Thrombocytopenia in pregnancy: differential diagnosis, pathogenesis, and management

Thrombocytopenia in pregnancy: differential diagnosis, pathogenesis, and management

Keith R. McCrae
Hematology-Oncology, BRB3, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, 10900 Euclid Avenue, Cleveland, OH 44106-4937, USA

In this manuscript, we will review the differential diagnosis of thrombocytopenia in pregnancy, highlight the clinical and laboratory ndings useful in dening the cause of thrombocytopenia in specic patients, and offer suggestions for management of thrombocytopenia in pregnant women.

CAUSES OF THROMBOCYTOPENIA IN PREGNANT WOMEN Gestational (incidental) thrombocytopenia Gestational, or incidental thrombocytopenia, is the most common cause of thrombocytopenia in pregnancy, affecting 5% of all pregnant women and accounting for more than 75% of cases of pregnancy-associated thrombocytopenia.4;710 Though the platelet count in patients with gestational thrombocytopenia usually remains above 110,000/ll, a platelet count as low as 70,000/ll in otherwise healthy pregnant women with no history of immune-mediated thrombocytopenia purpura (ITP) may be consistent with this disorder. The likelihood of an alternative, more signicant cause of thrombocytopenia increases substantially in patients with platelet counts below 70,000/ll. Though the pathogenesis of gestational thrombocytopenia is not well understood, it may involve factors such as hemodilution and/or accelerated platelet clearance.4;8 Gestational thrombocytopenia appears to be a variant of the physiologic thrombocytopenia that accompanies normal pregnancy. This disorder develops primarily in the late second or third trimester, and is not associated with an increased incidence of pregnancy-related complications or the delivery of thrombocytopenic offspring.4;711 These observations allow the evaluation of a thrombocytopenic, but otherwise healthy pregnant woman with no history of prior thrombocytopenia and a platelet count greater than 70,000/ll to be limited to a physical examination that includes careful blood pressure assessment, and a thorough examination of the peripheral blood lm.12;13 Conrmation of a normal platelet count prior to pregnancy decreases the probability of underlying immune thrombocytopenic purpura. Immune thrombocytopenia purpura (ITP) As in non-pregnant patients, the pathogenesis of ITP during pregnancy involves the actions of antiplatelet antibodies that recognize specic platelet glycoproteins. These antibodycoated platelets are then cleared by the reticuloendothelial system, primarily the spleen.14 Though ITP accounts for only approximately 1 case of thrombocytopenia per 1000 pregnancies and 5% of cases of pregnancy-associated thrombocytopenia, it is the most common cause of signicant thrombocytopenia in the rst trimester.3;4;7;15;16 A history of prior thrombocytopenia, underlying autoimmune disease or severe thrombocytopenia (platelet count < 50; 000=ll) makes a diagnosis of ITP more likely. In some cases, particularly in patients with a mildly reduced platelet count and no prior history of thrombocytopenia, it may be difcult to distinguish ITP from incidental thrombocytopenia. Levels of platelet-associated IgG are elevated in both disorders.17 Monoclonal antibody immobilizac 2003 Published by Elsevier Science Ltd. 

Abstract Thrombocytopenia in pregnant women may result from a number of diverse etiologies. While some of these are not associated with adverse pregnancy outcomes, others are associated with substantial maternal and/or neonatal morbidity and mortality. However, specic therapies, if instituted promptly, may signicantly improve the outcomes of affected patients and their offspring. Since the clinical features of many of these disorders often overlap, identifying a specic cause of thrombocytopenia in a pregnant patient may be difcult. However, through familiarity with the more common clinical and laboratory features of each of these disorders, accurate diagnosis may be achieved, and appropriate treatment instituted in most cases. In this review, we discuss the differential diagnosis of the more common causes of pregnancy-associated thrombocytopenia, and provide an overview of approaches to hematologic management. c 2003 Published by Elsevier Science Ltd.  KEY WORDS: thrombocytopenia; pregnancy; preeclampsia; platelets; HELLP; TTP

INTRODUCTION hrombocytopenia complicates up to 10% of all pregnancies. Though obstetricians manage most cases of pregnancy-associated thrombocytopenia, hematologists frequently consult on more complex cases. Thus, a working knowledge of the clinical features and management of thrombocytopenia in pregnant women is important for the practicing hematologist. Recent studies that included more than 4000 pregnant patients have demonstrated that the platelet count decreases by an average of approximately 10% in uncomplicated pregnancies. Most of this decrease occurs during the third trimester, and is associated with a shift in the histogram of platelet count distribution.1;2 However, the absolute platelet count remains within laboratory-established norms in most patients. Thrombocytopenia in pregnancy may result from a variety of causes (Table 1), ranging from benign disorders such as gestational thrombocytopenia to life threatening syndromes such as the HELLP (hemolysis, elevated liver function tests, low platelets syndrome).35 The time of onset of these disorders during pregnancy and their clinical manifestations often overlap, making the diagnosis of specic disorders difcult.6

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Table 1 Causes of pregnancy-associated thrombocytopenia Pregnancy specic Gestational (incidental) thrombocytopenia Preeclampsia HELLP syndrome Acute fatty liver of pregnancy Not pregnancy specic Immune thrombocytopenic purpura Thrombotic microangiopathies Thrombotic thrombocytopenic purpura Hemolytic uremic syndrome Systemic lupus erythematosus Viral infection (HIV, CMV, EBV) Antiphospholipid antibodies Disseminated intravascular coagulation (DIC) Bone marrow dysfunction Nutritional deciencies Drug-induced thrombocytopenia Type IIb von Willebrand disease Congenital Hypersplenism

Syndromes denoted by an asterisk are generally associated with isolated thrombocytopenia.

tion of platelet antigens (MAIPA) assays, which have been developed to measure antibodies reactive with specic platelet glycoproteins, have also failed to consistently differentiate these syndromes.18 Practically, however, in the absence of a platelet count prior to pregnancy, signicant thrombocytopenia (platelets < 100,000=ll) in the rst trimester, with a declining platelet count as gestation progresses, is most consistent with ITP. In contrast, mild thrombocytopenia developing in the second or third trimester and not associated with hypertension or proteinuria most likely represents incidental thrombocytopenia.15 Therapy of pregnancy-associated ITP should focus on the management of thrombocytopenia in the mother. Decisions concerning the need for therapy are determined by the absolute platelet count and whether active bleeding is present. Patients with platelet counts greater than 30,000/ll and no bleeding generally do not require treatment. However, in the presence of more severe thrombocytopenia, or bleeding, therapy should be initiated.12,15,19 Moreover, as pregnancy approaches term, more aggressive measures to raise the platelet count to a level sufcient to ensure adequate hemostasis during delivery and allow the administration of epidural anesthesia should be instituted. Most studies suggest that a platelet count > 50,000=ll is sufcient in this regard, though some recommend a platelet count > 100,000= ll.12;15;19;20 Due to their efcacy and low cost, many consider the rst line of therapy for ITP in pregnant patients to be corticosteroids.4;12;13;19 However, in addition to their toxicities in nonpregnant individuals, such as osteoporosis and weight gain, corticosteroids increase the incidence of pregnancy-induced hypertension and gestational diabetes, and may promote premature rupture of the fetal membranes. Therefore, some experts have suggested that high dose (2 gm/kg) intravenous 8
c 2003 Published by Elsevier Science Ltd. 

immunoglobulin (IVIg) should be employed as rst-line therapy for pregnancy-associated ITP.15 However, since responses to IVIg are often transient, multiple courses of therapy during gestation may be required, at signicant expense and patient inconvenience. Thus, though optimal rstline therapy for ITP in pregnant patients remains controversial, IVIg should at least be strongly considered when more than 10 mg/day of prednisone is required to maintain the maternal platelet count above 30,000/ll. IVIg may also be useful in raising the platelet count in preparation for delivery. Patients who do not respond satisfactorily to corticosteroids or IVIg are often referred for splenectomy. As in nonpregnant patients, remission of ITP is initially achieved in approximately 75% of pregnant women who undergo splenectomy.21 Splenectomy, if required, should be performed in the second trimester, as surgery early in pregnancy may induce premature labor, and splenectomy in the third trimester may be technically difcult due to obstruction of the surgical eld by the gravid uterus.4 Several reports of successful laparoscopic splenectomy in pregnant patients with ITP have recently appeared.2224 A small subset of thrombocytopenic patients will not respond satisfactorily to corticosteroids, IVIG or splenectomy, and other approaches must be considered.3 Some individuals who fail to respond to IVIg or corticosteroids used alone will respond to high doses of these agents (methylprednisolone, 1 gm, IVIg 12 gm/kg) administered in combination.4 Intravenous anti-D has also been used with success in a small series of pregnant women, though its safety has not been established in large numbers of pregnant patients.3 Little information concerning the safety and efcacy of third and fourth line agents in pregnant patients with refractory ITP is available. Experience with the use of immunosuppressive25 and cytotoxic agents26 is not extensive. Most such agents are contraindicated in the rst trimester of pregnancy due to their teratogenicity. This risk decreases after approximately 20 weeks, although the use of these drugs is still associated with an increased incidence of other pregnancy complications, such as premature labor.26 Danazol and vinca alkaloids are also best avoided during pregnancy,12 though a report describing the successful use of the latter in a pregnant patient has appeared.27 The offspring of mothers with ITP may also develop thrombocytopenia, as a result of the transplacental passage of maternal antiplatelet IgG.4;15 Between 1020% of these neonates are delivered with platelet counts below 50,000/ll, while platelet counts may be less than 20,000/ll in 5%.28 Bleeding complications at the time of delivery develop in 2550% of severely thrombocytopenic neonates,4;29 though intracranial hemorrhage is rare.11 Considerable effort has been devoted to developing management strategies to reduce bleeding complications in these infants, particularly intracranial hemorrhage, since interventions that raise the maternal platelet count are not effective in raising that of the fetus4 . These have been developed primarily to address the hypothesis that fetal intracranial hemorrhage is precipitated by head trauma during passage through the birth canal during a normal vaginal delivery.

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Thrombocytopenia in pregnancy: differential diagnosis, pathogenesis, and management

Several studies have attempted to dene clinical characteristics of mothers with ITP that predict for delivery of a thrombocytopenic neonate. These, however, have failed to demonstrate a consistent and reproducible correlation between the fetal platelet count at delivery and a number maternal characteristics,4;15 including the severity of maternal thrombocytopenia4;15 or the level of circulating maternal antiplatelet IgG.29 These observations, taken together with reports of divergent platelet counts in dizygotic twin offspring of a patient with ITP,31 demonstrate that the pathogenesis of neonatal thrombocytopenia is complex, and dependent not only upon the level of maternal antiplatelet antibody, but the rate of fetal megakaryocytopoiesis and the maturity of the fetal reticuloendothelial system.4 Of all parameters studied, perhaps the most reliable predictor of fetal thrombocytopenia is a history of thrombocytopenia at delivery in a prior sibling.32 Due to the inability of maternal clinical characteristics to predict neonatal thrombocytopenia, determination of the fetal platelet count requires invasive procedures such as fetal scalp sampling during labor, or percutaneous umbilical blood sampling (PUBS). The latter provides a more accurate estimate of the fetal platelet count, although it is associated with a complication rate (primarily bleeding and fetal bradycardia) of 01%.33 Since this approaches or exceeds the incidence of thrombocytopenia-related complications in the offspring of patients with ITP, two approaches to the management of these patients have evolved. One, supported by approximately 60% of perinatologists in the US,34 advocates a trial of labor for patients with ITP without prior determination of the fetal platelet count. This is based on the belief that severe thrombocytopenia and bleeding complications in the offspring of these individuals is uncommon, and that the incidence of fetal intracranial hemorrhage is unlikely to be reduced by Cesarean section.35 However, the latter supposition has not been subjected to randomized study, and has recently been questioned.36 A second approach advocates invasive determination of the fetal platelet count, generally by PUBS, and delivery by Cesarean section if the fetal platelet count is below 50,000/ll.19 Regardless of the mode of delivery, umbilical cord platelet counts should be obtained at the time of delivery on all offspring of mothers with ITP.12 Moreover, since the neonatal platelet count may decline for 45 days after delivery, daily monitoring is indicated, and therapy for immune thrombocytopenia should be instituted if it develops over this interval. preeclampsia with inherited thrombophilia has been proposed,42 this relationship remains controversial.43 Although the clinical manifestations of preeclampsia generally do not become evident until the third trimester, the lesion underlying the development of this disorder occurs early in pregnancy and involves decient remodeling of the maternal uterine vasculature by placental trophoblast cells.44;45 Abnormalities in the expression of cell adhesion molecules,46 activated metalloproteases,47 vascular endothelial cell growth factor (VEGF), and VEGF receptors48 by trophoblasts from preeclamptic women have been reported. The formation of a uteroplacental vasculature insufcient to supply adequate blood to the developing fetus results in fetoplacental hypoxia,49 leading to imbalances in the release and metabolism of prostaglandins, endothelin, and NO by placental and extraplacental tissues. These, as well as enhanced lipid peroxidation and other undened factors contribute to the hypertension, platelet activation and systemic endothelial dysfunction characteristic of preeclampsia.49 Thrombocytopenia develops in approximately 50% of patients with preeclampsia, with the severity usually proportional to that of the underlying disease. However, in occasional cases, the onset of thrombocytopenia precedes other manifestations of preeclampsia.4 Though the pathogenesis of thrombocytopenia in patients with preeclampsia is not well understood, it may involve enhanced platelet clearance due to adhesion of circulating platelets to damaged or activated endothelium, accelerated platelet activation due to hemostatic system activity and thrombin generation, and/or clearance of IgG-coated platelets by the reticuloendothelial system.4 Activation of the coagulation cascade occurs in most patients with preeclampsia. Though routine studies such as the PT, aPTT, and brinogen level usually remain normal, levels of more sensitive markers of hemostatic activity such as brinogen D-dimers and thrombinantithrombin complexes are elevated to a variable extent in most patients who develop thrombocytopenia.4 Though activation of hemostasis is unlikely to be the primary cause of thrombocytopenia in these patients, it is associated with more severe intrauterine growth retardation.50 The HELLP syndrome is often considered to be a variant of preeclampsia. This disorder occurs primarily in white, multiparous women above the age of 25 years,4 and is the most common cause of severe liver disease in pregnant women.51 Criteria for the HELLP syndrome include (1) microangiopathic hemolytic anemia (MAHA), (2) SGOT >70 U/L and (3) thrombocytopenia, with a platelet count below 100,000/ll.52 Patients usually present with severe epigastric and right upper quadrant pain, which need not be accompanied by hypertension and proteinuria. Despite their similarities, HELLP is associated with signicantly greater maternal and fetal morbidity and mortality than preeclampsia.4 Though the incidence of HELLP syndrome in subsequent pregnancies appears to be low, gestational hypertension occurs commonly in patients with a preceding pregnancy complicated by HELLP.53 The offspring of mothers with HELLP and preeclampsia may also become thrombocytopenic, though thrombocytopenia may not develop until after delivery.4 Absent umbilical artery end-diastolic velocity, a marker of fetal hypoxemia and acidosis, is a risk factor for thrombocytopenia in growth-rec 2003 Published by Elsevier Science Ltd. 

Preeclampsia and the HELLP syndrome Preeclampsia affects approximately 6% of all pregnancies, most often those of primigravidas less than 20 or greater than 30 years of age,4 and accounts for 17.6% of maternal deaths in the United States.37 The criteria for preeclampsia include hypertension and proteinuria (>300 mg protein/24 h) developing after 20 weeks of gestation.38 Preeclampsia in multiparous women may be associated with a change in partners or a long interval between pregnancies.39 A genetic role in the development of preeclampsia is likely, but remains incompletely dened;40 some studies suggest paternal as well as maternal genetic inuences.41 Though an association of

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tarded neonates.54 The pathogenesis of thrombocytopenia may reect the effects of prematurity and its complications, such as sepsis and acute respiratory distress.55 Though elevated levels of platelet-associated IgG may be present on the platelets of these neonates, these do not correlate with the development or severity of thrombocytopenia.4 More recent studies suggest a contribution of impaired megakaryocytopoiesis.56;57 Levels of thrombopoietin, though elevated in these infants, are lower than expected in comparison to those of older children with comparable degrees of thrombocytopenia.58 Decreased numbers of circulating megakaryocyte progenitors have also been observed in these infants.58 The severity of these effects may correlate with gestational age.59 Based on the premise that excessive platelet activation plays a central role in the development of preeclampsia and the HELLP syndrome, several studies have assessed the efcacy of prophylactic treatment of unselected or high-risk pregnant women with low dose aspirin for the primary prevention of preeclampsia. Aspirin, however, did not signicantly reduce the incidence of preeclampsia in either group.60;61 Management of preeclampsia and/or HELLP is supportive, and should be focused on medically stabilizing the patient prior to denitive therapy delivery of the fetus.37 Some have argued for conservative management, particularly in milder cases of preeclampsia or before 34 weeks gestational age, thereby providing additional time for fetal maturation. However, the primary indication for delaying delivery in severe preeclampsia or the HELLP syndrome is to gain 2448 h for fetal lung maturation to occur after administration of betamethasone.5;37 Platelet transfusions may be administered to raise the platelet count prior to cesarean section, though the survival of transfused platelets in patients with preeclampsia is diminished. If required, the coagulopathy resulting from preeclampsia-associated DIC should be managed with fresh frozen plasma;4 DIC severe enough to result in depletion of brinogen is uncommon in these disorders, but if present, hypobrinogenemia should be managed using cryoprecipitate. In most cases, the clinical manifestations of preeclampsia resolve within several days after delivery, although the platelet count may decline for an additional 2448 h.5 Occasional patients experience prolonged thrombocytopenia accompanied by an elevated LDH and multiorgan dysfunction after delivery. These manifestations may be reversed or ameliorated in some by plasma exchange62 and/or corticosteroids.63 However, these interventions need only be considered in patients who remain thrombocytopenic for more than 45 days after delivery or display progressive disease. Thrombotic thrombocytopenic purpura (TTP) and the hemolytic uremic syndrome (HUS) TTP and HUS share the central features of MAHA and thrombocytopenia. Though neither disease occurs exclusively during pregnancy, the incidence of both is increased in this setting.5;64 In some series, up to 10% of all cases of TTP have occurred in pregnant patients. TTP is dened by a pentad of symptoms that include MAHA, thrombocytopenia, neurologic abnormalities, fever, and renal dysfunction, though the pentad is present at the time of diagnosis in less than 40% of patients.5 The clinical manifestations of HUS are similar, though while neurologic abnormalities are usually more prominent in patients with TTP, renal dysfunction is more severe in patients with HUS. Recently, the role of congenital or acquired deciency of a specic vWF-cleaving protease in the pathogenesis of TTP has been suggested.65;66 This protease has been identied as ADAMTS13, a member of the ADAMTS family of metalloproteases.67 Levels of ADAMTS13 are markedly decreased in most patients with TTP. In patients with sporadic TTP, this deciency may result from antibodies against the protease,65;66 while patients with congenital variants of TTP harbor mutations in the ADAMTS13 gene.67 Interestingly, levels of ADAMTS13 decrease during normal pregnancy, perhaps accounting, in part, for the predisposition to development of thrombotic microangiopathy in this setting.68 TTP and HUS may be difcult to discern from one another, as well as from other pregnancy-specic causes of thrombocytopenia such as preeclampsia or the HELLP syndrome.6;69 Features that may be of use in differentiating these disorders are listed in Table 2. The extent of microangiopathic hemolysis is generally more severe in TTP or HUS than in preeclampsia or HELLP, and the former disorders are not associated with hypertension. The time of onset of TTP, HUS or the HELLP syndrome during pregnancy may also vary. In one report, TTP occurred primarily in the second trimester, with a mean onset of 23.5 weeks,70 though in a more recent report TTP developed primarily in the third trimester.6 Preeclampsia and the HELLP syndrome develop almost exclusively in the mid to late third trimester, with 90% of cases

Table 2 Differentiation of Pregnancy-Associated Microangiopathiesa MAHA Preeclampsia HELLP HUS TTP SLE APS AFLP + ++ ++ +++ + + Thrombocytopenia + +++ ++ +++ + + +/ Coagulopathy + +++ Hypertension +++ Renal Disease + + +++ +/ +/++ CNS Disease + +++ + + + Peak Time of Onset 3rd trimester 3rd trimester Postpartum 2nd trimester, term Anytime Anytime 3rd trimester

Abbreviations: MAHA, microangiopathic hemolytic anemia; , variably present; +, mild; ++, moderate; +++, severe. a Modied from McCrae and Cines, Sem. Hematol. 34:148, 1997.4

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Thrombocytopenia in pregnancy: differential diagnosis, pathogenesis, and management

developing after 34 weeks of gestation.4;5;37 In contrast, 90% of cases of HUS occur in the post-partum period, with a mean time to development of approximately 26 days after delivery. Measurement of plasma antithrombin levels may also assist in differentiating these disorders, as most patients with TTP and HUS maintain normal levels of antithrombin, while reduced antithrombin levels are common in patients with preeclampsia and HELLP.5 Another feature that distinguishes these disorders is their response to delivery. While preeclampsia or the HELLP syndrome usually improve following delivery, the course of pregnancy-associated thrombotic microangiopathies does not; hence pregnancy termination should not be considered therapeutic in patients with TTP or HUS.64 However, TTP responds equally well to plasma exchange in pregnant and non-pregnant patients, with >75% of patients achieving remission. Chronic relapsing TTP has also been managed during pregnancy by periodic plasma infusion.71 Plasma therapy may be less effective for pregnancy associated HUS, at least with regard to reversal of renal dysfunction. Nevertheless, encouraging results have been observed by some groups, and thus a therapeutic trial of this plasma exchange is indicated.6;72 Pregnancy-associated HUS is associated with substantial long-term maternal morbidity, including chronic renal insufciency and hypertension, even in individuals in whom the index episode is treated successfully.73 Though TTP and HUS may recur in subsequent pregnancies, the frequency with which they do so is uncertain.5 Several women with a familial history of pregnancy-associated HUS have developed their initial episode of HUS during pregnancy, and HUS has occurred in such individuals during therapy with oral contraceptives. The placental ischemia and increased incidence of premature delivery that complicate pregnancies in patients with thrombotic microangiopathies often lead to poor fetal outcomes.64 Acute fatty liver of pregnancy (AFLP) AFLP affects one of every 500010,000 pregnancies, and is most common in primaparas during the third trimester.74 A clue to the pathogenesis of AFLP is provided by the observation that in some series, a fetal deciency of long-chain 3hydroxy-acyl CoA dehydrogenase (LCHAD) or other enzymes involved in mitochondrial fatty acid oxidation was commonly present.75;76 A mutation of glutamic acid to glutamine at position 478 of LCHAD appears to be of particular importance in disease development.76 However, comparison of the frequency of this mutation in the population with the incidence of AFLP suggests that it accounts for only a subset of all AFLP cases. Women with AFLP present with malaise, nausea, epigastric and right upper quadrant pain, dyspnea, mental status changes, and cholestatic liver abnormalities. Diabetes insipidus may also occur, and hypoglycemia is common and often severe. Levels of brinogen and antithrombin are severely depressed, and 75% of patients manifest a prolonged PT accompanied by laboratory evidence of disseminated intravascular coagulation, perhaps related to decreased hepatic synthesis of antithrombin.5 Up to 50% of patients with AFLP may also meet criteria for preeclampsia. The extent of microangiopathic hemolysis and thrombocytopenia is generally mild compared to that observed in HELLP, TTP, or HUS.77 Management of patients with AFLP should be supportive, focusing on correction of hypoglycemia and electrolyte imbalances, as well as the underlying coagulopathy. Up to 10 days after delivery may be required for normalization of hemostatic abnormalities. Fetal mortality in this disorder approaches 15%, though maternal mortality occurs in less than 5% of cases.74 Other causes of pregnancy-associated thrombocytopenia As in the non-pregnant setting, HIV infection should be considered in any thrombocytopenic patient with risk factors.4 Approximately 25% of patients with systemic lupus erythematosus (SLE) develop thrombocytopenia secondary to platelet destruction due to antiplatelet antibodies, circulating immune complexes or other causes.78 Antiphospholipid antibodies (APLA) may be associated with preeclampsia in addition to thrombosis and recurrent fetal loss,79 and have been described in patients with syndromes resembling HELLP, HUS, or TTP which may not respond as well as expected to standard management approaches.5 Drug-induced thrombocytopenia occurs in the pregnant as well as the nonpregnant setting; an updated list of offending drugs is maintained at http://moon.ouhsc.edu/jgeorge/DITP.html. Surreptitious cocaine use has been associated with the development of a HELLP-like syndrome in pregnant women.80;81 Disseminated intravascular coagulation may complicate several obstetrical disorders, including preeclampsia, placental abruption, amniotic uid embolism, uterine rupture, and retention of a dead fetus,4 and may result in thrombocytopenia. Finally, congenital platelet disorders, such as the May Hegglin anomaly and other macrothrombocytopenias may be initially recognized during pregnancy; many of these may be diagnosed by careful examination of the peripheral blood lm.4;82;83 Pseudothrombocytopenia, an in vitro artifact attributable to platelet clumping caused by EDTA-dependent antiplatelet antibodies, may be transferred from mother to fetus following transplacental passage of the offending antibody.84 Finally, pregnancy-induced increases in levels of an abnormal vWF molecule that binds to platelets with increased afnity and enhances their clearance accounts for the thrombocytopenia that may develop in pregnant women with underlying Type IIb vWD.4;85

Practice points:
Gestational (incidental) thrombocytopenia is the most common
cause of thrombocytopenia in pregnancy. It is characterized by mild maternal thrombocytopenia and is not associated with adverse maternal or fetal outcomes.

Thrombocytopenia may be present in the offspring of mothers with

ITP, though the only factor likely to be useful in predicting whether thrombocytopenia will be present at the time of delivery is a history of neonatal thrombocytopenia in a prior sibling. Whether cesarean section reduces the incidence of intracranial hemorrhage during delivery of these neonates remains controversial, though most experts currently recommend vaginal delivery without prior determination of the fetal platelet count.

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13. ACOG Committee on Practice Bulletins: ACOG Practice Bulletin: thrombocytopenia in pregnancy. Int. J. Gynaecol. Obstet. 1999;67;117122. 14. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002; 346: 13995. 15. Gill KK, Kelton JG. Management of idiopathic thrombocytopenic purpura in pregnancy. Sem Hematol 2000; 37: 275283. 16. Bell WR, Kickler TS. Thrombocytopenia in pregnancy. Rheum Dis Clin North Am 1997; 23: 183191. 17. Lescale KB, Eddleman KA, Cines DB, Samuels P, Lesser ML, McFarland JG, Bussel JB. Antiplatelet antibody testing in thrombocytopenic pregnant women. Am J Obstet Gynecol 1996; 174: 10141018. 18. Boehlen F, Hohlfeld P, Extermann P, de Moerloose P. Maternal antiplatelet antibodies in predicting risk of neonatal thrombocytopenia. Obstet Gynecol 1999; 93: 169173. 19. George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, Blanchette VS, Bussel JB, Cines DB, Kelton JG, Lichtin AE, McMillan R, Okerbloom JA, Regan DH, Warrier I. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996; 88: 340. 20. Beilin Y, Zahn J, Comerford M. Safe epidural analgesia in thirty parturients with platelet counts between 69,000 and 98,000/ll. Anesth Analg 1997; 85: 385390. 21. Bussel JB. Splenectomy sparing strategies for the treatment and long term maintenance of chronic idiopathic immune thrombocytopenic purpura. Sem Hematol 2000; 37: 13. 22. Gottlieb P, Axelsson O, Bakos O, Rastad J. Splenectomy during pregnancy: an option in the treatment of autoimmune thrombocytopenic purpura. Br J Obstet Gynaecol 1999; 106: 373375. 23. Anglin BV, Rutherford C, Ramus R, Lieser M, Jones DB. Immune thrombocytopenic purpura during pregnancy: Laparoscopic treatment. J Soc Laparosc Surg 2001; 5: 6367. 24. Hardwick RH, Slade RR, Smith PA, Thompson MH. Laparoscopic splenectomy in pregnancy. J Laparoendosc Adv Surg Tech 1999; 9: 439440. 25. Ramsey-Goldman R, Schilling E. Immunosuppressive drug use during pregnancy. Rheum Dis Clin North Am 1997; 23: 149167. fer H, Kirch W. Cytotoxic therapy and pregnancy. 26. Ebert U, Lo Pharmacol Ther 1997; 74: 207220. 27. Grsoo Z, Rodriguez JJ, Stalnaker BL. Vincristine for refractory autoimmune thrombocytopenic purpura in pregnancy. J Repro Med 1995; 40: 739742. 28. Burrows RF, Kelton JG. Pregnancy in patients with idiopathic thrombocytopenic purpura: Assessing the risks for the infant at delivery. Obstet Gynecol Surv 1993; 48: 781788. 29. Samuels P, Bussel JB, Braitman LE, Tomaski A, Druzin ML, Mennutti MT, Cines DB. Estimation of the risk of thrombocytopenia in the offspring of pregnant women with presumed immune thrombocytopenic purpura. N Engl J Med 1990; 323: 229235. 30. Valat AS, Caulier MT, Devos P, Rugeri L, Wibaut B, Vaast P, Peuch F, Bauters F, Jude B. Relationships between severe neonatal thrombocytopenia and maternal characteristics in pregnancies associated with autoimmune thrombocytopenia. Br J Haematol 1998; 103: 397401.

Preeclampsia, HELLP, and the primary thrombotic microangiopathies

(TTP and HUS) share a number of features, such as thrombocytopenia and microangiopathic hemolytic anemia. However, by carefully noting specic clinical characteristics, these syndromes can be differentiated from one another in most cases.

The denitive therapy for preeclampsia and HELLP is delivery of the

fetus, while delivery does not alter the course of thrombotic microangiopathies. However, the latter respond equally well to plasma-based therapy in pregnant and non-pregnant patients.

Correspondence to: Keith R. McCrae, M.D., Associate Professor of Medicine, Department of Medicine, Hematology-Oncology, BRB3, Case Western Reserve University and University Hospitals of Cleveland, 10900 Euclid Avenue, Cleveland, OH 44106-4937, USA. Tel.: 216-368-1175; Fax: 1-216-368-1166; E-mail: kxm71@po.cwru.edu.

References 1. Sainio S, Kekom aki R, Riikonon S, Teramo K. Maternal thrombocytopenia at term: a population-based study. Acta Obstet Gynaecol Japonica 2000; 79: 744749. 2. Boehlen F, Hohlfeld H, Extermann P, Perneger TV, de Moerloose P. Platelet count at term pregnancy: a reappraisal of the threshold. Obstet Gynecol 2000; 95: 2933. 3. McCrae KR, Bussel JB, Mannucci PM, Remuzzi G, Cines DB. Platelets: an update on diagnosis and management of thrombocytopenic disorders. Hematology Am Soc Hematol Educ Program 2001: 282305. 4. McCrae KR, Samuels P, Schreiber AD. Pregnancy-associated thrombocytopenia: pathogenesis and management. Blood 1992; 80: 26972714. 5. McCrae KR, Cines DB. Thrombotic microangiopathy during pregnancy. Sem Hematol 1997; 34: 148158. 6. McMinn JR, George JN. Evaluation of women with clinically suspected thrombotic thrombocytopenic purpura-hemolytic uremic syndrome during pregnancy. J Clin Apheresis 2001; 16: 202209. 7. Crowther MA, Burrows RF, Ginsberg J, Kelton JG. Thrombocytopenia in pregnancy: diagnosis, pathogenesis and managment. Blood Rev 1996; 10: 818. 8. Shehata N, Burrows RF, Kelton JG. Gestational thrombocytopenia. Clin Obstet Gynecol 1999; 42: 327334. 9. Burrows RF, Kelton JG. Incidentally detected thrombocytopenia in healthy mothers and their infants. N Engl J Med 1988; 319: 142145. 10. Burrows RF, Kelton JG. Thrombocytopenia at delivery: a prospective survey of 6715 deliveries. Am J Obstet Gynecol 1990; 162: 731734. 11. Burrows RF, Kelton JG. Fetal thrombocytopenia and its relation to maternal thrombocytopenia. N Engl J Med 1993; 329: 14631466. 12. Letsky EA, Greaves M. Guidelines on the investigation and management of thrombocytopenia in pregnancy and neonatal alloimmune thrombocytopenia. Br J Haematol 1996; 95: 2136.

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Thrombocytopenia in pregnancy: differential diagnosis, pathogenesis, and management

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