Figure 2.

Agonists, receptors, and effector systems in platelet activation. The activation of platelets is induced by the interaction of several agonists with receptors expressed on the platelet membrane. Panels A, B, and C depict outside-in signalling mediated by thromboxane A₂, adenosine diphosphate, and thrombin, respectively. Thromboxane A₂ is synthesized by activated platelets from arachidonic acid through the cyclooxygenase pathway (A). Once formed, thromboxane A₂ can diffuse across the membrane and activate other platelets. In platelets, there are two splice variants of the TXA₂ receptor, TPα and TPβ, which differ in their cytoplasmic tail. TPα and TPβ couple to the proteins Gq and G12 or G13, all of which activate phospholipase C. Adenosine diphosphate is released from platelets and red cells. Platelets express at least two adenosine diphosphate receptors, P2Y₁ and P2Y₁₂, which couple to Gq and Gi, respectively (B). The activation of P2Y₁₂ inhibits adenylate cyclase, causing a decrease in the cyclic adenosine monophosphate level, and the activation of P2Y₁ causes an increase in the intracellular Ca²⁺ level. The P2Y₁₂ receptor is the major receptor able to amplify and sustain platelet activation in response to adenosine diphosphate. Thrombin is rapidly generated at sites of vascular injury from circulating prothrombin and, besides mediating fibrin generation, represents the most potent platelet activator (C). Platelet responses to thrombin are largely mediated through G-protein–linked protease-activated receptors, which are activated after thrombin-mediated cleavage of their N-terminal exodomain. Human platelets express PAR1 and PAR4. PAR1 couples to members of the G_12/13, G_q, and G_i protein families. Panel D depicts inside-out signalling. The effects of agonists mediated by the decrease in cAMP levels and increase in intracellular Ca²⁺ levels lead to platelet aggregation through the change in the ligand-binding properties of the glycoprotein IIb/IIIa (αIIbβ3), which acquires the ability to bind soluble adhesive proteins such as fibrinogen and von Willebrand factor. The release of adenosine diphosphate and thromboxane A₂ induces further platelet activation and aggregation. AA, arachidonic acid; ADP, adenosine diphosphate; cAMP, cyclic adenosine monophosphate; COX, cyclooxygenase; PAR, protease-activated receptors; PGH₂, prostaglandin H₂; PLA₂, phospholipase A₂; PLC, phospholipase C; TXAS, thromboxane synthase; TXA₂, thromboxane A₂. Reproduced from Davì and Patrono,⁹ with permission from the Massachusetts Medical Society