Novel antiplatelet targets in the treatment of acute coronary syndromes

Abstract

Acute coronary syndromes (ACS) are a global cause of mortality and morbidity that affect millions of lives worldwide. Following atherosclerotic plaque rupture, platelet activation and aggregation are the two major elements that initiate thrombus formation inside a coronary artery, which can obstruct blood flow and cause myocardial ischemia; ergo, antiplatelet therapy forms a major part of the treatment strategy for ACS. Patients with ACS routinely receive dual antiplatelet therapy (DAPT), which consists of aspirin and a platelet P2Y₁₂ inhibitor to both treat and prevent atherothrombosis. Use of platelet glycoprotein (GP) IIb/IIIa inhibitors is now limited due to the risk of severe bleeding and thrombocytopenia. Thus, administration of GPIIb/IIIa inhibitors is generally restricted to bail out thrombotic events associated with PCI. Furthermore, current antiplatelet medications mainly rely on thromboxane A₂ and P2Y₁₂ inhibition, which have broad-acting effects on platelets and are known to cause bleeding, which especially limits the long-term use of these agents. In addition, not all ACS patients treated with current antiplatelet treatments are protected from recurrence of arterial thrombosis, since many platelet mechanisms and activation pathways remain uninhibited by current antiplatelet therapy. Pharmacological antagonism of novel targets involved in platelet function could shape future antiplatelet therapies that could ultimately lead to more effective or safer therapeutic approaches. In this article, we focus on inhibitors of promising targets that have not yet been introduced into clinical practice, including inhibitors of GPVI, protease-activated receptor (PAR)-4, GPIb, 5-hydroxytryptamine receptor subtype 2A (5-HT_2A), protein disulfide isomerase, P-selectin and phosphoinositide 3-kinase β.

Keywords:

• Acute Coronary Syndrome
• antiplatelet therapy
• atherothrombosis
• bleeding
• PCI
• platelet

Acknowledgements

We would like to thank Prof Steve P. Watson for critical discussions. This work was supported by grants from Aljouf University (Saudi Arabia) and the National Institute for Health Research (NIHR).

Disclosures

Fawaz Alenazy: No conflicts of interest to report. Mark R. Thomas: Research grants: Novartis and Rigel Pharmaceuticals. Consultant/advisory board: Cytosorbents