Mechanisms of Platelet Activation and Antiplatelet Drugs

Abstract

Platelets are essential for primary hemostasis. However, upon activation, platelets also produce several pro-inflammatory and bioactive mediators promoting clot formation and inflammatory responses. A lot of clinical trails have shown that platelet hyperactivity is implicated in the pathogenesis of thrombus formation, and several vascular diseases. Accordingly, antiplatelet therapy may be a beneficial strategy to prevent and reduce the incidence of vascular thrombosis and inflammation. Platelet activation is a result of a complex signal transduction cascade reaction mediated by various constituents. When platelets are activated, the arachidonic acid-derived thromboxane A2 (TXA2) formation through the actions of cyclooxygenase (COX) and thromboxane synthase is an important inducer to activate platelet function. In addition, phospholipase C-mediated inositol 1,4,5-trisphosphate and diacylglycerol production, and subsequently induces calcium release from the dense tubular system and activates protein kinase C respectively, which leads to platelet activation. On the other hand, cyclic AMP and cyclic GMP, endogenous negative regulators of platelet responses, inhibit adhesion, aggregation, release of granule contents, production of TXA2, and intracellular Ca(superscript 2+) mobilization of platelets upon stimulation. Several antiplatelet agents targeting key pathways of platelet activation have been used in clinical therapy. These targets include platelet surface ADP P2Y12, integrin aIIbβ3 receptors, COX1, cyclic AMP, and cyclic GMP phosphodiesterases etc. Furthermore, our previous studies have found that some clinical drugs and natural products such as amlodipine, simvastatin, alpha-lipoic acid, c-phycocyanin and novel synthesized compounds all exert an antiplatelet activity through their specific mechanisms.