Novel Antiplatelet Therapy

Michael A. Gaglia Jr., MD, MSc; Steven V. Manoukian, MD; Ron Waksman, MD

Disclosures

Am Heart J. 2010;160(4):595-604. 

In This Article

Platelet Biology—Focus on P2Y12 and Thrombin Receptors

An understanding of the role of platelets in primary hemostasis is necessary to comprehend the process of thrombosis that ultimately results in ACS. Although a complete review of this intricate process is beyond the scope of this review, an overview with particular attention to the importance of the platelet agonists adenosine diphosphate (ADP) and thrombin follows.

Primary hemostasis is composed of three essential phases: platelet adhesion, activation, and aggregation (Figure 1). Disruption of the endothelium, through either vessel injury or atherosclerotic plaque rupture, exposes tissue factor; this activates a pathway that ultimately liberates thrombin through the coagulation pathway. The extracellular matrix is also exposed, thus initiating platelet adhesion. The most important substrates for platelet binding are collagen, which binds the glycoprotein (GP) Ib/IX/V platelet receptor, and von Willebrand Factor, which binds the GP VI receptor.[5] Adhesion initiates platelet activation through two key processes: shape change of the platelet surface membrane, which results in membrane protrusions to facilitate tethering to other platelets;[2] and the activation of complex intracellular signaling pathways that ultimately result in the release of platelet agonists such as ADP, thromboxane A2, and thrombin.[6] Such agonists subsequently activate other platelets. The last step in this process, aggregation, is facilitated by the expression of GpIIb-IIIa on the surface of activated platelets. This receptor undergoes a shape change with activation, allowing it to bind fibrinogen and von Willebrand Factor, thereby effecting the cross-linking of platelet to platelet and ultimately leading to the formation of a platelet thrombus.[7]

Figure 1.

Major platelet agonists and receptors involved in thrombus formation. Disruption of the endothelium exposes TF and collagen, liberating thrombin and initiating platelet adhesion via the GP Ib/Ix/V and GP VI platelet receptors. Adhesion also initiates the release of platelet agonists, including ADP and TXA2, which thereby activate other platelets. Activated platelets are then cross-linked by fibrinogen, leading to platelet thrombus formation. TXA2, Thromboxane A2; TF, tissue factor.

Receptors on the platelet surface are vital to the above process. This includes the thromboxane A2 receptor (which has two subtypes, TPα and TPβ), the GpIIb-IIIa receptor, the P2Y12 receptor, and the protease activated receptors (PAR). The P2Y12 receptor is coupled to the Gi protein and is activated by the binding of ADP, which then liberates the αi and βγ subunits. The αi subunit inhibits adenylyl cyclase, resulting in a decrease in intracellular cyclic adenosine monophosphate (cAMP) levels. This thereby decreases cAMP-mediated phosphorylation of the vasodilator-stimulated phosphoprotein (VASP).[8–10] This protein is important for two reasons: first, it results in activation of the GpIIb-IIIa receptor; second, measurement of its phosphorylated form (VASP-P) is essentially a measure of overall P2Y12 activity, with higher levels of VASP-P representing relatively more P2Y12 inhibition.[11] This has been applied with good effect to the VASP phosphorylation assay, which uses flow cytometry to measure levels of VASP-P. The βγ subunit of the Gi protein has a similar effect, but through a different mechanism. βγ activates phosphatidylinositol-3-kinase, which then activates both a serine threonine protein kinase B and Rap1b. These guanosine 5′-triphosphate-binding proteins then lead to GpIIb-IIIa receptor activation.[10]

As our understanding of platelet biology grows, the PAR-mediated pathway is also emerging as a therapeutic target. Human platelets express two types of PAR, PAR-1 and PAR-4.[12] Both are G-protein coupled receptors that bind thrombin, the most potent known physiological agonist of platelets that also is crucial to the coagulation cascade.[13–15] PAR-1 appears to have higher affinity for thrombin than PAR-4, although the relative importance of PAR-1 versus PAR-4 is still somewhat unclear.[16] Thrombin binding to PAR-1 cleaves the receptor, initiating an intracellular signaling process facilitated by various G-proteins. Specifically, G12 and G13 ultimately lead to cytoskeletal changes that likely mediate platelet shape change; whereas Gq and Gi lead to increased intracellular cAMP and calcium, leading to GpIIb-IIIa activation and thereby contributing to platelet activation.[7,15,17]

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