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Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4573-4580
Pregnancy-Associated Thrombocytopenia Revisited: Assessment and
Follow-Up of 50 Cases
By
Nadine Ajzenberg,
Marie Dreyfus,
Cécile Kaplan,
Jeannine Yvart,
Bernard Weill, and
Gil Tchernia
From the Departments of Biological Hematology and of Biophysics,
Hôpital Bicêtre, Assistance Publique-Hôpitaux de
Paris et Faculté de Médecine Paris-Sud, Le
Kremlin-Bicêtre, France; The Platelet Immunology Department,
INTS, Paris, France; and the Laboratory of Clinical Immunology,
Hôpital Cochin, Paris, France.
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ABSTRACT |
Thrombocytopenia detected during pregnancy addresses the issue of
its mechanism and of the possible occurrence of neonatal thrombocytopenia. To further investigate these issues, 50 women referred to us because of thrombocytopenia detected during pregnancy (platelet count, <150 × 109/L), were extensively
studied, as well as their offspring. Among these thrombocytopenic
women, we used the threshold of 70 × 109/L to
differentiate between mild and severe thrombocytopenia. Whatever the
severity of thrombocytopenia, we found biological features of an
autoimmune disorder in 48% of the women, and chronic thrombocytopenia
in 55%. A familial thrombocytopenia was evidenced in 1 case. These 50 women gave birth to 63 neonates, among whom 24 were thrombocytopenic,
either at birth or during the first week of life. Neonatal
thrombocytopenia could only be predicted in multiparous women, on the
basis of previous neonatal thrombocytopenia in older siblings,
and/or when maternal platelet life span study, performed before
pregnancy, had evidenced an autoimmune thrombocytopenia (AITP)-like profile. These results suggest that, in case
of pregnancy-associated thrombocytopenia, familial and immunological
studies, combined with postdelivery iterative platelet counts, should
be performed to properly characterize the thrombocytopenia. Moreover,
the platelet count of the neonate should be carefully assessed at birth
and during the following days, a platelet life span study should be performed after delivery in the mother, because these two parameters are likely to bring valuable information regarding the forthcoming pregnancies and the risk of neonatal thrombocytopenia.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
THROMBOCYTOPENIA, observed in about 7%
of pregnancies, may be related to previously acquired or inherited
diseases or to pregnancy-related complications such as pre-eclampsia,
sepsis, or obstetrical disseminated intravascular
coagulation.1,2 In 75% of the cases, thrombocytopenia
cannot be referred to any of these etiologies. In such cases,
pregnancy-associated thrombocytopenia is generally assumed to be
secondary to an increased platelet consumption within the placental
circulation and/or to hormonal inhibition of
megakaryocytopoiesis; it has also been called asymptomatic thrombocytopenia, because it is considered to be devoid of any clinical
adverse manifestation in the mother or in the offspring.3,4 It has recently been defined as a mild thrombocytopenia that resolves spontaneously after delivery and should not be associated with fetal
thrombocytopenia.5 However, several studies have described a fetal and/or neonatal thrombocytopenia occurrence in 4% to
13% of these cases.6,7 The mechanism of neonatal
thrombocytopenia is not elucidated so far and addresses the issue of a
possible undetected maternal autoimmunity.8
To assess this hypothesis, we performed an extensive study in a
selected population of women referred because of thrombocytopenia detected during pregnancy. We found biological features of an autoimmune disorder in 48% of the women of our series; furthermore, thrombocytopenia persisted after pregnancy in 55% of the women.
| |
PATIENTS |
Seventy-five women in whom thrombocytopenia (defined as a platelet
count <150 × 109/L) had been detected during
pregnancy were referred to us by different obstetrical centers.
Twenty-five were excluded because information concerning their
offspring was lacking or because of loss of follow-up during or after
pregnancy. Fifty women who entered the study were investigated either
during pregnancy (31 cases) or after delivery (19 cases). At the first
visit, they were asked to recall any thrombocytopenic past episode and
to bring any platelet count that could have been performed before pregnancy. Women with previous history of autoimmune thrombocytopenia (AITP), systemic lupus erythematosus, or human immunodeficiency virus
(HIV) infection were systematically excluded. None exhibited any
pregnancy associated complications prone to induce thrombocytopenia, such as sepsis, pre-eclampsia, Hemolysis Elevated Liver Enzymes Low
Platelets (HELLP) syndrome, or disseminated intravascular coagulation.1
Sixty-four neonates were born to these 50 women; 63 of 64 were
evaluated, because 1 who died with a Di George syndrome on day 42 was excluded. Platelet counts were performed either at birth, on
umbilical cord or peripheral venous blood (50 cases), or during the
first week of life (13 cases), depending on local procedures. When
neonatal thrombocytopenia, defined as a platelet count less than 150 × 109/L, had been identified, platelet counts
were performed until normalization, whereas clinical and biological
studies were performed to further define its mechanism.
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MATERIALS AND METHODS |
Immunological tests.
Assessment of platelet-associated IgG (PAIgG) was performed using
isotopic methods.9 Circulating or associated antiplatelet autoantibodies were identified by immunocapture assays monoclonal antibody-specific immobilization of platelet antigens
(MAIPA test)10 using monoclonal antibodies
against platelet glycoproteins (GP) IIb-IIIa, Ib-IX, and Ia-IIa as
previously described.8
Diagnosis of materno-fetal antiplatelet allo-immunization was assessed
by identification of parental platelet antigen incompatibility and
screening of maternal serum against both a panel of phenotyped donors'
and the father's platelets.
Serum anticardiolipin antibodies were detected using the enzyme-linked
immunoassay described by Harris et al.11 GPL and MPL units
were defined as the antibody reactivity of 1 µg/mL of purified
anticardiolipin IgG or IgM (kindly provided by E.N. Harris, Louisville,
KY). Antinuclear antibodies were detected by indirect immunofluorescence on 4-µm rat liver sections.12
Antithyroglobulin antibodies were detected using enzyme-linked
immunosorbent assay (ELISA).13
Isotopic study.
111Indium-labeled autologous or heterologous platelets were
infused 2 to 16 months after delivery, after verification of adequate contraception and/or of  human chorionic gonadotrophin
(HCG) level less than 5 IU/L.14 Informed consent was
obtained from all patients. Several parameters were studied to define
the different patterns of the platelet life span. The mean platelet
survival time was calculated using linear and exponential models.
Platelet recovery in the circulation was extrapolated from the survival curves to time zero.15 The respective splenic/precordial
and hepatic/precordial activity ratios were calculated on platelet infusion (T0), 30 minutes later (T30), and at maximum (Tmax) and plotted on a graph to show early and late distribution of
111In-platelets in these organs. A normal platelet life
span obtained in 7 healthy volunteers after informed consent had been
given was characterized by a mean platelet survival time of 208 hours (range, 192 to 232 hours) and an increment of splenic/precordial sequestration ratio = 1.5 between T30 and Tmax.8
A thrombocytolysis evocative of AITP also called an AITP-like
profile was defined by a mean platelet survival time of less than
130 hours together with a significant secondary increment of the
splenic/precordial sequestration ratio, with the value at Tmax being
more than 1.5-fold the value of the T30 ratio.16 A profile
of hypersplenism was characterized by a mean platelet survival time
less than 160 hours, with an immediate increased splenic/precordial
sequestration ratio and no further increment after T30.
Statistical analysis.
Mean and standard deviation (SD) values were calculated for each
parameter analyzed.  2-test was used to compare data
between groups.
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RESULTS |
Mothers.
Fifty women who had displayed thrombocytopenia during 63 pregnancies
were studied (Tables 1 and
2). The mean nadir of the platelet count during pregnancy
was 69 × 109/L (SD, 29× 109/L),
ranging from 12 to 142 × 109/L. In 26 women (32 of 63 pregnancies), the platelet count was less than 70 × 109/L, with a mean nadir of 46 × 109/L
(SD, 14× 109/L). Systematic inquiries disclosed that
thrombocytopenia was already present before pregnancy in 4 women (7 pregnancies) in whom it had been incidentally detected, although not
further investigated, during a preoperative assessment or a long-term
follow-up for Hodgkin's disease.
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Table 1.
Evolution of Biological Parameters Throughout 32 Pregnancies Associated With Severe Thrombocytopenia (Platelet Count
<70 × 109/L)
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Table 2.
Evolution of Biological Parameters Throughout 31 Pregnancies With Mild Thrombocytopenia (Platelet Count  70
× 109/L)
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No severe bleeding episode was observed during pregnancy; nevertheless,
a specific treatment was administered in 22 cases according to the
usual procedures applied in the various centers. This treatment had
been initiated early in pregnancy in 4 cases or in the prepartum period
in 18 cases. It included either high-dose intravenous IgG (IvIgG; 4 cases), oral steroids (10 cases), or platelet transfusion (1 case).
IvIgG had been associated with oral steroids in 3 cases. Furthermore,
platelet concentrates had been infused in 4 women after unsuccessful
IvIgG and/or oral steroid therapy, due to a severe
thrombocytopenia in 1 case, before a cesarean section in 2 cases, and
in 1 case of hemorrhagic delivery.
Therapy resulted in a complete correction, as defined by a platelet
count greater than 150 × 109/L in 5 cases. There was
only a partial response in 13 cases, with a 50% increment of the
platelet count in 6 cases or an increment ranging from 20% to 50% in
7 cases. In 4 cases, the treatment failed to increase the platelet
count.
A long-term follow-up of the platelet count was performed after
delivery in 47 women (55 pregnancies). In 26 women (30 pregnancies) thrombocytopenia was actually chronic, as the platelet
count remained less than 150 × 109/L long after
delivery (from 2 to 36 months), with a mean nadir of 101 × 109/L (range, 35 to 146 × 109/L).
Maternal thrombocytopenia recurred or was aggravated during the
subsequent pregnancies in all cases, including all 4 multiparous women
whose thrombocytopenia had resolved after the first delivery (Tables 1
and 2).
Immunological results are shown in Tables 1 and 2. All of the maternal
platelets were sampled for PAIgG (43 during pregnancy). Elevated PAIgG
levels (>1,000 IgG/platelet) were observed in 17 cases, 2 of which
had received IgG infusion on the days before sampling. It was the only
biological abnormality in 7 of 17 cases and was not considered
specific. In contrast, a total of 21 women were considered as having
biological signs of autoimmunity, because the MAIPA test and/or
any other autoantibodies tests resulted positive. Among them, 8 tested
iteratively during and after pregnancy were found con- sistently
positive. Six were tested only during pregnancy and 7 after delivery.
No difference in frequency of detected abnormalities was observed
whatever the period of determination (during and/or after
pregnancy). A direct MAIPA test, performed in 17 of 50 cases, evidenced
an anti-GPIIb-IIIa autoantibody in 4 women with no antiplatelet
antibody detected in the serum. An indirect MAIPA test was performed in
the serum of 48 of 50 women sampled during pregnancy in 39 cases. A
circulating anti-GPIb-IX autoantibody was found in 11 cases. An
anticardiolipin antibody (IgM >10 U MPL or IgG >15 U GPL) was found
in 7 cases and an antinuclear antibody (>1/50) was found in 2 cases.
An antithyroglobulin antibody was detected in 2 cases and was related
to an autoimmune thyroiditis in 1 of them.
Conversely, 24 women found negative for both the MAIPA test and
anticardiolipin or antinuclear antibodies were considered as not having
signs of autoimmunity. Five women were considered as not evaluable
because only one of these tests was performed and resulted negative.
Platelet life span was studied in 32 of 50 women within 2 to 16 months
after delivery (Table 3). Twenty women were
thrombocytopenic at that time, with a platelet count ranging from 11 to
146 × 109/L.
A normal platelet life span was found in only 3 cases. Features of
hypersplenism were observed in 9 cases. AITP-like features were found
in 18 of 32 cases. Platelet life span features could not be precisely
related to any of these patterns in the last 2 cases.
To assess the implications of the severity of thrombocytopenia during
pregnancy, two groups of women were constituted according to the
platelet count threshold of 70 × 109/L
(Table 4): 2 multiparous women had to be
excluded because of discordant results in their offspring (see below).
Comparing the two groups for maternal and neonatal parameters, there
was no difference regarding both the number of mothers diagnosed with chronic thrombocytopenia after pregnancy and the number of
thrombocytopenic neonates. Among the 32 evaluated cases, an AITP-like
profile was observed in 11 of 17 cases in the group of severe
thrombocytopenia as compared with 7 of 14 in the group of mild
thrombocytopenia. Surprisingly, biological signs of autoimmunity were
found more frequently in the group of mild thrombocytopenia (14 of 22 as compared with 7 of 22; P < .05).
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Table 4.
Comparison of the Data Obtained in the Two Groups of
Mothers According to Their Platelet Count (Threshold,
70 × 109/L) During Pregnancy
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Fetuses and newborns.
Percutaneous umbilical blood sampling was performed in 22 fetuses
stemmed from 21 women at gestational ages ranging from 32 to 38 weeks.
Whereas no fetal bleeding was observed, fetal bradycardia occurred in 1 case, leading to cesarean section a few hours after sampling. Among the
22 fetuses, 4 disclosed moderate thrombocytopenia, with platelet counts
of, respectively, 70, 80, 106, and 115 × 109/L and
were delivered without complication, either by cesarean section or by
vaginal delivery.
Sixty-three babies were included in the study. Nineteen were born after
a cesarean section because of fetal thrombocytopenia, detected by fetal
blood sampling in 2 cases, thrombocytopenia observed in the previous
siblings in 1 case, maternal thrombocytopenia in 1 case, or an
obstetrical reason in 15 cases.
The platelet count was found normal in 39 neonates, which was further
confirmed within the first week of life in 25 of them. Thrombocytopenia
was found in 24 neonates, either at birth (15 cases) or during the
first week of life (9 cases; Table 5). The mean nadir of postnatal platelet count in the 24 thrombocytopenic newborns was 52 × 109/L (range, 13 to 140 × 109/L) and was reached on day 4 (range, 0 to 15 days). Only
1 of the 24 thrombocytopenic newborns displayed hemorrhagic symptoms (petechiae and a scalp hematoma) after a vaginal delivery and was
treated by oral steroids (1 mg/kg/d and tapered) until day 69, when the
platelet count increased to 80 × 109/L. The platelet
count at birth was 75 × 109/L and reached a nadir of
13 × 109/L on day 15.
Treatment with IvIgG (1 g/kg/d ×1 or 0.4 g/kg/d ×5) was
performed in 10 cases and resulted in a complete correction in 4 cases or in a transient efficacy in 2 cases. In the 4 remaining cases, data
were not available. Thrombocytopenia resolved spontaneously in 2 cases.
Evolution was favorable in all cases, with a normalization of platelet
count within 11 days (range, 8 to 25 days) in the 8 cases in which it
could be assessed.
A nonimmune neonatal pathology that could account for neonatal
thrombocytopenia was found in 3 cases: 1 case of neonatal
staphylococcus infection, 1 neonatal Rotavirus infection, and 1 intrauterine growth retardation.17
A parental human platelet antigen incompatibility was found in 5 of the
11 cases in which it was assessed. However, despite the presence of
thrombocytopenia in 3 newborns, the diagnosis of maternofetal
alloimmunization could not be ascertained, due to the absence of
detectable alloantibody in the mother's serum.
To find out predictors of neonatal thrombocytopenia, two groups of
neonates were constituted according to their platelet count and
compared regarding siblings' platelet counts and maternal parameters
(Table 6). The offspring of multiparous
women were consistently either thrombocytopenic or not thrombocytopenic
in 10 of 12 cases. In these 10 cases, we found the platelet count to be
normal or decreased in the same proportion in all siblings. This
finding supports the hypothesis of the predictive value of this
parameter (P < .05), although in a small subset of cases.
Discrepancy in the 2 remaining cases was as follows. In 1 case,
neonatal thrombocytopenia in the first-born was most probably related
to intrauterine growth retardation (birth weight, 1,980 g in a
full-term newborn), whereas the sibling had a normal platelet count
both on percutaneous umbilical blood sampling and at birth. In the last
case, antenatal platelet count was found within the normal range in
each of the 2 successive siblings. However at birth, the firstborn had
exhibited a moderate thrombocytopenia with a platelet nadir or day 5, whereas the second one had a persistent normal platelet count up to day
3.
When excluding the 2 cases discussed above, maternal chronic
thrombocytopenia was associated with neonatal thrombocytopenia in 11 of
16 women who delivered thrombocytopenic neonates as compared with 14 of
29 who did not (Table 6). An AITP-like profile and neonatal
thrombocytopenia in the previous siblings were significantly more
frequently associated with the occurrence of neonatal thrombocytopenia (11 of 12 compared with 7 of 19 and 4 of 4 compared with 0 of 6, respectively). Conversely, the occurrence of neonatal thrombocytopenia did not correlate with the severity of the maternal gestational thrombocytopenia.
| |
DISCUSSION |
Thrombocytopenia, when detected during pregnancy, addresses the issue
of a possible related autoimmunity. Most of the studies performed
hitherto aimed at identifying, among maternal thrombocytopenias, those
of immune origin and at defining criteria predictive of severe fetal
thrombocytopenia.7,18 However, both specific diagnostic
tools of an immune origin of thrombocytopenia in the mother and
predictive maternal markers of fetal thrombocytopenia during pregnancy
are still missing.
The present work was designed to better understand the mechanisms of
maternal thrombocytopenia during pregnancy and its consequences in the
offspring in a small subset of thoroughly investigated women. This
group of patients referred to a highly specialized center does not
reflect the overall population of thrombocytopenic pregnant women.
However, the following conclusions can be reached.
(1) Maternal studies when performed in this group of thrombocytopenic
women showed asymptomatic autoimmunity in 21 of 44 cases. Whether it
can evolve towards a symptomatic autoimmune disorder is yet unknown.
The follow-up is less than 5 years in our study, which does not allow
any definite conclusion regarding this issue.
However, these results confirm that some pregnancy-associated
thrombocytopenia may be of immune origin,3 with a risk of neonatal thrombocytopenia.
(2) The diagnosis of familial thrombocytopenia, easy to achieve, was
established in 1 of our 50 cases. It should be systematically searched
for before proposing costly and invasive investigations in a pregnant
woman with thrombocytopenia, because no maternal or neonatal bleeding
complications have ever been reported in most of familial
thrombocytopenias (such as May-Hegglin syndrome or Mediterranean
thrombocytopenia).19
(3) Thrombocytopenia detected during pregnancy did not resolve after
delivery in 26 of 47 cases, indicating that 55% of them were actually
chronic thrombocytopenia incidentally detected during pregnancy rather
than pregnancy-associated thrombocytopenia. Moreover, in our hands, the
platelet count during pregnancy was not a reliable predictive marker of
the evolution of the maternal disease or of the occurrence of neonatal
thrombocytopenia: among women with mild thrombocytopenia (platelet
count within 70 to 150 × 109/L), 43% delivered
thrombocytopenic neonates and 57% had chronic thrombocytopenia.
Furthermore, 64% displayed biological signs of autoimmunity and 50%
had an AITP-like profile. It should be noted that all 4 women whose
thrombocytopenia had been detected before pregnancy displayed an
AITP-like profile. The diagnosis of gestational thrombocytopenia,
according to the guidelines of George et al,5 could be
ascertained after delivery in only 8 of 50 cases. However, among these
8 women, 5 displayed biological signs of autoimmunity, associated in 1 case with an AITP-like profile. Pregnancy-associated thrombocytopenia
can therefore be a misleading terminology that should not be used
unless platelet count is found to be normal in the months after
delivery. The diagnosis of pregnancy-associated thrombocytopenia is
impossible to ascertain in primiparous women in the absence of previous
platelet count determination. Furthermore, immunological studies should be performed to detect hidden autoimmunity.8
(4) As previously shown,7,20 we did not find any
statistical correlation between the occurrence of neonatal
thrombocytopenia and any of the following maternal parameters: platelet
count during pregnancy, evaluation of PAIgG, and characterization of
circulating and platelet-associated autoantibodies. Furthermore, no
difference was observed in the neonates whether or not mothers had
received a specific treatment aimed at increasing the platelet count
during pregnancy. However, among the 4 women who displayed
platelet-associated anti-GPIIb-IIIa autoantibodies, 3 delivered
thrombocytopenic newborns. A recent study suggested that circulating
anti-GPIIb-IIIa autoantibodies were likely to be more frequently
associated with AITP than with gestational thrombocytopenia but could
not be conclusive due to the small number of patients.21
Likewise, in our study, the question of whether platelet-associated
anti-GPIIb-IIIa autoantibody could be associated with hidden
autoimmunity remains speculative.
In women found to be thrombocytopenic during pregnancy, we think that a
follow-up of platelet count after pregnancy, which has never been
extensively achieved,22 would most probably provide some
help in evaluating the risk of neonatal thrombocytopenia in subsequent
pregnancies. Indeed, the women of our series displaying chronic
thrombocytopenia after pregnancy had, to some extent, delivered more
frequently thrombocytopenic newborns (11 of 16 v 14 of 29).
This might be of interest when the previous siblings' platelet count
is not available.
(5) In contrast, two parameters in multiparous women significantly
correlated with the occurrence of neonatal thrombocytopenia. First, the
maternal platelet life span, as an AITP-like profile is significantly
more often found in the group of women who delivered thrombocytopenic
neonates. Unfortunately, it cannot be performed during pregnancy and
the results can only be used for subsequent pregnancies. Second is the
notion of neonatal thrombocytopenia in a previous sibling. It confirms
previous studies showing that, when neonatal thrombocytopenia cannot be
ascribed to any recognized cause, its recurrence is likely in the
forthcoming siblings.23
(6) Because of the postnatal decrease of platelet count observed in
most cases, severe neonatal thrombocytopenia may be delayed, occurring
a few days after birth. This could account for the low incidence of
neonatal thrombocytopenia reported in the offspring of thrombocytopenic
women when the platelet count is only performed at
birth.3,4,18 Moreover, 9 of the 24 thrombocytopenic
neonates of our series had a normal platelet count at birth, which
suggests that, in the offspring of thrombocytopenic women, the platelet count should be checked not only at birth, but also within days 3 to 5. We found that the nadir of thrombocytopenia was reached later than
previously reported.18 This may be due to the cases in
which sequential platelet counts were performed only once a week and
emphasizes the need of platelet count assessment several times a week
in thrombocytopenic neonates until recovery.
Finally, when thrombocytopenia has been detected during pregnancy,
whatever the maternal platelet count, and awaiting larger prospective
studies based on the overall population of pregnant women to confirm
our results, we suggest the following: (1) a familial study should be
undertaken, to rule out a familial thrombocytopenia; (2) an
immunological study should be performed to detect an asymptomatic maternal autoimmune disorder; (3) the platelet count of the newborn should be performed at birth and repeated twice during the first week
of life; (4) iterative maternal platelet counts should be achieved
within the 6 months after delivery to detect chronic thrombocytopenia;
(5) in our experience, platelet life span study resulted to be of great
interest even when platelet count had returned to a normal level,
because it led us to detect a compensated thrombocytolysis in a
noticeable number of patients; and (6) neonatal thrombocytopenia is
most likely to recur in the offspring of a woman who gave birth to a
first thrombocytopenic newborn and/or when the maternal life
span study is in favor of an AITP-like profile.
| |
ACKNOWLEDGMENT |
The authors thank the physicians who referred their patients from
Hôpital Cochin, Hôpital Notre Dame de Bon Secours,
Hôpital St Michel, Hôpital St Vincent de Paul, Institut
Mutualiste Montsouris, Institut de Puériculture, Paris, France;
Hôpital Antoine Béclère, Clamart, France;
Hôpital François Quesnay, Mantes la Jolie, France;
Hôpital Jean Rostand, Ivry sur Seine, France; Hôpital Louise Michel, Evry, France; Centres Hospitaliers de Compiègne, d'Evreux, de Gonesse, de Neuilly sur Seine, de Saint Cloud, France; and Clinique du Vert Galant, Tremblay en France. The assistance of
Monique Dehan in the preparation of the manuscript is gratefully acknowledged.
| |
FOOTNOTES |
Submitted January 13, 1998;
accepted August 10, 1998.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Nadine Ajzenberg, MD,
Laboratoire d'Hématologie, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Bicêtre Cedex, France;
e-mail: etudba{at}mailhost.kb.inserm.fr.
| |
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Abstract
Introduction