Drug-induced immune-mediated thrombocytopenia--from purpura to thrombosis.

891 I 1949, Ackroyd reported the abrupt onset of severe thrombocytopenia and purpura in patients receiving the sedative allylisopropylacetylcarbamide (Sedormid).1 All the patients had taken Sedormid previously and had become sensitized to it. Today, this classic picture of drug-induced, immunemediated thrombocytopenia is most often caused by quinine in outpatients and by vancomycin in hospitalized patients, as discussed by Von Drygalski et al. in this issue of the Journal (pages 904–910). In 1973, Rhodes, Dixon, and Silver described thrombocytopenia and thrombosis occurring a week after the initiation of heparin therapy and provided evidence of an immune pathogenesis for this complication of heparin therapy.2 In clinical trials of glycoprotein IIb/IIIa antagonists (abciximab, eptifibatide, or tirofiban), the abrupt onset of severe thrombocytopenia occurred in about 0.5 to 1% of patients who were receiving the agent for the first time; this unusual pattern of druginduced thrombocytopenia was also found to have an immunemediated pathogenesis.3 These three distinct drug-induced immune-mediated thrombocytopenic syndromes — quinine-induced immune thrombocytopenia, heparininduced thrombocytopenia and thrombosis, and thrombocytopenia within hours after a first exposure to a glycoprotein IIb/IIIa antagonist — differ from one another considerably with respect to pathogenesis, severity of thrombocytopenia, clinical manifestations, diagnostic laboratory tests, and treatment. Classic drug-induced immunemediated thrombocytopenia (the quinine type) is caused by unusual antibodies that bind not to the drug alone but to complexes of drug (or drug metabolite) bound to platelet glycoproteins — typically, glycoprotein IIb/IIIa (fibrinogen receptor), glycoprotein Ib/IX (von Willebrand factor receptor), or both. The antibody-coated platelets are cleared from the circulation by macrophages of the mononuclear–phagocytic system, which recognize the Fc “tails” of the drug-dependent antibodies. Platelets bear thousands of copies of glycoproteins IIb/IIIa and Ib/IX, and consequently, the antibodies in these cases cause severe thrombocytopenia; in about 85 to 90% of patients, the nadir platelet count is less than 20,000 per cubic millimeter. A useful clinical rule, in fact, is that immune-mediated thrombocytopenia is unlikely to be druginduced unless it is this severe. One exception is the immune thrombocytopenia caused by carbimazole: in that instance, the moderate degree of thrombocytopenia (median platelet count at nadir, 60,000 per cubic millimeter) can be explained by the fact that the drug forms a complex with a less abundant glycoprotein, platelet–endothelial-cell adhesion molecule 1. Another, and a major, exception to this clinical rule is heparin-induced thrombocytopenia (see graph). In classic drug-induced immune-mediated thrombocytopenia, isolated thrombocytopenia Drug-Induced Immune-Mediated Thrombocytopenia — From Purpura to Thrombosis