Platelet glycoprotein V spatio-temporally controls fibrin formation

Abstract

The activation of platelets and coagulation at vascular injury sites is crucial for hemostasis but can promote thrombosis and inflammation in vascular pathologies. Here, we delineate an unexpected spatio-temporal control mechanism of thrombin activity that is platelet orchestrated and locally limits excessive fibrin formation after initial hemostatic platelet deposition. During platelet activation, the abundant platelet glycoprotein (GP)V is cleaved by thrombin. We demonstrate, with genetic and pharmacological approaches, that thrombin-mediated shedding of GPV does not primarily regulate platelet activation in thrombus formation but rather has a distinct function after platelet deposition and specifically limits thrombin-dependent generation of fibrin, a crucial mediator of vascular thrombo-inflammation. Genetic or pharmacologic defects in hemostatic platelet function are unexpectedly attenuated by specific blockade of GPV shedding, indicating that the spatio-temporal control of thrombin-dependent fibrin generation also represents a potential therapeutic target to improve hemostasis.