BackgroundOur prior Genome Wide Association Study (GWAS) of thrombin-induced platelet aggregation identified a G protein-coupled receptor kinase 5 (GRK5) non-coding variant (rs10886430-G) that strongly associated with increased platelet reactivity to thrombin. This variant predisposed to increased risk for stroke, pulmonary embolism, and venous thromboembolism. MethodsPlatelets from GRK5 mutant mice have been shown to have increased thrombin sensitivity, indicating that GRK5 may be a negative regulator of platelet activation. However, this has not been studied in a platelet specific manner. We therefore used platelet specific GRK5 mutant mice and models of thrombosis and pulmonary embolism. ResultsWe now demonstrate that mice lacking GRK5 specifically in platelets had a mild increase in thrombin responses in vitro and a shortened time to arterial thrombosis in vivo. In addition, platelet GRK5 mutant mice had increased thrombin, but not collagen induced thrombus burden in a mouse model of pulmonary embolism. ConclusionThese data indicate that platelet GRK5 has a significant role in limiting platelet responses to thrombin.