Biased signaling in PAR1 and PAR4 in platelets. Biased agonists and interactions with other receptors result in biased signaling and platelet responses based on which pathways are favored. MMP2 requires αIIbβ3 as a cofactor to sensitize PAR1 (red) for thrombin signaling. In low concentrations of thrombin, PAR1 is favored over PAR4 (blue) signaling through Gαq and Gα12 pathways. MMP1 biases PAR1 signaling through the Gα12 pathway. PAR4 heterodimerization with P2Y12 (green) induces arrestin pathway signaling. Cathepsin G cleaves PAR4 at an additional site, increases calcium mobilization, and platelet aggregation. CatG, cathepsin G.