In this Review, we provide an overview of advances in antiplatelet therapy in the setting of ACS, focusing on novel drugs that have already been approved for clinical use, in addition to emerging agents at different phases of clinical development. However, a detailed description of the role of novel oral anticoagulants is beyond the scope of this Review, and the use of such agents is only briefly mentioned.
Mechanisms of atherothrombosis
Plaque rupture, fissure, or erosion exposes the subendothelial layer and leads to the recruitment and activation of platelets, as well as the generation of excessive levels of thrombin, which ultimately results in the formation of a fibrin-rich thrombus.1, 2, 3, 4 NSTE-ACS is frequently characterized by a nonocclusive or transiently occlusive thrombus, whereas a more stable and occlusive thrombus is typical in STEMI.1 Platelet-activated thrombosis involves three principal steps: platelet adhesion, activation and recruitment of additional platelets, and platelet aggregation (Figure 1).3, 4, 16 Platelet adhesion during the initial rolling phase is mediated by interactions between the GP Ib/V/IX receptor complex, located on the surface of the platelet, and von Willebrand factor (vWF) bound to collagen exposed at the site of vascular injury.17 Rolling also brings the collagen receptors GP VI and GP Ia on platelets into contact with collagen.17 Binding of collagen to these receptors initiates platelet activation and triggers intracellular mechanisms that shifts platelet integrins to a high-affinity state, which induces the release of activating factors, in turn promoting aggregation, further recruitment, and further activation of circulating platelets.3, 4, 16, 17 These factors include ADP, epinephrine, serotonin, thrombin, and thromboxane A2.3, 4 Platelet activation by these and other mediators (such as collagen) induces changes in platelet shape, expression of proinflammatory molecules (such as P-selectin and soluble CD40 ligand) and platelet procoagulant activity.3, 4, 16 The final step in platelet aggregation and thrombus formation involves the conversion of platelet GP IIb/IIIa (the main receptor mediating platelet aggregation) into its active form, which subsequently binds to the extracellular ligands fibrinogen and vWF, leading to platelet aggregation and thrombus formation mediated by platelet–platelet interaction.17, 18 In addition, vascular injury also exposes subendothelial tissue factor, which forms a complex with factor VIIa, activating the clotting cascade and leading to thrombin generation.19 However, only a modest amount of thrombin is produced as a result of the coagulation cascade; its main source within a platelet plug is the surface of activated platelets.16, 20 Thrombin converts fibrinogen to fibrin, generating a fibrin-rich clot, and further activates platelets by binding to protease-activated receptor (PAR)-1 and PAR-4.3, 4, 21, 22 Pathogenic thrombosis, therefore, involves a complex interplay between platelets and plasma components (coagulation factors) that interact in an auto-amplified process (Figure 1).