Prevention of reoccluding platelet-rich thrombi in canine femoral arteries with a novel peptide antagonist of platelet glycoprotein IIb/IIIa receptors

Abstract

The composition of an evolving arterial thrombus may be a determinant of how effectively pharmacologic agents prevent reocclusion after initially successful thrombolysis. In this study, reoccluding platelet- or fibrin-rich thrombi as delineated by scanning electron microscopy were produced selectively in the femoral arteries of dogs with the use of electrically induced vascular injury or implantation of copper wire, respectively. Initial thrombolysis after intravenous infusion of tissue-type plasminogen activator (1 mg/kg over 30 minutes) was less frequent in the preparation producing platelet-rich thrombi than in that producing fibrin-rich thrombi (lysis in 19 of 24 versus 18 of 18, p = 0.06). In dogs with initial arterial recanalization, intravenous infusion of arginine-glycine-aspartate-O-methyltyrosine amide (RGDY), which competes with fibrinogen for binding to platelet glycoprotein IIb/IIIa receptors, prevented reocclusion caused by recurrence of platelet-rich thrombi in six of six dogs within 90 minutes; reocclusion occurred in five of seven saline-infused control dogs (p = 0.02). RGDY was only partially effective in preventing reocclusion caused by recurrence of fibrin-rich thrombi (reocclusion in three of six versus five of six controls, p = 0.54). Similar results were obtained with aspirin in both preparations. At least 98% of platelet aggregation induced ex vivo by collagen was inhibited by either RGDY or aspirin. In contrast with aspirin, however, platelet function returned to normal within 1 hour after discontinuation of RGDY. Thus, the relative proportions of platelets or fibrin incorporated into thrombi influence the efficacy of both tissue-type plasminogen activator for inducing thrombolysis and antiplatelet agents for preventing reocclusion. RGDY is a potent, short-acting inhibitor of platelet aggregation that effectively prevents reocclusion under conditions in which platelet deposition predominates.