A comprehensive review of the ten main platelet receptors involved in platelet activity and cardiovascular disease.

Am J Blood Res 2023;13(6):168-188 www.AJBlood.us /ISSN:2160-1992/AJBR0149811 Review Article A comprehensive review of the ten main platelet receptors involved in platelet activity and cardiovascular disease Mehrnoosh Hashemzadeh1,2, Fathima Haseefa1, Lee Peyton2,3, Mehrdad Shadmehr4, Abdullah M Niyas1, Aamir Patel1, Ghena Krdi1, Mohammad Reza Movahed1,4 University of Arizona College of Medicine, Phoenix, AZ, USA; 2Pima College, Tucson, AZ, USA; 3Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, MN, USA; 4University of Arizona, Tucson, AZ, USA 1 Received February 22, 2023; Accepted June 10, 2023; Epub December 25, 2023; Published December 30, 2023 Abstract: Cardiovascular disease (CVD) is a major cause of death worldwide. Although there are many variables that contribute to the development of this disease, it is predominantly the activity of platelets that provides the mechanisms by which this disease prevails. While there are numerous platelet receptors expressed on the surface of platelets, it is largely the consensus that there are 10 main platelet receptors that contribute to a majority of platelet function. Understanding these key platelet receptors is vitally important for patients suffering from myocardial infarction, CVD, and many other diseases that arise due to overactivation or mutations of these receptors. The goal of this manuscript is to review the main platelet receptors that contribute most to platelet activity. Keywords: Cardiovascular disease, platelet receptors, GPIb-IX-V, P2X1, GPVI, α2β1, TXA2, GPIIb/IIIa, PAR1, PAR4, P2Y1, P2Y12 Introduction Platelets play an integral role in the development of cardiovascular disease (CVD), which is a leading cause of death for a large portion of the world. The cause of CVD, which often manifests into myocardial infarction or stroke, can be attributed to a variety of variables such as diet, genetics, tobacco use, and cholesterol levels. Platelets are also responsible for the development of acute coronary syndrome (ACS) due to ST elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), and unstable angina. For healthy individuals, circulating platelets are largely in the inactive form having little interaction with vessel walls. Both cardiovascular disease and acute coronary syndrome are merely two examples of pathologic events that can occur due to the untimely or unwanted activation of platelets. Platelets are small, disk-shaped, anucleate cell fragments with a primary role of hemostasis and clotting of blood. Platelets also play a role in innate immunity. Developed from megakaryocytes in the bone marrow, platelets have a life span of roughly 10 to 12 days [1]. There has been great attention on the development of antiplatelet medications due to the high number of deaths attributed to CVD or ACS every year. In 2012, sales of antiplatelet pharmaceuticals totaled 12.5 billion dollars worldwide. In the same year for the United States, sales of antiplatelet medications accounted for nearly 17 percent of worldwide sales or 5.1 billion dollars [2]. With an increasing number of people suffering from platelet-related medical conditions, the development of new drugs that can inhibit platelets via the numerous platelet receptors is an active area of research and development. Platelets play a role in the development of acute coronary syndrome by stimulating an inflammatory response within the atherosclerotic plaque [3, 4]. Activated platelets have the ability to https://doi.org/10.62347/NHUV4765 Comprehensive review of ten main platelet receptors release inflammatory mediators, such as chemokines and cytokines, and induce the release of inflammatory modulators from leukocytes and endothelial cells [5]. For example, platelets interact with macrophages through P-selectins on the platelet surface, which then enhances the activation of transcriptional nuclear factorkB (NF-kB), further inducing the release of chemokines and cytokines. At the same time, platelets respond to these inflammatory mediators and are then induced to continue releasing inflammatory mediators, creating a vicious cycle of inflammation as well as the formation of an atherosclerotic plaque. Within an atherosclerotic plaque, the interaction between platelets induces the release of adhesion molecules and chemokines from leukocytes and endothelial cells, leading to the production of reactive oxygen species. Additionally, platelets contribute to further activation of leukocytes, which cumulatively leads to destabilization of the plaque and triggers the onset of acute coronary syndrome. Among the cytokines that platelets use in this inflammatory process are CD40 ligand (CD40L), P-selectins, and integrins [5]. A recent study suggested that circulating neutrophils have the ability to stimulate the bone marrow to release more immature platelets from megakaryocytes, which boosts the development of CVD [6]. These immature platelets can enhance the inflammatory process, thus increasing the risk of arterial thrombosis, ischemia, and myocardial infarction. Furthermore, abnormalities in platelet function (e.g., increased sensitivity to agonists) have been observed in patients with hypertension, which is a known risk factor for ACS [7]. There are several different types of transmembrane receptors located on the surface of platelets. These receptors include integrins (αIIbβ3, α2β1, α5β1, α6β1, αVβ3), glycoprotein toll-like receptors (TLRs), leucine-rich repeat receptors, seven-pass-transmembrane domain receptors (also known as G proteincoupled receptors or GPCRs), immunoglobulin superfamily proteins (glycoprotein VI, FcγRIIA), tyrosine kinase receptors, C-selectin receptors, and various other types [8]. Despite the numerous receptors located on the surface of platelets, much attention has been paid to several specific receptors due to their potential to attenuate platelet activity. The receptors responsible for the initial recruitment of platelets 169 (GPIb-IX-V), adhesion and aggregation (GPVI, α2β1, GPIIabβ3), and amplification (P2X1, P2Y1, P2Y12, PAR-1, PAR-4, TPα) have all been extensively studied [9]. The purpose of this article is to compile an upto-date review of the main platelet receptors that are largely responsible for platelet activity. Although there are a variety of other receptors located on the surface of platelets, the 10 aforementioned receptors are considered to be the most important related to CVD, ACS, and other platelet-related disorders due to the unwanted or overactivation of platelets in circulation (Figure 1). This review will discuss the hemostatic role of platelets in healthy individuals, how platelets are involved in ACS and CVD, the crystal structure of the aforementioned main platelet receptors bound to their respective ligands, and the function of these receptors in platelet activation. Platelets, hemostasis, and cardiovascular d (...truncated)