Thrombin overcomes the thrombosis defect associated with platelet GPVI/FcRγ deficiency

作者：Pierre Mangin, Cindy L. Yap, Christelle Nonne, Sharelle A. Sturgeon, Isaac Goncalves, Yuping Yuan, Simone M. Schoenwaelder, Christine E. Wright, François Lanza, Shaun P. Jackson · 发表于：Blood · 年份：2006 · DOI：10.1182/blood-2005-10-4244 · 被引用次数：147 · 研究领域：Platelet Disorders and Treatments、Antiplatelet Therapy and Cardiovascular Diseases、Venous Thromboembolism Diagnosis and Management

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 re...