Abolition of cyclic flow variations in stenosed, endothelium-injured coronary arteries in nonhuman primates with a peptide fragment (VCL) derived from human plasma von willebrand factor-glycoprotein Ib binding domain

Abstract

Background: Platelets play an important role in the pathophysiology of acute coronary syndromes. The interaction between the platelet glycoprotein Ib receptor and von Willebrand factor is a critical event allowing platelet adhesion and aggregation and subsequent thrombus formation in vessels with high shear rates and damaged endothelium. Therefore, we tested the hypotheses that VCL, an antagonist of von Willebrand-glycoprotein Ib binding domain, (1) attenuates/ abolishes cyclic flow variations in stenosed, endothelium-injured coronary arteries in nonhuman primates and (2) reduces botrocetin-induced platelet aggregation in vitro after intravenous in vivo administration. Methods and Results: Cyclic flow variations were established in anesthetized, open-chest baboons (n=18). The baboons were divided into three groups. One group (n=8) received a bolus of VCL (4 mg/kg IV) followed by an infusion (6 mg · kg-1 · h-1) for 90 minutes (schedule A). Another group (n=6) received a 2-mg/kg bolus followed by an infusion of 3 mg · kg-1 · h-1 for 90 minutes (schedule B). The third group received a placebo infusion of normal saline. Under dosing schedule A, cyclic flow variations were abolished in 7 of 8 baboons after 33±18 minutes and markedly attenuated in 1. The frequency of cyclic flow variations fell from 18±9.4 per hour during the control period to 1±2.5 per hour after VCL infusion, P 3 hours and returned in 2 of 7 after 2 to 2.5 hours. Under schedule B, cyclic flow variations were abolished in 3 of 6 baboons and markedly reduced in the remainder. The number of cyclic flow variations fell from 17±4.8 per hour during the control period to 5±4.9 per hour after the VCL infusion, P