In mice lacking GPVI/FcRgamma, mild vascular injury was associated with a 30% reduction in thrombus growth, and concurrent thrombin inhibition produced a much greater defect in thrombus formation.
Does thrombin inhibition affect arterial thrombus formation and bleeding time in mice lacking the GPVI/FcRgamma-chain complex?
Thrombin plays a major role in overcoming the hemostatic and thrombotic defect associated with GPVI/FcRgamma deficiency, suggesting GPVI antagonists may require concurrent anticoagulants for full antithrombotic potential.
Fibrillar collagens are among the most potent activators of platelets and play an important role in the initiation of thrombosis. The glycoprotein VI (GPVI)/FcRgamma-chain complex is a central collagen receptor and inhibitors of GPVI produce a major defect in arterial thrombogenesis. In this study we have examined arterial thrombus formation in mice lacking the GPVI/FcRgamma-chain complex (FcRgamma(-/-)). Using 3 distinct arterial thrombosis models involving deep vascular injury, we demonstrate that deficiency of GPVI/FcRgamma is not associated with a major defect in arterial thrombus formation. In contrast, with milder vascular injury deficiency of GPVI/FcRgamma was associated with a 30% reduction in thrombus growth. Analysis of FcRgamma(-/-) platelets in vitro, using thrombin-dependent and -independent thrombosis models, demonstrated a major role for thrombin in overcoming the thrombosis defect associated with GPVI/FcRgamma deficiency. Inhibition of thrombin in vivo produced a much greater defect in thrombus formation in mice lacking GPVI/FcRgamma compared with normal controls. Similarly, thrombin inhibition produced a marked prolongation in bleeding time in FcRgamma(-/-) mice relative to wild-type mice. Our studies define an important role for thrombin in overcoming the hemostatic and thrombotic defect associated with GPVI/FcRgamma deficiency. Moreover, they raise the interesting possibility that the full antithrombotic potential of GPVI receptor antagonists may only be realized through the concurrent administration of anticoagulant agents.
Mangin et al. (Wed,) conducted a other in Arterial thrombosis. GPVI/FcRgamma deficiency and thrombin inhibition vs. Wild-type mice / normal controls was evaluated on Arterial thrombus formation. In mice lacking GPVI/FcRgamma, mild vascular injury was associated with a 30% reduction in thrombus growth, and concurrent thrombin inhibition produced a much greater defect in thrombus formation.