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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 587-599
Fibrinogen Receptor Antagonist-Induced Thrombocytopenia in
Chimpanzee and Rhesus Monkey Associated With Preexisting
Drug-Dependent Antibodies to Platelet Glycoprotein IIb/IIIa
Bohumil Bednar,
Jacquelynn J. Cook,
Marie A. Holahan,
Michael E. Cunningham,
Patricia A. Jumes,
Rodney A. Bednar,
George D. Hartman, and
Robert J. Gould
From the Departments of Pharmacology and Medicinal Chemistry, Merck
Research Laboratories, West Point, PA.
Most clinical trials with fibrinogen receptor antagonists (FRAs)
have been associated with thrombocytopenia. This report describes the
occurrence of thrombocytopenia 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 antiaggregatory dose of another potent
antagonist, L-734,217, caused no change in platelet count. These
compounds did not affect platelet count in five other chimpanzees or
numerous other nonhuman primates. Flow cytometric analysis showed
drug-dependent antibodies (DDAbs) in the plasma of chimpanzee A-264
that bound to platelets of chimpanzees, humans, and all other primates
tested only in the presence of the compounds that induced
thrombocytopenia. Rhesus monkey 94-R021 experienced thrombocytopenia upon administration of a different antagonist, L-767,679, and several
prodrugs that are converted into the active form, L-767,679, in the
blood. More than 20 other FRAs, including those that induced thrombocytopenia in chimpanzee A-264, had no effect on platelet count
in this monkey. Flow cytometric measurements again identified 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 human
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.
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