title: Increased thrombin responsiveness in platelets from mice lacking glycoprotein V.
abstract: 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 the hypotheses that GP V is involved in thrombin-induced platelet activation, in GP Ib-IX expression, and in other platelet responses by generating GP V null mice. Contrary to expectations, GP V -/- platelets were normal in size and expressed normal amounts of GP Ib-IX that was functional in von Willebrand factor binding, explaining why defects in GP V have not been observed in Bernard-Soulier syndrome, a bleeding disorder caused by a lack of functional GP Ib-IX-V. Moreover, in vitro analysis demonstrated that GP V -/- platelets were hyperresponsive to thrombin, resulting in increased fibrinogen binding and an increased aggregation response. Consistent with these findings, GP V -/- mice had a shorter bleeding time. These data support a role for GP V as a negative modulator of platelet activation. Furthermore, they suggest a new mechanism by which thrombin enhances platelet responsiveness independent of activation of the classical G-protein-coupled thrombin receptors.
authors.affiliation: COR Therapeutics, Inc., South San Francisco, CA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Ramakrishnan
authors.forename: P S
authors.initials: PS
authors.lastname: Reeves
authors.forename: F
authors.initials: F
authors.lastname: DeGuzman
authors.forename: U
authors.initials: U
authors.lastname: Deshpande
authors.forename: K
authors.initials: K
authors.lastname: Ministri-Madrid
authors.forename: R B
authors.initials: RB
authors.lastname: DuBridge
authors.forename: D R
authors.initials: DR
authors.lastname: Phillips
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000502:physiology*; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010980:Platelet Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D013917:Thrombin / Q000502:physiology*
chemical_list: D010980:Platelet Membrane Glycoproteins; D013917:Thrombin