Thrombocytopenia occurs in approximately 10% of pregnant women, and may result from a variety of causes ranging from benign disorders such as gestational thrombocytopenia to life threatening syndrome such as HELLP (hemolysis, elevated liver function tests, and low platelet syndrome). Some of these conditions are associated with substantial maternal and/or neonatal morbidity and mortality. However, specific therapies, if instituted promptly, may significantly improve the outcomes of affected patients and their offspring. Particularly management of high risk cases should be coordinated in joint obstetric hematology clinics.
Gestational (Incidental) Thrombocytopenia (GT) affects 5% of all pregnancies and accounting for more than 75% of cases of pregnancy-associated thrombocytopenia. In GT, platelet counts are typically >70 × 109/l, but in rare cases counts may be as low as 50 × 109/l. The fall in platelet count is mainly due to hemodilution and it does not have any adverse effects on mother or foetus. Characteristically GT is mild and asymptomatic. There is no past non-pregnant medical history of thrombocytopenia in the mother. It occurs late in pregnancy (second trimester, more pronounced at labour). There is no association of pregnancy-related complications or the delivery of thrombocytopenic offspring. There is no association with maternal or neonatal hemorrhage; and it resolves spontaneously after delivery.
Immune thrombocytopenia purpura (ITP): It is the most common cause of significant thrombocytopenia in the first trimester. The pathogenesis involves the destruction of antiplatelet-antibodies-coated platelet by the RE system, primarily the spleen. A history of prior thrombocytopenia, underlying autoimmune disease or severe thrombocytopenia (platelet count <50 x 109/l) are suggestive of ITP. Moreover it is usually associated with neonatal thrombocytopenia.
The goal of treatment of patients of ITP is remission with a focus on the management of thrombocytopenia in the mother and decision about mode of delivery. Patients with platelet counts < 30 x 109/l and history of bleeding generally require treatment. Moreover, as pregnancy approaches term, more aggressive measures to raise the platelet count to a level sufficient to ensure adequate hemostasis during delivery should be instituted. A platelet count > 50 x 109/l is sufficient in this regard, though some recommend a platelet count > 100 x 109/l. Corticosteroids are considered to be first line of therapy; however, due to their toxicities such as hypertension and diabetes, continuous monitoring of blood pressure and sugar is mandatory. Moreover it may also promote premature rupture of the fetal membranes. Therefore, alternatively, high dose (2 gm/kg) IV immunoglobulin (IVIg) may be employed as first-line therapy.15 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 x 109/l.
Splenectomy, if required, should be performed in the second trimester, as surgery early in pregnancy may induce premature labor.
Preeclampsia and the HELLP syndrome: Thrombocytopenia develops in approximately 50% of patients with preeclampsia, with the severity usually proportional to that of the underlying disease. The onset of thrombocytopenia may precede other manifestations of preeclampsia. It is believed that the pathogenesis of thrombocytopenia in patients with preeclampsia involves 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 RE system. Activation of the coagulation cascade occurs in most patients with preeclampsia. Though routine studies such as the PT, aPTT, and fibrinogen level usually remain normal, levels of more sensitive markers of hemostatic activity such as fibrinogen D-dimers and thrombin–antithrombin complexes are elevated to a variable extent in most patients who develop thrombocytopenia. 32 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. The HELLP syndrome is often considered to be a variant of preeclampsia. Criteria for the HELLP syndrome include52
• Microangiopathic hemolytic anemia (MAHA)
• SGOT >70 U/L
• Platelet count < 100 x 109/l.
Despite their similarities, HELLP is associated with significantly greater maternal and fetal morbidity and mortality than preeclampsia. Patients with HELLP syndrome are at a risk for renal failure, consumptive coagulopathy, abruptio placentae, pulmonary and cerebral edema, subcapsular liver hematoma, and hypovolemic shock. Fetal complications of HELLP syndrome include perinatal death, IUGR, preterm delivery and neonatal thrombocytopenia. The offspring of mothers with HELLP and preeclampsia may also become thrombocytopenic.
Management of preeclampsia and/or HELLP is supportive, and should be focused on medically stabilizing the patient and manage them conservatively till 34 weeks. Platelet transfusions may be administered to raise the platelet count prior to caesarean 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 fibrinogen is uncommon in these disorders, but if present, hypofibrinogenemia 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 another 24-48 h. |
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Management of preeclampsia and/or HELLP is supportive, and should be focused on medically stabilizing the patient and manage them conservatively till 34 weeks. Platelet transfusions may be administered to raise the platelet count prior to caesarean 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 fibrinogen is uncommon in these disorders, but if present, hypofibrinogenemia 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 another 24-48 h.
Microangiopathies leading to Thrombocytopenia: Thrombotic thrombocytopenic purpura (TTP), Hemolytic uremic syndrome (HUS) and DIC share the central features of MAHA and thrombocytopenia. TTP is a rare but life-threatening disease characterized by pentad of symptoms i.e. MAHA, thrombocytopenia, neurologic abnormalities, fever, and renal dysfunction. 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. Levels of ADAMTS13 are markedly decreased in most patients with TTP. Congenital ADAMTS13deficiency is caused by reduced synthesis of ADAMTS13 due to genetic defect. Acquired TTP is, at least in part, caused by inactivation and removal of ADAMTS13 from plasma due to the development of anti-ADAMTS13 auto-antibodies. TTP and HUS may be difficult to differentiate from one another, as well as from other pregnancy-specific causes of thrombocytopenia such as preeclampsia or the HELLP syndrome. 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. Further, 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. Thus differentiation of TTP from other MAHA is very important as platelets are contraindicated in this condition rather it is managed with fresh frozen plasma. TTP responds equally well to plasma exchange in pregnant and non-pregnant patients. 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. Patients with TTP are thus managed with FFP till their platelet count is >70 x 109/l till surgery is planned. The placental ischemia and increased incidence of premature delivery that complicate pregnancies in patients with thrombotic microangiopathies often lead to poor fetal outcomes.
DIC may complicate several obstetrical disorders, including preeclampsia, placental abruption, amniotic fluid embolism, uterine rupture, and retention of a dead fetus, and may result in thrombocytopenia. Differentiation of both these conditions from DIC is also very important which has some underlying cause, is associated with decrease in coagulation factors and fibrinogen, accentuation of fibrinolytic system along with thrombocytopenia and thus management depends upon correction of underlying cause first and replacement o coagulation factors, fibrinogen, platelets and heparin therapy if required.
Acute fatty liver of pregnancy (AFLP): AFLP affects one of every 5000–10,000 pregnancies, and is most common in primaparas during the third trimester. 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 fibrinogen 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. The extent of microangiopathic hemolysis and thrombocytopenia is generally mild. Management is 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 approaches 15%, though maternal mortality occurs in less than 5% of cases.
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 Likewise 25% of patients with systemic lupus erythmatosis (SLE) develop thrombocytopenia secondary to platelet destruction due to antiplatelet antibodies, circulating immune complexes or other causes. Antiphospholipid antibodies (APLA) may also be associated with preeclampsia in addition to thrombosis and recurrent fetal loss. The possibility of congenital platelet disorders etc should always be kept in mind as many of these may be diagnosed by careful examination of the peripheral blood film. 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. Finally drug-induced thrombocytopenia occurs in the pregnant as well as the nonpregnant women. History of drug intake and it’s with drawl is the first step in management of these patients.
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