EFFECTS OF INTEGRELIN ON PLATELET-FUNCTION IN FLOW MODELS OF ARTERIALTHROMBOSIS

The effects of intravenous Integrelin, an antagonist of platelet glyco protein (GP) IIb-IIIa, were studied ex vivo in flow models of platelet adhesion/aggregation in patients undergoing angioplasty. Blood was co llected from each patient before, during, and after a 24-h Integrelin infusion (0.75 mu g/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 adh esion onto von Willebrand factor (vWF)/collagen, followed by platelet aggregation, in a perfusion system; and (b) direct platelet aggregatio n induced by elevated levels of shear stress imposed by a cone-and-pla te viscometer. Neither aspirin nor heparin, also given to the patients , affected platelet adhesion or aggregation in these flow models. In t he perfusion studies, platelet adhesion to vWF/collagen I was not inhi bited 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 mi n into the Integrelin infusion (plasma Integrelin levels: 759 +/- 69 n g/ml) compared with baseline samples. Within 24-48 h after termination of the Integrelin, direct shear-induced platelet aggregation and plat elet aggregation subsequent to adhesion returned to or near baseline i n each of the patients studied. We conclude that Integrelin administer ed in vivo inhibits both platelet aggregation subsequent to initial pl atelet adhesion and direct shear-induced platelet aggregation under pa thologic flowing conditions. After discontinuation of the drug, these inhibitory effects do not persist in vivo as long as the inhibitory ef fect on aggregation produced by c7E3 (the monoclonal antibody against GPIIb-IIIa).