Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management

Abstract

Drug-induced immune thrombocytopenia (DITP) can be triggered by a wide range of medications. Although many cases of DITP are mild, some are characterized by life-threatening bleeding symptoms. The pathogenesis of DITP is complex, in that at least six different mechanisms have been proposed by which drug-induced antibodies can promote platelet destruction. It is possible in many cases to identify antibodies that react with platelets in the presence of the sensitizing drug, but the required testing is technically demanding and not widely available. Therefore, a decision on whether to discontinue an implicated medication in a patient suspected of having DITP must be made on clinical grounds. An algorithm is available that can be helpful in assessing the likelihood that a particular drug caused thrombocytopenia, but the most important aspects of patient management are a high index of suspicion and a careful history of drug exposure in an individual who presents with acute, often severe thrombocytopenia of unknown etiology. How drugs induce platelet-reactive antibodies and how, once formed, the antibodies cause platelet destruction following exposure to the drug is poorly understood. Further studies to address these issues and characterize more completely the range of drugs and drug metabolites that can cause DITP are needed.

Figure 1. A model for drug-dependent antibody binding

Left: Antibodies capable of causing drug-dependent thrombocytopenia recognize an epitope on a platelet glycoprotein but the reaction is too weak for significant numbers of antibody molecules to bind in the absence of drug. Right: The sensitizing drug contains structural elements that are complementary to charged (+/-) or hydrophobic domains (H) on the glycoprotein epitope and the complementarity determining region (CDR) of the antibody and improves the “fit” between the two proteins, increasing the K_A to a value that permits binding to occur at levels of antibody, antigen and drug achieved in the circulation after ingestion of the drug. From DW Bougie et al, 2006 [21] with permission of the publisher.

Figure 2. Development of chronic autoimmne thrombocytopenia in a patient who presented initially with thrombocytopenia caused by sulfamethoxazole (SMX)-dependent, platelet-reactive antibodies

SMX-dependent antibodies were identified in acute phase serum together with GPIIb/IIIa-specific non-drug-dependent autoantibodies. Persistent non-drug-dependent antibodies reactive with autologous platelets were identified during Weeks 1, 5, and 9. SMX = sulfamethoxazole; ICH = intracranial hemorrhage; IVIgG = intravenous gamma globulin. From RH Aster, 2000 [38] with permission of the publisher.