Increased thrombin responsiveness in platelets from mice lacking glycoprotein V

A role for glycoprotein (GP)V in platelet function has been proposed on the basis of observations that GP V is the major thrombin substrate on intact platelets cleaved during thrombin-induced platelet aggregation, and that GP V promotes GP Ib-IX surface expression in heterologous cells. We tested th e hypotheses that GP V is involved in thrombin-induced platelet activation, in CP Ib-IX expression, and in other platelet responses by generating GP V null mice. Contrary to expectations, CP V -/- platelets were normal in siz e and expressed normal amounts of GP Ib-IX that was functional in von Wille brand factor binding, explaining why defects in CP V have not been observed in Bernard-Soulier syndrome, a bleeding disorder caused by a lack of funct ional GP Ib-IX-V. Moreover, in vitro analysis demonstrated that GP V -/- pl atelets were hyperresponsive to thrombin, resulting in increased fibrinogen binding and an increased aggregation response. Consistent with these findi ngs, GP V -/- mice had a shorter bleeding time. These data support a role f or GP V as a negative modulator of platelet activation. Furthermore, they s uggest a new mechanism by which thrombin enhances platelet responsiveness i ndependent of activation of the classical C-protein-coupled thrombin recept ors.