect is purely quantita-
and when effective, acts promptly (i.e., 7-10 days). tive. Indeed, the claim has been made that only young
Our own limited experience with vincristine in patients platelets are hemostatically effective.94


I Robson HN, Davidson LSP: Purpura in pregnancy with 2. Epstein RD. Lozner EL, Coffey TS. Davidson CS: Congenital
special reference to idiopathic thrombocytopenic purpura. Lancet thrombocytopenic purpura. Purpura hemorrhagica in pregnancy
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