Drug-induced immune thrombocytopenia: an overview of pathogenesis

Abstract

Many drugs are capable of causing antibody-mediated thrombocytopenia. Four, and perhaps five, different mechanisms have been implicated in the pathogenesis of this family of disorders. Some drugs become bound covalently to platelet membrane glycoproteins in vivo and stimulate the production of hapten-dependent antibodies that recognize drug-membrane protein targets. Others, such as quinidine, quinine, and sulfonamide antibiotics, induce the formation of an unusual class of antibodies that bind to membrane glycoproteins only when the drug (or one of its metabolites) is present in solution. Certain drugs trigger the production of true autoantibodies capable of binding to cell membrane glycoproteins in the absence of drug. Heparin-induced immune thrombocytopenia (HIT) is associated with antibodies specific for complexes formed between heparin and platelet factor 4 (PF4), a basic protein of the chemokine family found normally in platelet alpha granules. Immune complexes consisting of heparin, PF4, and antibodies are important in the pathogenesis of HIT, but the exact mechanisms by which they cause platelet destruction and, in some patients, thrombosis are not yet fully understood. Finally, thrombocytopenia in patients treated with recently introduced inhibitors of the platelet fibrinogen receptor (ligand mimetics) is thought to result from antibodies specific for ligand-induced binding sites (LIBS) on this receptor, but this mechanism has not yet been established.