Hematologic Complications of Pregnancy

Gestational Thrombocytopenia

Most patients with gestational thrombocytopenia generally have a platelet count of 120,000 to 149,000/mm ³ . However, approximately 1% of patients with gestational thrombocytopenia will have a platelet count of 50,000 to 99,000/mm ³ . These patients require no therapy, and the fetus appears to be at negligible risk of being born with clinically significant thrombocytopenia or a bleeding diathesis. This distinct entity was first suggested but not specifically defined in a study published in 1986 by Hart and colleagues. In this report, 28 of 116 pregnant women (24%) who were evaluated prospectively during an 8-month period had platelet counts less than 150,000/mm ³ at least once during pregnancy. In all 17 patients who were followed after delivery, platelet counts returned to normal. These researchers were actually describing gestational thrombocytopenia before the condition had been recognized as a distinct entity. Samuels and colleagues also investigated 74 mothers with gestational thrombocytopenia. Regardless of platelet antibody status, none of the infants born to these mothers demonstrated thrombocytopenia. Burrows and Kelton have further shown that there is little risk to the mother or neonate in cases of gestational thrombocytopenia. In their study of 1357 healthy pregnant women, 112 (8.3%) had platelet counts less than 150,000/mm ³ . The lowest platelet count was 97,000/mm ³ . The incidence of thrombocytopenia (platelet count <150,000/mm ³ ) in the infants of these 112 women was 4.3%, not statistically different from infants born to healthy pregnant women without thrombocytopenia (1.5%). None of these infants had platelet counts less than 100,000/mm ³ . Indeed, the reports by Samuels and colleagues and Burrows and Kelton have convincingly demonstrated that gestational thrombocytopenia is a distinct and common entity that requires no treatment. However, the obstetrician must use judgment in giving this diagnosis because no test exists for this disorder. If platelet counts continue to fall to levels below 50,000/mm ³ , other diagnoses should be entertained.

The decrease in platelet count that occurs in gestational thrombocytopenia is not merely the result of dilution of platelets with increasing blood volume; it also appears to be due to an acceleration of the normal increase in platelet destruction that occurs during pregnancy. This is demonstrated by the fact that the mean platelet volume is increased in patients with gestational thrombocytopenia, and thrombopoietin levels often rise. A platelet count below 50,000/mm ³ is a reason for further investigation. If the platelet counts fall below 20,000/mm ³ or if clinical bleeding is present, then intervention is warranted. However, this scenario is rare, and it is difficult to determine whether these patients with profound thrombocytopenia have gestational thrombocytopenia or thrombocytopenia from another cause. Platelet antibody testing should only be utilized if suspicion is high for immune thrombocytopenic purpura (ITP). This would include a platelet count less than 50,000/mm ³ .

Immune Thrombocytopenic Purpura

ITP affects 1 to 3 per 1000 pregnancies and rarely causes neonatal complications. Although rare cases of neonatal thrombocytopenia have been reported, fetal complications are virtually nonexistent. Therefore the focus should be on maternal disease and well-being.

In general, pregnancy has not been determined to initiate ITP or to change its severity , but rare exceptions do exist. Harrington and associates were the first to demonstrate that ITP was humorally mediated, and Shulman and colleagues showed that the mediator of this disorder was immunoglobulin G (IgG). These findings were confirmed when Cines and Schreiber developed the first platelet antiglobulin test, a radioimmunoassay, in 1979. Newer assays have shown that these autoantibodies may be directed against specific platelet surface glycoproteins, including the IIb/IIIa and Ib/IX complexes. In vivo, after the platelets are coated with antibody, they are removed from circulation by binding to the Fc receptors of macrophages in the reticuloendothelial system, especially the spleen. Approximately 90% of women with ITP have platelet-associated IgG. Unfortunately, this is not specific for ITP. These tests may be positive in other autoimmune disorders. To make the issue more confusing, the pathogenesis of ITP in children and adults usually differs. Childhood ITP most often follows a viral infection and clinically presents with petechiae and bleeding. This form of ITP is generally self-limited and disappears over time. Conversely, adults have milder bleeding and easy bruisability and are often diagnosed after a prolonged period of subtle symptoms. Adult ITP usually runs a chronic course, and long-term therapy is often eventually needed. Many pregnancies occur in women in their late teens and early twenties. In these women with a history of ITP, it may be difficult to ascertain whether the patient has childhood ITP or adult ITP. The distinction is important for counseling concerning long-term prognosis.

ITP has a predisposition for women aged 18 to 40 years, with an overall female-male ratio of 1:7. It is often a diagnosis of exclusion. The patient must have isolated thrombocytopenia with an unremarkable peripheral smear. She must have only bleeding clinically consistent with a depressed platelet count, such as petechiae. She must not be taking any medication, herbal compound, or illicit drug (such as cocaine) that may cause thrombocytopenia. Finally, the patient must have no other disease process than can cause thrombocytopenia, such as those listed in the box earlier in this chapter. The American Society of Hematology (ASH) has published a review of ITP that details the diagnostic and therapeutic guidelines.

Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome

These two conditions are characterized by microangiopathic hemolytic anemia and severe thrombocytopenia. Pregnancy does not predispose a patient to these conditions, but they should be considered when evaluating the gravida with severe thrombocytopenia. Thrombotic thrombocytopenic purpura (TTP) is characterized by a pentad of findings, which are shown in Box 49.2 . The complete pentad occurs only in approximately 40% of patients, but approximately 75% have a triad of microangiopathic hemolytic anemia, thrombocytopenia, and neurologic changes. Pathologically, these patients have thrombotic occlusions of arterioles and capillaries. These occur in multiple organs, and no specific clinical manifestation for the disease is recognized. The clinical picture reflects the organs that are involved.

TTP/hemolytic uremic syndrome (HUS) may mimic preeclampsia. Because preeclampsia is much more common than this disorder, it should be considered first. However, delay in diagnosing TTP/HUS can have fatal consequences .

To diagnose the hemolytic anemia associated with TTP, the patient must have a negative indirect antiglobulin (Coombs) test. This rules out an immune-mediated cause for the hemolytic anemia. Lactate dehydrogenase (LDH) should be elevated, the indirect bilirubin should be increased, and haptoglobin should be decreased, indicating ongoing hemolysis. Schistocytes are usually seen on the peripheral smear, if it is carefully reviewed. These tests all signify hemolysis, but specificities and sensitivities differ. For instance, LDH can be elevated in liver disease. Schistocytes are very specific but often do not appear on the peripheral smear until hemolysis is severe. The clinician should use the clinical picture, as well as some of these tests, to make the diagnosis of hemolysis. To be classified as TTP, the platelet count should be less than 100,000/mm ³ . In renal insufficiency associated with TTP, the urine sediment is usually normal with an occasional red blood cell (RBC). This finding helps distinguish this disorder from a lupus flare, which more often has associated hematuria and casts. The serum creatinine is usually greater than 2 mg/dL. This degree of renal dysfunction is unusual, but not rare, in preeclampsia. Proteinuria, more than a trace amount, is usually seen on urine dipstick.

The neurologic findings in TTP are usually nonspecific. They include headache, confusion, and lethargy . Infrequently, generalized tonic-clonic seizures occur. Terrell and coworkers examined the epidemiology of TTP/HUS occurring in Oklahoma between 1996 and 2004. In 206 reported cases, they found that 37% were idiopathic. However, 13% were associated with an autoimmune disease, and 7% occurred in pregnancy and postpartum. These researchers were able to project that the annual incidence of suspected TTP/HUS is 11 cases per million population, whereas the annual incidence of proven cases is 4.5 cases per million. If this disease is so rare, why include it in a text on obstetrics? This is because if untreated, TTP carries a 90% mortality rate, whereas treatment with plasma exchange decreases the mortality rate to 20%. Therefore obstetricians must be aware of this disease process so it can be quickly and aggressively treated. If a patient has an atypical presentation of preeclampsia with hematologic findings and it continues to worsen, a diagnosis of TTP should be entertained.

Tsai and colleagues have found that a decrease of ADAMTS13 activity is strongly associated with TTP. This metalloprotease, also known as the von Willebrand cleaving enzyme , cleaves unusually large multimers of von Willebrand factor (ULVWf). Activity can be decreased from a decrease in the metalloprotease or antibodies against it. If a deficiency in the activity and/or concentration of ADAMTS13 is apparent, ULVWf circulates in increased amounts, leading to increased platelet aggregation and the initiation of TTP. ADAMTS13 can be readily assayed in clinical laboratories. Ferrari and colleagues have shown that all four immunoglobulin subclasses of anti-ADAMTS13 antibodies are associated with TTP, but the IgG4 subclass is most common. Congenital TTP is usually associated with a mutation of ADAMTS13 that leads to a profound decrease in its activity. Moatti-Cohen and colleagues queried the French registry of thrombotic microangiopathies and found that 24% of women who developed TTP during pregnancy had the congenital type (Upshaw-Schulman syndrome) compared with less than 5% of total adult cases. Weiner has published the most extensive literature review concerning TTP. In this series of 45 patients, 40 developed the disease antepartum, and 50% occurred before 24 weeks’ gestation. The mean gestational age at onset of symptoms was 23.4 weeks. This finding may be helpful when trying to distinguish TTP from other causes of thrombocytopenia and microangiopathic hemolytic anemia that occur during gestation. In Weiner's review, the fetal and maternal mortality rates were 84% and 44%, respectively. These mortality rates are overly pessimistic, because this series included many patients who contracted the disease before plasma infusion/exchange therapy was used to treat TTP.

However, TTP may be confused with rarely occurring early-onset severe preeclampsia. In preeclampsia, antithrombin III levels are frequently low, and this is not the case with TTP. Therefore this test may be a useful discriminator between these two disorders.

Although HUS has many features in common with TTP, it usually has its onset in the postpartum period. Patients with HUS display a triad of microangiopathic hemolytic anemia, acute nephropathy, and thrombocytopenia. HUS is rare in adults, and the thrombocytopenia is usually milder than that seen in TTP, with only 50% of patients having a platelet count less than 100,000/mm ³ at the time of diagnosis. The thrombocytopenia worsens as the disease progresses. A major difference between TTP and HUS is that 15% to 25% of patients with HUS develop chronic renal disease. HUS often follows infections with verotoxin-producing enteric bacteria. Cyclosporine therapy, cytotoxic drugs, and oral contraceptives may predispose adults to develop HUS. The majority of cases of HUS that occur in pregnancy develop at least 2 days after delivery. In fact, in one series, only 9 of 62 cases (14.5%) of pregnancy-associated HUS occurred antepartum. Four of these nine patients developed symptoms on the day of delivery. The mean time from delivery to development of HUS in patients in this series was 26.6 days. The maternal mortality rate may exceed 50% in postpartum HUS; however, this mortality rate is based on historic data. With plasmapheresis and dialysis, the likelihood of maternal death is probably much less. It is not important to make the distinction between TTP and HUS, because the initial therapy for both disorders is plasmapheresis.

Platelet Storage Pool Disease

Platelet storage pool disease is a deficiency of delta granules, which are dense granules stored within the platelet. Normal platelets contain three to eight of the granules in each platelet. They store serotonin, ADP, ATP, calcium and magnesium. It may be associated with epistaxis, mucocutaneous bleeding, or occasionally surgical bleeding. If there are less than three granules/platelet, then a patient is diagnosed with this disorder. Testing is performed by electron microscopy and is available from many reference laboratories. It is of particular concern to obstetric anesthesiologists who place epidural and spinal blocks. The inheritance pattern is usually autosomal dominant but can be variable. Civaschi and colleagues studied 65 pregnancies in 34 women with different forms of inherited platelet disorders and found that none of the patients with delta storage pool disease experienced any bleeding complications as the quantitative platelet count is normal. Many anesthesiologists and obstetricians will require that a patient with a platelet delta granule deficiency undergoes platelet transfusion before allowing epidural analgesia.