Regulation of TP thromboxane receptor expression and activity by selective P2Y12 receptor antagonists in human platelets: Consequences for dual antiplatelet therapy?

Activation of platelet expressed G protein-coupled receptors (GPCRs) by TxA2 (TP receptor) and ADP (P2Y1 and P2Y12R) plays a central role in the development of the arterial thrombosis.

Aspirin, which inhibits TxA2 generation, and P2Y12R antagonists are effective anti-platelet agents with their combination, termed dual antiplatelet therapy (DAPT), forming a powerful therapeutic tool in the treatment and prevention of arterial thrombosis.

However, the need for DAPT is under debate with suggestions that effective P2Y12R antagonism may decrease TP receptor activity thus rendering the use of aspirin superfluous or even detrimental by increasing patient bleeding.

Recent compelling preliminary evidence suggests that specific P2Y12R antagonists regulate TP receptor expression and function in vitro and critically in vivo in patients.

This timely proposal will provide a mechanistic insight into how specific P2Y12R antagonists are able to inhibit platelet TP receptor activity helping to inform the debate regarding P2Y12R antagonist monotherapy versus DAPT in acute coronary syndrome (ACS) patients.

As part of this work, studies focussed on those patients with high bleeding risk, and therefore potentially with the most to gain from changes in clinical practice, will be undertaken helping to define the risks versus benefits of DAPT.