Outline of the signaling events leading to PAR-mediated protein kinase B/Akt activation in platelets. Thrombin and thrombin receptor-activating peptides induce Akt activation in platelets through secreted ADP that stimulates G_i signaling pathways in which Src kinase and PI 3-kinase play an important role. G_12/13 signaling potentiates Akt phosphorylation mediated by G_i pathways, and costimulation of G_12/13 and G_i signaling can induce the same extent of Akt phosphorylation achieved by PAR agonists in normal platelets. Activation of G_12/13 signaling might mediate its potentiating effects through Src kinase activation, and Src kinase plays an important role in ADP- and thrombin-mediated Akt phosphorylation. The mechanism and the specific member of Src family kinases contributing to Akt phosphorylation are not clear. Note that consistent with our previous observations, PAR stimulation in platelets does not lead to direct G_i activation.²