Drug-induced thrombocytopenia: pathogenesis, evaluation, and management

Abstract

Although drugs are a common cause of acute immune-mediated thrombocytopenia in adults, the drug etiology is often initially unrecognized. Most cases of drug-induced thrombocytopenia (DITP) are caused by drug-dependent antibodies that are specific for the drug structure and bind tightly to platelets by their Fab regions but only in the presence of the drug. A comprehensive database of 1301 published reports describing 317 drugs, available at www.ouhsc.edu/platelets, provides information on the level of evidence for a causal relation to thrombocytopenia. Typically, DITP occurs 1 to 2 weeks after beginning a new drug or suddenly after a single dose when a drug has previously been taken intermittently. However, severe thrombocytopenia can occur immediately after the first administration of antithrombotic agents that block fibrinogen binding to platelet GP IIb-IIIa, such as abciximab, tirofiban, and eptifibatide. Recovery from DITP usually begins within 1 to 2 days of stopping the drug and is typically complete within a week. Drug-dependent antibodies can persist for many years; therefore, it is important that the drug etiology be confirmed and the drug be avoided thereafter.

Figure 1. A proposed model for drug-dependent antibody binding to an epitope on a platelet glycoprotein

Left: Antibodies capable of causing drug-dependent thrombocytopenia react weakly with an epitope on a glycoprotein. The K_A for this interaction is too small to allow significant numbers of antibody molecules to bind in the absence of drug. Right: 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. Drug interacts with the target protein and antibody to improve 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 Bougie DW et al, Blood. 2006;108:922–927 with permission.)