The relationship between cyclo-oxygenase isoforms and platelets in the cardiothoracic system

At present, the cyclo-oxygenase inhibitor aspirin and the P2Y12 receptor blocker clopidogrel are commonly combined to prevent recurrent thrombosis after acute coronary syndrome events. Variable responses to this drug combination have driven the development of prasugrel and ticagrelor, two more potent P2Y12 blockers that constitute a superior therapy when used with aspirin. In parallel, investigations of non-steroidal anti-inflammatory drugs – the drug class that aspirin belongs to – suggest that cyclo-oxygenase inhibition can contribute to thrombosis. This thesis has investigated the relationship between cyclo-oxygenase inhibition within the cardiothoracic system and pathways of platelet activation. It has been demonstrated in vitro that the effects of aspirin vary with the level of P2Y12 blockade: at low levels of P2Y12 inhibition aspirin increases the overall anti-platelet effect, although with high levels of P2Y12 blockade aspirin has little to no effect. By giving healthy volunteers prasugrel it was determined that these in vitro observations hold true in man – aspirin added little to the anti-platelet effect of prasugrel and furthermore aspirin reduced urinary metabolites of the anti-thrombotic hormone prostacyclin. These data suggest that concomitant use of aspirin with strong P2Y12 blockers could lessen the overall anti-thrombotic effect. Whilst initial experiments used 96-well plate assays to model platelet activation, responses in traditional light transmission aggregometry were also investigated. By investigating parameters affecting the pharmacology of P2Y12 blockers and aspirin, it has been possible to ascertain key differences in the way these techniques model platelet aggregation. In addition, immunoblotting and functional studies of tissues from wild type and COX-1 or COX-2 deficient mice suggest that COX-1 is the predominant isoenzyme found within the cardiothoracic system. Overall, this thesis questions the therapeutic usefulness of aspirin in combination with potent P2Y12 receptor blockers and provides a basis for future work to redefine the role of aspirin in clinical populations