Effects of Integrelin on platelet function in flow models of arterial thrombosis

The effects of intravenous Integrelin, an antagonist of platelet glycoprotein (GP) IIb-IIIa, were studied ex vivo in flow models of platelet adhesion/aggregation in patients undergoing angioplasty. Blood was collected from each patient before, during, and after a 24-h Integrelin infusion (0.75 micrograms/kg/min; plasma Integrelin levels, 312-759 ng/ml). The effects of Integrelin administered in vivo were evaluated by using two different models of platelet thrombus formation: (a) platelet adhesion onto von Willebrand factor (vWF)/collagen, followed by platelet aggregation, in a perfusion system; and (b) direct platelet aggregation induced by elevated levels of shear stress imposed by a cone-and-plate viscometer. Neither aspirin nor heparin, also given to the patients, affected platelet adhesion or aggregation in these flow models. In the perfusion studies, platelet adhesion to vWF/collagen I was not inhibited by in vivo Integrelin. In contrast, in each of the six patients studied by using blood collected after 45 min of Integrelin infusion, there was a decrease in the size of platelet aggregates compared with patient baseline samples. In the viscometer experiments, shear-induced platelet aggregation was reduced by 61-71% in samples collected 45 min into the Integrelin infusion (plasma Integrelin levels: 759 +/- 69 ng/ml) compared with baseline samples. Within 24-48 h after termination of the Integrelin, direct shear-induced platelet aggregation and platelet aggregation subsequent to adhesion returned to or near baseline in each of the patients studied. We conclude that Integrelin administered in vivo inhibits both platelet aggregation subsequent to initial platelet adhesion and direct shear-induced platelet aggregation under pathologic flowing conditions, After discontinuation of the drug, these inhibitory effects do not persist in vivo as long as the inhibitory effect on aggregation produced by c7E3 (the monoclonal antibody against GPIIb-IIIa).