Interactions between the endothelial mediator’s nitric oxide and prostacyclin, and platelet P2Y12 receptor blockade
An often explored hypothesis is that in at risk patients the chances of experiencing a thrombotic event is associated with the level of P2Y12 platelet blockade. However, studies have failed to show any benefits of ex vivo platelet function tests (PFT) and subsequent tailoring of treatment in patients receiving dual anti-platelet therapy (DAPT). This failure is possibly because these tests do not consider the environment in which platelets reside in vivo. Namely, that the strong synergies between P2Y12 inhibitors, prostacyclin (PGI2) and nitric oxide (NO) mean that in vivo platelet reactivity will be a function of the level of P2Y12 receptor blockade and levels of endothelial-derived NO and PGI2. This thesis investigates the relationship between P2Y12 blockade and endothelial mediators, emphasising the role of the endothelium in pathways of platelet activation. Initial in vitro platelet aggregation, release and flow cytometry experiments demonstrated the powerful, synergistic interactions between P2Y12 blockade, NO and PGI2. Immunoassays highlighted that cAMP rather than cGMP is the major driver of this synergy. By giving healthy individuals standard P2Y12 blockers it was determined that these in vitro observations hold true in man, with platelet responses powerfully influenced by the presence of NO and PGI2. Furthermore, in patients with peripheral arterial disease (PAD) NO and PGI2 strongly interacted with P2Y12 blockade to inhibit platelet activation, adding further evidence that the in vivo environment is vital in determining platelet reactivity during DAPT. Overall, this thesis highlights the importance of endothelial mediators in determining the therapeutic efficacy of P2Y12 blockers, highlighting that endothelial function testing alongside ex vivo PFT could enhance risk prediction. It also provides a future basis to redefine optimal DAPT regimens in clinical populations, suggesting that alongside potent P2Y12 receptor blockade, enhancement of inhibitory cyclic nucleotide pathways in platelets, rather than the co-administration of aspirin, could represent an effective therapeutic approach.
- Theses