Glycoprotein (
GP) IIb/IIIa antagonists are effective therapeutic agents, but elicit
thrombocytopenia with a frequency that approaches 2%. Here, we provide evidence that
thrombocytopenia in humans treated with the
GP IIb/IIIa antagonist
roxifiban is immune mediated. Two patients underwent conversion to a highly positive
drug-dependent antibody (
DDAB) status temporally associated with
thrombocytopenia. Despite the continued presence of DDABs, the fall in platelet count was reversed by discontinuation of
drug treatment, pointing to the exquisite
drug dependency of the immune response. DDABs appear to bind to neoepitopes in
GP IIb/IIIa elicited on antagonist binding. This information was used to develop an
enzyme-linked
immunosorbent assay (ELISA) for
DDAB using solid-phase
GP IIb/IIIa. A high level of specificity is indicated by the observation that
DDAB binding is dependent on the chemical structure of the
GP IIb/IIIa antagonist and that only 2% to 5% of human blood donors and 5% of chimpanzees present with pre-existing DDABs. Furthermore, none of 108 nonthrombocytopenic patients from the phase II
roxifiban study showed an increase in antibody titer. Absorption of
thrombocytopenia plasma with platelets reduced the
DDAB ELISA signal, indicating that the test detects physiologically relevant
antibodies. Screening patients for pre-existing or increasing
DDAB titer during treatment with
GP IIb/IIIa antagonists may reduce the incidence of
drug-induced
thrombocytopenia.