III. In disseminated cancers, release of procoagulant tumor products (e.g., mucin from adenocarcinoma) predisposes to thrombosis. The hypercoagulability seen with advancing age has been attributed to increased platelet aggregation and reduced release of PGI2 from endothelium. Smoking and obesity promote hypercoagulability by unknown mechanisms.
Among the acquired thrombophilic states, two are particularly important clinical problems and deserve special mention: • Heparin-induced thrombocytopenia (HIT) syndrome. This syndrome occurs in up to 5% of patients treated with unfractionated heparin (for therapeutic anti-coagulation). It is marked by the development of autoantibodies that bind complexes of heparin and platelet membrane protein (platelet factor-4) (Chapter 12). Although the mechanism is unclear, it appears that these antibodies may also bind similar complexes present on platelet and endothelial surfaces, resulting in platelet activation, aggregation, and consumption (hence thrombocytopenia), as well as causing endothelial cell injury. The overall result is a prothrombotic state, even in the face of heparin administration and low platelet counts. Newer low-molecular-weight fractionated heparin preparations induce autoantibodies less frequently but can still cause thrombosis if antibodies have already formed.
• Anti-phospholipid antibody syndrome. This syndrome (previously called the lupus anti-coagulant syndrome) has protean clinical manifestations, including recurrent thromboses, repeated miscarriages, cardiac valve vegetations, and thrombocytopenia. Depending on the vascular bed involved, the clinical presentations can include pulmonary embolism (following lower extremity venous thrombosis), pulmonary hypertension (from recurrent subclinical pulmonary emboli), stroke, bowel infarction, or renovascular hypertension. Fetal loss does not appear to be explained by thrombosis, but rather seems to stem from antibody-mediated interference with the growth and differentiation of trophoblasts, leading to a failure of placentation. Anti-phospholipid antibody syndrome is also a cause of renal microangiopathy, resulting in renal failure associated with multiple capillary and arterial thromboses (Chapter 14).
The name anti-phospholipid antibody syndrome came from the detection in patients of circulating antibodies that bind to phospholipids. But this name is misleading, as it is believed that the most important pathologic effects are mediated through binding of the antibodies to epitopes on proteins that are somehow induced or “unveiled” by phospholipids. Suspected antibody targets include β2-glycoprotein I, a plasma protein that associates with the surfaces of endothelial cells and trophoblasts, and prothrombin. In vivo, it is suspected that these antibodies bind to these and perhaps other proteins, thereby inducing a hypercoagulable state through uncertain mechanisms. However, in vitro, the antibodies interfere with phospholipids and thus inhibit coagulation (hence the name lupus anticoagulant, also a misnomer). The antibodies also frequently provide a false-positive serologic test for syphilis because the antigen in the standard assay for syphilis is embedded in cardiolipin.