Molecular Drivers of Platelet Activation: Unraveling Novel Targets for Anti-Thrombotic and Anti-Thrombo-Inflammatory Therapy

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death globally—partly a consequence of increased population size and ageing—and are major contributors to reduced quality of life. Platelets play a major role in hemostasis and thrombosis. While platelet activation and aggregation are essential for hemostasis at sites of vascular injury, uncontrolled platelet activation leads to pathological thrombus formation and provokes thrombosis leading to myocardial infarction or stroke. Platelet activation and thrombus formation is a multistage process with different signaling pathways involved to trigger platelet shape change, integrin activation, stable platelet adhesion, aggregation, and degranulation. Apart from thrombotic events, thrombo-inflammation contributes to organ damage and dysfunction in CVDs and is mediated by platelets and inflammatory cells. Therefore, in the past, many efforts have been made to investigate specific signaling pathways in platelets to identify innovative and promising approaches for novel antithrombotic and anti-thrombo-inflammatory strategies that do not interfere with hemostasis. In this review, we focus on some of the most recent data reported on different platelet receptors, including GPIb-vWF interactions, GPVI activation, platelet chemokine receptors, regulation of integrin signaling, and channel homeostasis of NMDAR and PANX1.

Purinergic interplay between erythrocytes and platelets in diabetes-associated vascular dysfunction

“…This leads to the pathology by not only promoting thrombus formation but also causing microvascular embolization and endothelial dysfunction that accelerate progression of local vascular damage [14,29]. This process significantly contributes to diabetes-associated cardiovascular events such as myocardial infarction and stroke [30].…”

“…Several purinergic receptors including A 2A , A 2B , P2X 1 , P2Y 1 , and P2Y 12 receptors are expressed and functional in human platelets [26,32]. Activation of pannexin-1 in platelets via collagen leads to an exchange of calcium and ATP [30]. Extracellular ATP activates P2X 1 receptors leading to platelet shape change through extracellular calcium influx [4,31].…”

Molecular Research on Platelet Activity in Health and Disease 2.0

“…Chatterjee and collaborators exhaustively provide an update of research on GPVI activation, GPIb-vWF interactions, regulation of integrin signalling, chemokine receptors, and channel homeostasis of PANX1 and NMDAR, highlighting that these receptors, involved in platelet activation, may represent new molecular targets for anti-thrombotic and anti-thrombo-inflammatory therapies [ 11 ]. Braune and colleagues discuss the important role of prostanoids [including prostaglandin-D2 (PGD2), prostaglandin-E1, -E2, and E3 (PGE1, PGE2, PGE3), prostaglandin F2 (PGF2), prostacyclin (PGI2), and thromboxane-A2 (TXA2)] in hemostasis by regulating blood platelets, through both inhibitory and activating mechanisms, depending on the type of prostanoid [ 12 ].…”

Design of a Platelet-Mediated Delivery System for Drug-Incorporated Nanospheres to Enhance Anti-Tumor Therapeutic Effect

“…Based on this mechanism, platelets naturally target to the tissues. Considering the application of platelets as the natural carrier of drugs, it should be noted that platelets have a unique characteristic of activation which can be observed by aggregation and degranulation to maintain their biological functions [ 27 , 28 ]. When activated, platelets lose their ability for targeting to the tumor tissue and materials uptake [ 29 ].…”