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 BINDINGDOMAIN

Background Platelets play an important role in the pathophysiology of acute coronary syndromes. The interaction between the platelet glycopr otein Ib receptor and von Willebrand factor is a critical event allowi ng 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-gly coprotein Ib binding domain, (1) attenuates/ abolishes cyclic flow var iations in stenosed, endothelium-injured coronary arteries in nonhuman primates and (2) reduces botrocetin-induced platelet aggregation in v itro after intravenous in vivo administration. Methods and Results Cyc lic flow variations were established in anesthetized, open-chest baboo ns (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 mi nutes (schedule B). The third group received a placebo infusion of nor mal saline. Under dosing schedule A, cyclic flow variations were aboli shed 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 pe r hour during the control period to 1 +/- 2.5 per hour after VCL infus ion, P < .002. After cessation of infusion, cyclic flow variations rem ained abolished in 5 of 7 animals for >3 hours and returned in 2 of 7 after 2 to 2.5 hours. Under schedule B, cyclic flow variations were ab olished in 3 of 6 baboons and markedly reduced in the remainder. The n umber of cyclic flow variations fell from 17 +/- 4.8 per hour during t he control period to 5 +/- 4.9 per hour after the VCL infusion, P < .0 01. The cyclic flow variations returned spontaneously at 38 +/- 40 min utes under this dosing schedule. Placebo infusion of saline had no eff ect on cyclic flow frequency or severity. VCL administration was assoc iated with slight prolongation in bleeding time and a reduction in bot rocetin-induced platelet aggregation. The bleeding time increased from a control time of 88 +/- 32 to 276 +/- 204 seconds, P < .03, and from 142 +/- 28 to 176 +/- 36 seconds, P = .056, for schedules A and B, re spectively. VCL decreased platelet aggregation in response to botrocet in (20 mu g/mL), from a control value of 66 +/- 30.3 to 33 +/- 31.3 Om ega, P < .05, and from 64 +/- 23.5 to 46 +/- 15.8 Omega, P = .006, for dosing schedules A and B, respectively. Conclusions Therefore, admini stration of a peptide fragment corresponding to von Willebrand-glycopr otein Ib binding domain (1) is effective in abolishing cyclic flow var iations in stenosed, endothelium-injured coronary arteries and (2) red uces platelet aggregation in vivo in response to botrocetin in nonhuma n primates.