This special type of drug-induced thrombocytopenia (discussed in more detail in Chapter 4) merits brief mention because of its clinical importance. Moderate to severe thrombocytopenia develops in 3% to 5% of patients after 1 to 2 weeks of treatment with unfractionated heparin. The disorder is caused by IgG antibodies that bind to platelet factor 4 on platelet membranes in a heparin-dependent fashion. Resultant activation of the platelets induces their aggregation, thereby exacerbating the condition that heparin is used to treat—thrombosis. Both venous and arterial thromboses occur, even in the setting of marked thrombocytopenia, and may cause severe morbidity (e.g., loss of limbs) and death. Cessation of heparin therapy breaks the cycle of platelet activation and consumption. The risk of this complication is lowered (but not prevented entirely) by use of low-molecular-weight heparin preparations.
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ThromboticMicroangiopathies:ThromboticThrombocytopenicPurpuraandHemolyticUremicSyndrome
The term thrombotic microangiopathies encompasses a spectrum of clinical syndromes that include thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). As originally defined, TTP is associated with the pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, transient neurologic deficits, and renal failure. HUS also is associated with microangiopathic hemolytic anemia and thrombocytopenia but is distinguished from TTP by the absence of neurologic symptoms, the dominance of acute renal failure, and frequent occurrence in children (Chapter 14). Clinical experience has blurred these distinctions, as many adults with TTP lack one or more of the five criteria, and some patients with HUS have fever and neurologic dysfunction. Fundamental to both conditions is the widespread formation of platelet-rich thrombi in the microcirculation. The consumption of platelets leads to thrombocytopenia, and the narrowing of blood vessels by the platelet-rich thrombi results in a microangiopathic hemolytic anemia. All of the thrombotic microangiopathies produce renal damage of variable severity, and their pathogenesis is discussed in greater detail in Chapter 14.
It is important to note that although DIC and the thrombotic microangiopathies share features such as microvascular occlusion and microangiopathic hemolytic anemia, they are pathogenically distinct. Furthermore, unlike in DIC, in TTP and HUS activation of the coagulation cascade is not of primary importance, and so the results of laboratory tests of coagulation (e.g., the PT and PTT tests) usually are normal.
Coagulation disorders result from either congenital or acquired deficiencies of clotting factors. Acquired deficiencies are most common and often involve several factors simultaneously. As discussed in Chapter 8, vitamin K is required for the synthesis of prothrombin and clotting factors VII, IX, and X, and its deficiency causes a severe coagulation defect. The liver synthesizes several coagulation factors and also removes many activated coagulation factors from the circulation; thus, hepatic parenchymal diseases are common causes of complex hemorrhagic diatheses. As already discussed, DIC also may lead to multiple concomitant factor deficiencies. Rarely, autoantibodies may cause acquired deficiencies limited to a single factor.
Hereditary deficiencies of many coagulation factors also have been identified. Hemophilia A (a deficiency of factor
VIII) and hemophilia B (Christmas disease, a deficiency of factor IX) are X-linked traits, whereas other deficiencies are autosomal recessive disorders. Of the inherited deficiencies, only von Willebrand disease, hemophilia A, and hemophilia B are sufficiently common to warrant further consideration.