Platelet kinetics in dogs treated with a glycoprotein IIb/IIIa peptide antagonist

Platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonists have been highly effective inhibitors of platelet aggregation in pre-clinical studies and in clinical trials. However, decreased platelet counts have been docum ented in preclinical studies and in some patients receiving GPIIb/IIIa anta gonists. We evaluated changes in platelet kinetics and fate in dogs receivi ng the GPIIb/IIIa receptor antagonist RPR 109891 orally for 4 days. Dogs re ceiving RPR 109891 hail a 22-52% decrease in platelet count with the nadirs at 35 days after initiation of treatment. Platelet survival time was reduc ed by 19%, and platelet half-life was reduced by 63%. Indium-111-labeled pl atelets were rapidly cleared from the blood within I hour after administrat ion of RPR 109891 on treatment days I and 2. This clearing was associated w ith a sharp increase in radioactivity in spleen but not in liver or lung. P latelet clearance was markedly attenuated on treatment days 3 and 4. Platel et counts returned to baseline within 1 week after discontinuation of treat ment. These data indicate that RPR 109891 causes rapid and selective seques tration of platelets: in the spleen.