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 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
Pierre
P
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
Yap
Cindy L
CL
Nonne
Christelle
C
Sturgeon
Sharelle A
SA
Goncalves
Isaac
I
Yuan
Yuping
Y
Schoenwaelder
Simone M
SM
Wright
Christine E
CE
Lanza
Francois
F
Jackson
Shaun P
SP
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000209:etiology / Q000517:prevention & control; D001792:Blood Platelets / Q000737:chemistry; D001808:Blood Vessels / Q000293:injuries; D004195:Disease Models, Animal; D006629:Hirudins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation; D010980:Platelet Membrane Glycoproteins / Q000172:deficiency*; D017452:Receptors, IgG / Q000172:deficiency*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000502:physiology*; D013927:Thrombosis / Q000209:etiology* / Q000517:prevention & control
D006629:Hirudins; D010980:Platelet Membrane Glycoproteins; D017452:Receptors, IgG; C098341:platelet membrane glycoprotein VI; D013917:Thrombin