<i>GRK5</i> polymorphism turns up the volume on PAR1

In this issue of Blood, Yarman et al 1 describe the mechanism that links a polymorphism in the first intron of G-protein-coupled receptor (GPCR) kinase 5 (GRK5) to hyperreactive platelets and thrombosis.The intronic variant (rs1886430) leads to decreased GRK5 protein expression, resulting in prolonged protease-activated receptor 1 (PAR1) signaling (see figure).These new mechanistic insights may provide a strategy for using personalized genetics to guide treatment options.Platelets flow through the bloodstream, primed to sense changes in the extracellular environment.Surface receptors are exquisitely designed to detect and respond to disruptions in vascular integrity.The initial response is rapidly amplified by soluble agonists such as thrombin, ADP, and thromboxane that activate their respective GPCRs and subsequent intracellular second messenger cascades.These initiating events are well