Platelets are small anucleate cells which play a fundamental role in haemostasis restricting blood loss following vessel injury. They also play a critical role in arterial thrombus formation in acute coronary syndromes (ACS). Platelets can respond to small molecule agonists leading to an aggregation response forming a clot or thrombus. Two particularly relevant small molecule agonists are thromboxane (TxA2) and ADP which act on different G protein coupled receptors (GPCRs), present on the platelet plasma membrane. ADP acts through P2Y1 and P2Y12 receptors while TxA2 acts through thromboxane (TP) receptors. Current clinical practice to reduce the risk of thrombus formation in ACS patients employs a dual antiplatelet therapy (DAPT) approach. DAPT consists of a P2Y12 receptor antagonist to block the effects of ADP at P2Y12, and aspirin to ablate the synthesis of TxA2. Notably DAPT, although clinically efficacious, can have the significant side-effect of patient bleeding. However, emerging in vivo and in vitro evidence suggests certain P2Y12 receptor antagonists can reduce the activity of TP receptors and modulate their expression. If specific P2Y12 receptor antagonists can reduce thromboxane receptor activity, the use of aspirin in DAPT may be unnecessary with its removal potentially reducing major bleeding risk. In this thesis, the thromboxane and P2Y12 receptors expression is shown to be deeply connected where co-expression of both receptors bilaterally increases surface receptor expression which is increased further by P2Y12 receptor antagonist Ticagrelor. Further, thromboxane receptor reactivity to agonists is reduced by Ticagrelor pre-treatment in human platelets and cells co-expressing P2Y12R. Lastly, through co-immunoprecipitation, this thesis reports a novel physical interaction between the thromboxane receptor and the P2Y12 receptor which appeared to be further stabilised by Ticagrelor. These findings aim to improve our mechanistic understanding of the interplay between P2Y12 receptor antagonists and the thromboxane receptor in order to inform clinical practice and supplement past and ongoing P2Y12 receptor antagonist monotherapy trials, that challenge the paradigm of DAPT. <br/
