Platelets are the smallest, yet arguably the most pivotal blood constituent in the context of haemostasis and wound healing. However, vascular perturbations that result in ischaemic tissue injury has implicated platelets as a major player in the disease progression caused by arterial thrombosis. Platelets responses are influenced by the auto- and paracrine release of prothrombotic ligands acting upon platelet-expressed G-protein coupled receptors (GPCRs). These receptors initiate distinct intracellular signal pathways responsible for the interrelated processes of platelet adhesion, activation, secretion and aggregation. Of the many platelet expressed GPCRs, the activation of the P2Y12 receptor (P2Y12R) is well known to be responsible for sustained aggregation and thus thrombus formation. Consequently, the P2Y12R is an attractive and efficacious target for drug development, birthing the modern standard of care of dual antiplatelet therapy (DAPT) in patients with acute coronary syndromes (ACS). Of the currently available antiplatelet agents, ticagrelor has been shown to be superior both in clinical trials and laboratory studies. However, much debate exists around the pharmacodynamics attributed to ticagrelor and how this may influence its perceived clinical superiority. Additionally, amid concerns of the increased bleeding risk associated with ticagrelor as with all antiplatelet agents, recent international expert consensus guidelines have emerged to provide clarity on how and when to switch pharmacotherapies. Therefore, the aim of this thesis was to further define the pharmacodynamics of ticagrelor antiplatelet therapy, characterising the drugs mode of action, onset and reversibility. Assessment of the inhibitory effect of ticagrelor on P2Y12R activation was facilitated by bioluminescence resonance energy transfer (BRET2) technology in P2Y12R-transfected cells and complemented by observations seen with light transmission aggregometry in isolated human platelets. Our results demonstrate that ticagrelor acts as an inverse agonist in a concentration-dependent manner. Further, the proposed reversibility of this drug is questioned with data suggesting that versus ADP, this drug acts in an irreversible manner. This may impact upon clinical practice regarding antiplatelet therapy administration, especially in consideration of the currently available switching guidelines.
|Date of Award||21 Jan 2021|
- The University of Bristol
|Supervisor||Stuart J Mundell (Supervisor) & Thomas W Johnson (Supervisor)|