Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + INTRODUCTION Download Section PDF Listen +++ ++ The antiphospholipid syndrome is an acquired thrombotic disorder associated with circulating autoantibodies to anionic phospholipid–protein complexes. These antibodies were first detected as inhibitors of the partial thromboplastin time in patients with systemic lupus erythematosus (SLE) and, for this reason, were called “lupus anticoagulant,” although this finding is not limited to patients with lupus. + PATHOGENESIS Download Section PDF Listen +++ ++ The disorder is generally considered to be autoimmune, although a direct causal relationship between antiphospholipid antibodies and thrombosis or pregnancy problems has not been demonstrated. The antiphospholipid antibodies found in the syndrome usually react with phospholipid bound to a plasma protein. A number of pathogenetic mechanisms have been proposed for the antiphospholipid syndrome, and it is possible that several of these act in concert to cause the disorder. + CLINICAL FEATURES Download Section PDF Listen +++ ++ Patients usually present with manifestations of thrombosis and/or pregnancy complications or loss. The disease usually presents in patients between ages 35 and 45 years. Both sexes are equally susceptible. The disorder is considered “secondary antiphospholipid syndrome” if the patient has a recognizable autoimmune disease, or “primary antiphospholipid syndrome” if there is no associated disorder. Table 84–1 summarizes the clinical manifestations of the antiphospholipid syndrome. The antiphospholipid syndrome should be considered in patients with recurrent thromboses in unusual locations. Venous and/or arterial thromboses may occur at any site but are most frequent in the lower extremities. Patients with concurrent inherited thrombophilia who develop antiphospholipid antibodies are at increased risk for thrombosis. Immune thrombocytopenia, usually of mild to moderate severity, occurs frequently in patients with antiphospholipid syndrome. Rarely, patients may develop a catastrophic form of the antiphospholipid syndrome, with severe, widespread vascular occlusions, despite intense anticoagulant treatment, often leading to death. Recurrent pregnancy loss occurs often in women with the antiphospholipid syndrome. About one-half of the abortions occur after the first trimester. Some patients develop a bleeding disorder because of a concurrent coagulopathy, such as acquired hypoprothrombinemia, or because of acquired inhibitors of factor VIII (see Chap. 82). ++Table Graphic Jump LocationTABLE 84–1CLINICAL MANIFESTATIONS OF THE ANTIPHOSPHOLIPID SYNDROMEView Table||Download (.pdf) TABLE 84–1 CLINICAL MANIFESTATIONS OF THE ANTIPHOSPHOLIPID SYNDROME Venous and arterial thromboembolism* Pregnancy complications attributable to placental insufficiency, including spontaneous pregnancy losses, intrauterine growth restriction, preeclampsia, preterm labor, and placental abruption* Thrombocytopenia Thrombotic and embolic stroke* Cerebral vein thrombosis* Livedo reticularis, necrotizing skin vasculitis Coronary artery disease Valvular heart disease Kidney disease Pulmonary hypertension Acute respiratory distress syndrome Atherosclerosis and peripheral artery disease Nonthrombotic retinal disease Adrenal failure, hemorrhagic adrenal infarction* Budd-Chiari syndrome, mesenteric and portal vein obstructions, hepatic infarction, esophageal necrosis, gastric and colonic ulceration, gallbladder necrosis* Catastrophic antiphospholipid syndrome with thrombotic microangiopathy* *Manifestations that qualify as consensus criteria for diagnosis of antiphospholipid syndrome. Source: Williams Hematology, 9th ed, Chap.131, Table 131–4. + LABORATORY FEATURES Download Section PDF Listen +++ ++ Diagnosis of the antiphospholipid syndrome requires demonstration of antibodies against phospholipids and/or relevant protein cofactors. The most widely recommended tests for antiphospholipid syndrome are anticardiolipin (aCL), anti-β2 glycoprotein (GP)-I (IgG and IgM), and lupus anticoagulant (LA). aCL, IgG and IgM assays are the most sensitive but the least specific. Anti-β2GPI IgG and IgM assays are more specific but less sensitive. Lupus anticoagulant assays, of which the dilute Russell viper venom time is the most common, generally tend to be the least sensitive but the most specific. No single test is sufficient for diagnosis, and usually a panel of tests is used. + DIFFERENTIAL DIAGNOSIS Download Section PDF Listen +++ ++ The diagnosis of antiphospholipid syndrome is based on consensual (research) criteria, as presented in Table 84–2. Vasculitis may cause vascular occlusion in patients with autoimmune diseases. The catastrophic antiphospholipid syndrome should be differentiated from thrombotic microangiopathies (including thrombotic thrombocytopenic purpura) (see Chap. 90), disseminated vasculitis, or disseminated intravascular coagulation (see Chap. 85). The “lupus anticoagulant” as the cause of prolongation of the activated partial thromboplastin time should be differentiated from specific coagulation factor deficiencies or other inhibitors by using appropriate laboratory procedures. Antiphospholipid antibody levels may be elevated artifactually or because of specific infections, such as syphilis, Lyme disease, HIV, or hepatitis C. ++Table Graphic Jump LocationTABLE 84–2SYDNEY INVESTIGATIONAL CRITERIA FOR DIAGNOSIS OF ANTIPHOSPHOLIPID SYNDROME (APS)View Table||Download (.pdf) TABLE 84–2 SYDNEY INVESTIGATIONAL CRITERIA FOR DIAGNOSIS OF ANTIPHOSPHOLIPID SYNDROME (APS) Clinical Vascular thrombosis (one or more episodes of arterial, venous, or small vessel thrombosis). For histopathologic diagnosis, there should not be evidence of inflammation in the vessel wall. Pregnancy morbidities attributable to placental insufficiency, including three or more otherwise unexplained recurrent spontaneous miscarriages, before 10 weeks of gestation. Also, one or more fetal losses after the 10th week of gestation, stillbirth, episode of preeclampsia, preterm labor, placental abruption, intrauterine growth restriction or oligohydramnios that are otherwise unexplained. Laboratory aCL or anti-β2GPI IgG and/or IgM antibody present in medium or high titer on two or more occasions, at least 12 weeks apart, measured by standard ELISAs. Lupus anticoagulant in plasma, on two or more occasions, at least 12 weeks apart detected according to the guidelines of the International Society of Thrombosis and Hemostasis Scientific Standardization Committee on Lupus Anticoagulants and Phospholipid-Dependent Antibodies. “Definite APS” is considered to be present if at least one of the clinical criteria and one of the laboratory criteria are met. aCL, anticardiolipin; aPL, antiphospholipid; β2 GPI, β2-glycoprotein I; ELISA, enzyme-linked immunosorbent assay; Ig, immunoglobulin. Data from Miyakis S, Lockshin MD, Atsumi T et al: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4:295–306, 2006. + TREATMENT, COURSE, AND PROGNOSIS Download Section PDF Listen +++ +++ Thrombosis ++ Acute thrombosis in the antiphospholipid syndrome is treated the same as thrombosis from any cause. Patients with the antiphospholipid syndrome who develop spontaneous thromboembolism should receive long-term, possibly lifelong, oral anticoagulation. Clinical studies have not shown conclusive evidence that a higher intensity of anticoagulant therapy should be maintained. Hydroxychloroquine therapy appears to have an antithrombotic effect in patients with the antiphospholipid syndrome and SLE. Patients with the catastrophic antiphospholipid syndrome may benefit from treatment with anticoagulants, glucocorticoids, and plasma exchange or intravenous gamma-globulin. There is anecdotal successful experience with rituximab. Antiphospholipid antibodies may spontaneously disappear and its presence should be monitored. +++ Pregnancy Loss ++ Pregnant patients who have antiphospholipid antibodies but have no history of clinical problems do not require treatment. Women who have antiphospholipid antibodies, and who have spontaneously lost three or more pregnancies should receive aspirin and heparin during the pregnancy and after delivery. For example, one suggested regimen calls for treatment with aspirin (80 mg) daily and unfractionated heparin (5000 U subcutaneously every 12 hours) or low-molecular-weight heparin (LMWH) at prophylactic dose beginning with diagnosis of the pregnancy and continuing at least until delivery. A recent randomized trial, however, did not show superiority of LMWH plus aspirin over aspirin alone in prevention of miscarriage. Patients who have had systemic thromboembolism should be considered for oral anticoagulation for 6 to 12 weeks after delivery. Breastfeeding is possible if the baby is administered usual vitamin K treatment. ++ For a more detailed discussion, see Jacob H. Rand and Lucia Wolfgast: The Antiphospholipid Syndrome. Chap. 131 in Williams Hematology, 9th ed.