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

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 w...

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Bibliographic Details
Published in:Blood 2006-06, Vol.107 (11), p.4346-4353
Main Authors: Mangin, Pierre, Yap, Cindy L, Nonne, Christelle, Sturgeon, Sharelle A, Goncalves, Isaac, Yuan, Yuping, Schoenwaelder, Simone M, Wright, Christine E, Lanza, Francois, Jackson, Shaun P
Format: Article
Language:English
Subjects:
Animals
Arterial Occlusive Diseases - etiology
Arterial Occlusive Diseases - prevention & control
Blood Platelets - chemistry
Blood Vessels - injuries
Disease Models, Animal
Hirudins - pharmacology
Mice
Mice, Knockout
Platelet Activation
Platelet Membrane Glycoproteins - deficiency
Receptors, IgG - deficiency
Thrombin - antagonists & inhibitors
Thrombin - physiology
Thrombosis - etiology
Thrombosis - prevention & control
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Summary: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.
ISSN:0006-4971