Do specific drugs affect platelet receptor expression thereby increasing patient risk upon their withdrawal?

Heart attacks occur when a blockage called a thrombosis develops in the blood vessels of the heart which is a major cause of morbidity and mortality. Platelets, the major blood cell involved in thrombosis development, can be switched on to become sticky by a wide variety of mediators. ADP is one of the most important of these mediators, activating platelets through receptors, including the P2Y12 receptor (P2Y12R), expressed on the platelet surface. Activation of the platelet expressed P2Y12R by ADP provides a major positive feed-forward signal to amplify platelet responses to a wide variety of platelet aggregation agonists. For this reason, pharmacological blockade of P2Y12Rs forms a powerful therapeutic tool in the treatment and prevention of arterial thrombosis associated with coronary atherosclerosis.
There are a number of clinically used drugs that block the ability of ADP to bind to the P2Y12R thereby inhibiting platelet activation. Ongoing studies in my laboratory(1) suggest that these drugs can act in a more complex manner than previously envisaged directly changing the behaviour of P2Y12Rs and their surface expression to influence platelet activity in an ADP-independent manner. Intriguing recent clinical trials have shown a rebound increase in thrombotic events following withdrawal of P2Y12R antagonist (2,3). No studies have been undertaken to explore if this is as a consequence of drug-induced changes in platelet function. In this regard recent preliminary studies from our laboratory show that specific antiplatelet drugs increase P2Y12R surface expression and following their withdrawal have the potential to enhance receptor signalling. Do these drug-induced changes in platelet receptor expression confer an increased risk of thrombosis upon patients upon drug withdrawal?
In this translational project you will explore the functional consequences of antiplatelet drug administration and their subsequent withdrawal upon platelet receptor expression and function. You will assess if following cessation of administration drug-induced changes in platelet receptor expression and activity may lead to a period of platelet hyper-responsiveness in patients. This project will allow us to determine if following cessation of administration drug-induced changes in platelet receptor expression and activity may lead to a period of platelet hyper-responsiveness in patients. This greater understanding of the ability of drugs to modulate platelet receptor surface expression and activity may allow us to better construct therapeutic approaches to the prevention of thrombosis in heart disease.
In order to undertake this programme of research you will be supported by an established network of clinical (Bristol Heart Institute) and industrial (Astra Zeneca) collaborators. This grouping will provide you with both the logistical support and access to patient samples from ongoing clinical trials at the University Hospitals Bristol NHS Foundation Trust. You will receive training in a wide variety of relevant techniques ranging from advanced fluorescent single cell imaging microscopy through to the measurement of cell signalling pathways and have access to wide range of specific and more generic training courses through the Bristol Doctoral College (http://www.bristol.ac.uk/doctoral-college/)

Please do contact me at [Email Address Removed] if you would like further information about this exciting opportunity.