Fibrinogen receptor antagonist-induced thrombocytopenia in chimpanzee and rhesus monkey associated with preexisting drug-dependent antibodies to platelet glycoprotein IIb IIIa

Most clinical trials with fibrinogen receptor antagonists (FRAs) have been associated with thrombocytopenia. This report describes the occurrence of t hrombocytopenia in one chimpanzee and one rhesus monkey upon administration of potent FRAs. Chimpanzee A-264 experienced profound thrombocytopenia on two occasions immediately upon intravenous administration of two different potent FRAs, L-738,167 and L-739,758. However, an equally efficacious antia ggregatory dose of another potent antagonist, L-734,217, caused no change i n platelet count. These compounds did not affect platelet count in five oth er chimpanzees or numerous other nonhuman primates. Flow cytometric analysi s showed drug-dependent antibodies (DDAbs) in the plasma of chimpanzee A-26 4 that bound to platelets of chimpanzees, humans, and all other primates te sted only in the presence of the compounds that induced thrombocytopenia. R hesus monkey 94-R021 experienced thrombocytopenia upon administration of a different antagonist, L-767,679, and several prodrugs that are converted in to the active form, L-767,679, in the blood. More than 20 other FRAs, inclu ding those that induced thrombocytopenia in chimpanzee A-264, had no effect on platelet count in this monkey. Flow cytometric measurements again ident ified DDAbs that reacted with platelets of all primates tested and required the presence of L-767,679. Screening for DDAbs in the plasma of 1,032 huma n subjects with L-738,167 and L-739,758 demonstrated that the incidence of these preexisting antibodies in this population was 0.8% +/- 0.6% and 1.1% +/- 0.6%, respectively. (C) 1999 by The American Society of Hematology.