A 33-year-old woman who has been trying to become pregnant for 8 years is evaluated after receiving positive pregnancy test results. Medical history is significant for three miscarriages occurring 6 years ago, 3 years ago, and 1 year ago, each of which occurred early in her pregnancy. She had an unprovoked venous thromboembolism 18 months ago. Her last menstrual period was approximately 5 weeks ago.
Results of physical examination, including vital signs and abdominal examination, are normal.
Results of laboratory studies show a prolonged activated partial thromboplastin time (aPTT). A mixing study does not correct the aPTT
The most appropriate next diagnostic step is testing for the lupus inhibitor and antiphospholipid antibody. The antiphospholipid antibody sometimes interferes with the coagulation cascade as measured by the activated partial thromboplastin time or prothrombin time and causes a prolongation that is not corrected with a corresponding mix that includes normal plasma. These antibodies, although they prolong in vitro coagulation tests, are associated with an increased risk of venous (approximately two thirds) and arterial thromboembolism. There also is a strong correlation between these antibodies and pregnancy loss, presumably due to placental insufficiency in affected patients secondary to thrombosis. The diagnosis of antiphospholipid antibody syndrome requires a history of a thrombotic event (including recurrent fetal loss) in association with a persistent lupus anticoagulant or persistently elevated levels of IgG anticardiolipin or β2-glycoprotein I antibodies. Lupus anticoagulants or elevated levels of antiphospholipid antibodies are frequently present in patients with systemic lupus erythematosus; they also occur in patients with cancer or infections (such as HIV) and in association with the use of certain drugs (for example, hydralazine, procainamide, or phenothiazines); the latter cases are often associated with IgM antibodies and do not result in a hypercoagulable state.
The factor V Leiden mutation results in resistance to activated protein C. In heterozygotes with the prothrombin G20210A mutation, prothrombin antigen and activity measurements are elevated by approximately 30% over those of normal persons. Among unselected white patients presenting with an initial symptomatic episode of deep venous thrombosis, 12% to 20% are heterozygous for the factor V Leiden mutation and 6% heterozygous for the prothrombin G20210A mutation, compared with 6% and 2%, respectively, in asymptomatic control populations. Neither the factor V Leiden mutation nor the prothrombin G20210A mutation is associated with increased fetal loss.
Hyperhomocysteinemia is associated with an increased risk of venous and arterial thrombosis. Plasma homocysteine levels are determined by genetic and environmental factors, the latter including primarily dietary intake of folic acid, vitamin B12, and vitamin B6. Administration of these B vitamins can lower plasma homocysteine levels, but this intervention has not yet been shown to reduce the risk of recurrent vascular events. Hyperhomocysteinemia is not associated with recurrent fetal loss.
- Antiphospholipid antibody syndrome consists of a history of a thrombotic event (including recurrent fetal loss) in association with a persistent lupus anticoagulant or persistently elevated levels of anticardiolipin or β2-glycoprotein I antibodies.