Platelet Signaling Pathways and New Inhibitors

Abstract

The major physiological role of platelets is in the formation of hemostatic plugs at sites of penetrating vascular injury that serve to limit blood loss. The aberrant intravascular activation of platelets can, if unchecked, lead to thrombotic events that cause myocardial infarction and stroke. Many antiplatelet agents are used clinically to limit platelet activation in patients at risk of arterial thrombotic events. However, their use can be associated with a significant risk of bleeding. An improved understanding of platelet signaling mechanisms should identify safer targets for antiplatelet therapy. Our understanding of the breadth and complexity of signaling pathways that marshal platelet activation has expanded rapidly over the past decade.1–4 Recent work published in Arteriosclerosis, Thrombosis, and Vascular Biology ( ATVB ) and other journals has provided further insight into the regulation of platelet signaling events and identified new targets against which to develop novel antiplatelet agents. One of the cornerstones of current antiplatelet therapy targets ADP-mediated platelet activation and aggregation via the P2Y12 receptor. However, a major challenge of the thienopyridine-based P2Y12 inhibitors, such as clopidogrel and prasugrel, is the occurrence of high on-treatment platelet reactivity, defined as a higher than expected platelet response to agonist.5 Armstrong et al6 have recently described an important contribution of platelet turnover to high on-treatment platelet reactivity. In vitro and ex vivo studies demonstrated that the relatively short half-life of clopidogrel and prasugrel was associated with poor inhibition of aggregation of newly formed reticulated platelets upon ADP stimulation.6 By comparison nonthienopyridine-based P2Y12 inhibitors, such as ticagrelor, maintained a good level of platelet inhibition even when untreated platelets were introduced.6 However, further studies are required to establish if there is any clinical benefit of nonthienopyridine-based P2Y12 inhibitors in the context of high on-treatment platelet reactivity. In addition to expressing P2Y12, …