Anti-Human vWF Monoclonal Antibody, AJvW-2 Fab, Inhibits Repetitive Coronary Artery Thrombosis without Bleeding Time Prolongation in Dogs

The antithrombotic and antihaemostatic effects of the monoclonal antibody against human vWF (AJvW-2 Fab) were investigated in comparison with those of the monoclonal antibody against platelet GPIIb/IIIa (abciximab) in dogs. The ex vivo platelet aggregation and template bleeding time were measured before, 5, 90, 210 min and 24 h after injection of either AJvW-2 Fab or abciximab in anesthetized beagle dogs. Plasma concentration, vWF occupancy and plasma vWF antigen level were also measured by ELISA. In addition, the antithrombotic effect was evaluated in a canine model of repetitive coronary thrombosis (Folts model). AJvW-2 Fab significantly inhibited the ex vivo botrocetin-induced platelet aggregation at 0.18 mg/kg (53% plasma vWF occupancy) and also inhibited cyclic flow reductions (CFRs) at 0.06 mg/kg (31% occupancy). A significant prolongation of the bleeding time was observed at 1.8 mg/kg (95% occupancy), which was 30 times as high as the antithrombotic effective dose. Whereas, abciximab significantly inhibited both the ex vivo ADP-induced platelet aggregation and CFRs at 0.8 mg/kg, which was the minimally effective dose, also resulting in a significant prolongation of the bleeding time. These results suggest that blockade of the GPIb–vWF axis with AJvW-2 Fab leads to the inhibition of thrombus formation in the stenosed coronary arteries without less bleeding time prolongation than the GPIIb/IIIa blockade with abciximab.