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Clinical pharmacology
New P2Y12 inhibitors
  1. Robert F Storey
  1. Correspondence to Professor Robert F Storey, Department of Cardiovascular Science, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK; r.f.storey{at}

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The management and prevention of arterial thrombosis has been transformed by the recognition of the role of platelets in this process and the development of effective antiplatelet drugs. The limited role of thromboxane A2 in platelet activation explains why aspirin therapy, which effectively inhibits release of thromboxane A2 by platelets, is insufficient in high risk conditions such as acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI). The platelet P2Y12 receptor, one of two adenosine diphosphate (ADP) receptors on platelets, plays a central and unique role in platelet activation through amplifying the effects of numerous platelet agonists (figure 1).1 Platelet activation leads not only to aggregation but also to the release of pro-thrombotic and pro-inflammatory granule contents as well as the formation of thrombin. Strong amplification of all these platelet responses by P2Y12 explains why this receptor plays such an important part in thrombosis and haemostasis and is a successful target for antiplatelet drugs.

Figure 1

Mechanisms of platelet activation and site of action of platelet inhibitors. Numerous platelet surface receptors initiate platelet activation leading to platelet aggregation, release of alpha and dense granule contents, and conversion of the platelet surface membrane to a catalytic surface for thrombin generation (‘platelet procoagulant activity’). Collagen binding to GPVI is an important stimulus for thromboxane A2 release. ADP released from dense granules binds to P2Y1 and P2Y12 receptors and P2Y12 acts as a powerful amplification system for platelet activation and all the functional responses associated with this. Platelet alpha granule contents support coagulation and, through multiple mechanisms, drive the inflammatory response associated with thrombosis. The sites of action of important antiplatelet drugs are shown. Adapted from Storey.1

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