Platelet function and molecular targets of antiplatelet agents. Initial platelet adhesion to damaged vessel walls is mediated by exposed collagen binding to platelet surface GPVI and integrin α2β1 and by VWF binding to the platelet surface GPIb-X-V complex. Thrombin, generated by the coagulation cascade, is a potent activator of human platelets via 2 platelet surface receptors: PAR1 and PAR4. Three groups of platelet surface receptors provide important positive feedback loops for platelet activation: (1) P2Y₁ and P2Y₁₂ receptors are stimulated by ADP released from platelet dense granules; (2) 5-HT_2A receptors are stimulated by serotonin (5-HT) released from platelet-dense granules; (3) the thromboxane prostanoid (TP) receptor is stimulated by TXA₂ generated by the platelet COX1-dependent signaling pathway. Platelet-to-platelet aggregation is mediated by fibrinogen and, at high shear flow, VWF binding to the activated molecular conformation of GPIIb-GPIIIa. Platelet-monocyte adhesion is initially mediated by the binding of platelet surface P-selectin (which is only expressed on the platelet surface after platelet degranulation) to its constitutively expressed counterreceptor PSGL-1 on the monocyte surface. Molecular targets of FDA-approved antiplatelet agents are shown in blue. Unfractionated heparin, low-molecular-weight heparin, and direct thrombin inhibitors such as lepirudin, argatroban, bivalirudin, and dabigatran, unlike PAR1 antagonists, are anticoagulants rather than specific antiplatelet drugs. However, their inhibition of thrombin results in less platelet activation. Molecular targets of antiplatelet agents in clinical development are shown in green. Investigational strategies for novel antiplatelet agents are shown in red. LMWH, low molecular weight heparin; PG, prostaglandin; PSGL-1; P-selectin glycoprotein ligand 1; TX, thromboxane; UFH, unfractionated heparin. (Reproduced with permission from Michelson.¹ )