The P2Y12 receptor, pivotal to platelet activation, has been targeted in the development of antithrombotics for use in ACS in particular. The direct substrate of energy metabolism, adenosine diphosphate (ADP) binds to the P2Y12 receptor. ADP is also stored in platelet granules. This ADP binding results in activation of the platelet which causes a conformational shape change, activation of the critical glycoprotein (GP) IIb/IIIa integrin complex, and platelet aggregation.
Ticagrelor (Brilinta) , the first P2Y12 receptor platelet antagonist to be marketed binds at a site on the P2Y12 receptor away from the ADP-binding site, producing a non-competitive inhibition. The thienopyridines, clopidogrel (Plavix/Iscover) and prasugrel, bind directly to the ADP binding site on the P2Y12 receptor, irreversibly blocking this site. Cangrelor is a direct and reversible P2Y12 antagonist. It was developed as an antiplatelet agent for intravenous use with rapid onset and offset action. Structurally, cangrelor is the analog of ATP, the weak endogenous antagonist of the P2Y12 receptor
Antiplatelet agents that block the P2Y12 receptor have complementary effects with aspirin in terms of platelet inhibition because their mechanism of action is different than that of aspirin, which blocks cyclo-oxygenase-1 causing a decrease in thromboxane A2.
Aspirin is indicated as acute and chronic antiplatelet therapy in acute coronary syndrome (ACS), including non-STEMI.
Dual antiplatelet therapy
Clopidogrel and aspirin are also indicated in NSTEMI, with superior efficacy over aspirin alone for the first twelve months. Of course, the bleeding risks are slightly increased with dual antiplatelet therapy; however, the bigger issue with clopidogrel seems to be irregularity in its clinical effect because of genetic polymorphism.
This clopidogrel resistance is mediated through cytochrome (P450)2C19 enzyme effect, an effect not relevant with prasugrel or ticagrelor. Like clopidogrel, the thienopyridine prasugrel inhibits the ADP-binding site of the P2Y12 receptor while ticagrelor inhibits the P2Y12 receptor at a different (non-ADP binding) site. [Cavalliari et al., 2011].
Overall ticagrelor appears to be more effective in preventing ischaemic events, with a similar rate of major bleeding.
The current paradigms in discussion of thrombosis have returned to considering the platelet as a functional part in the coagulation cascade as the platelet is in fact the main source of thrombin for the coagulation pathway. The platelet plug initiates a platelet-derived platelet activation positive feedback loop that promotes the formation of a haemostatic plug based on the combination of platelet aggregation and coagulation. Coagulation promotes a fibrin meshwork to bind the platelets and the rented tissue together.
Platelet adhesion and activation and subsequent platelet aggregation is a process that has to-date been characterised thus wise in terms of receptor-mediated mechanisms:
- Platelet adhesion is mediated by binding of platelet surface receptor glycoprotein Ib-IX-V complex to von Willebrand factor in the subendothelial matrix (i.e. site of exposed collagen). Platelet collagen receptor GP Ia-IIa binds collagen.
- These result in the activation of the GPIIb/IIIa integrin complex, the most abundant receptor on the platelet surface and these integrins then bind soluble adhesive substrates such as fibrinogen and vWF. This represents the final common pathway of platelet aggregation. At this stage, thrombus formation is well underway through platelet-platelet interactions producing most of the thrombin needed for the coagulation cascade.
- ADP acts as platelet substrate messenger and reacts with the P2Y1 and P2Y12 platelet receptors. Stimulation of P2Y12 receptors amplifies the aggregation of platelets, induced by 5-HT (serotonin), TXA2 (thromboxane), and thrombin (Xa).
- Thromboxane is generated from arachidonic acid by the action of cyclooxygenase into prostaglandin endoperoxides and then thromboxane synthase into thromboxane A2, which washes downstream and promotes thrombus formation and microvasculature contraction.
- Thrombin itself is a potent platelet activator
Pharmacological properties of P2Y 12 receptor inhibitors:
The IIb/IIIa integrin complex acts as docking station for fibrin to “cross-link” platelets together. The P2Y12 receptor has been most well characterised for pharmacotherapeutic applications: its natural ligand, ADP; and its inhibitors clopidogrel, prasugrel, and ticagrelor.
Also recall or recognise that haemostasis and inflammation are inherently combined through substrate mediators like ADP. ADP-mediated activation of P2Y12 is a common activating pathway between haemostasis and inflammation.
References
Harmsze, Ankie & Robijns, Karen & Werkum, Jochem & Breet, Nicoline & Hackeng, Chris & Berg, Jurriën & Ruven, Henk & Klungel, O.H. & Boer, Anthonius & Deneer, Vera. (2010). The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response. Thrombosis and haemostasis. 103. 920-5. 10.1160/TH09-08-0516.
Mansour, Alexandre, Christilla Bachelot-Loza, Nicolas Nesseler, Pascale Gaussem, and Isabelle Gouin-Thibault. 2020. “P2Y12 Inhibition beyond Thrombosis: Effects on Inflammation” International Journal of Molecular Sciences 21, no. 4: 1391. https://doi.org/10.3390/ijms21041391
Minno, Matteo Nicola Dario Di, Anna Guida, Marina Camera, Susanna Colli, Giovanni Di Minno, and Elena Tremoli. “Overcoming Limitations of Current Antiplatelet Drugs: A Concerted Effort for More Profitable Strategies of Intervention.” Annals of Medicine 43, no. 7 (2011/11/01 2011): 531-44. https://doi.org/10.3109/07853890.2011.582137. https://doi.org/10.3109/07853890.2011.582137.
Nawarskas, James J. and Snowden, Stanley S. “Critical appraisal of ticagrelor in the management of acute coronary syndrome.” Therapeutics and Clinical Risk Management 7; 2011: 473–88. http://dx.doi.org/10.2147/TCRM.S19835.
