The activation of receptors for collagen, ADP, and AYPGQV (thrombin receptor PAR4 agonist peptide) results in the stimulation of signaling pathways that converge on the activation of the integrin αIIbβ3, its conversion from a low to a high ligand affinity binding state (inside-out integrin signaling). This enables the binding of fibrinogen to the integrin, which stimulates outside-in signaling through the receptor, which is required for platelet spreading, irreversible platelet aggregation, stable thrombus formation, and clot retraction. The absence of JAM-A results in augmented outside-in signaling and associated functional responses. This suggests that JAM-A serves to suppress inappropriate or premature platelet activation through increasing the threshold of activation signals required to trigger platelet function.