Targeting Platelet Thrombin Receptor Signaling to Prevent Thrombosis

Abstract

Platelets contribute fundamentally to ischemic heart disease, and antiplatelet therapy has been critical to reducing acute thrombotic complications of atherosclerotic disease. Thrombin, by acting on protease activated receptors (PAR), is one of the most potent platelet activators. PAR-1 antagonists may therefore provide more comprehensive antithrombotic effects. We review the pathophysiology of atherothrombosis, platelet activation by thrombin, the role of platelet protease activated receptors (PAR), and the clinical data supporting their use.

Aspirin in the prevention of cardiovascular events in patients with diabetes

“…von Willebrand factor, tissue factor and collagen), which leads to platelet activation. [13][14][15][16] Activated platelets release additional prothrombotic mediators, such as adenosine diphosphate (ADP) and thromboxane A 2 (TXA 2 ), which activate additional platelets locally and release components necessary for clot formation (e.g. thrombin).…”

“…[13][14][15] Activated platelets also produce pro-inflammatory signals that recruit inflammatory cells to the area. [16] These inflammatory cells produce cytokines that stimulate endothelial and smooth muscle cells to produce tissue factor, the initiator of coagulation. [17] Activation of the coagulation cascade results in a fibrin meshwork that (along with cross-linking of platelets, endothelial cells and leukocytes) blocks the vascular interior ( Figure 1).…”

“…[17] Activation of the coagulation cascade results in a fibrin meshwork that (along with cross-linking of platelets, endothelial cells and leukocytes) blocks the vascular interior ( Figure 1). [13][14][15][16] Aspirin reduces clot formation by decreasing production of TXA 2 , a key platelet activator. [10,[18][19][20][21] Aspirin irreversibly binds to and inhibits the COX enzymes [22] (particularly COX-1), which are responsible for TXA 2 synthesis and production of prostaglandins, which aid in vascular hemostasis, protection of the gut and regulation of renal blood flow (Figure 2).…”

The role of platelets in hemostasis and the effects of snake venom toxins on platelet function

“…Platelets can be activated by adhesion interactions as well as by the binding of various platelet agonists to specific surface receptors (Figure 1) (Wallace and Smyth, 2013). When activated, platelets undergo changes in terms of the organization of proteins that form the cytoskeleton.…”

Current State and Novel Approaches of Antiplatelet Therapy

“…Active thrombin bound to GPIbα activates platelets and facilitates stimulation of the G-protein-coupled 7-transmembrane receptor, protease-activated receptor-1; thrombin also activates human platelets via protease-activated receptor-4. 25,26 In activated platelets, secretion of the agonist, ADP, and activation of the cyclooxygenase pathway leading to synthesis and secretion of thromboxane A2 (TxA2) reinforce platelet activation by autocrine stimulation of G-protein-coupled receptors for ADP (P2Y1 and P2Y12) 27 or TxA2, respectively ( Figure 1). In this way, activation via primary platelet receptors, GPIb-IX-V/GPVI, or secondary receptors for ADP, TxA2 or, thrombin leads to activation of the platelet integrin, αIIbβ3 (GPIIb/ IIIa) that binds fibrinogen or vWF and mediates platelet aggregation.…”