Abstract Number: PB0378
Meeting: ISTH 2022 Congress
Background: Dual antiplatelet therapy (DAPT) targeting both TP receptor ligand production and P2Y12 receptor activation is standard following percutaneous coronary intervention (PCI) in coronary artery disease patients. Trial data remain inconclusive but suggest redundancy of aspirin in the presence of strong P2Y12 inhibitors such as ticagrelor or prasugrel.
Aims: To explore potential interplay between the Gαq-coupled TP and Gαi-coupled P2Y12 receptor pathways at the levels of surface expression, molecular interaction and platelet function
Methods: Platelets were obtained with informed consent from acute coronary syndrome (ACS) patients undertaking DAPT, or from healthy volunteers. Platelet activation was assessed by ratiometric monitoring of ligand-induced calcium flux. Receptor expression in platelets and HEK293T cells transiently overexpressing tagged P2Y12 and TP receptors was assessed by flow cytometry. Receptor interaction was assessed by immunoprecipitation and Western blotting from lysed cells.
Results: Longitudinal comparisons of platelet responses from patients at the end of DAPT revealed significant reduction in U46619-induced, TP-mediated calcium flux in the presence of ticagrelor plus aspirin, compared to aspirin alone. However, patient ticagrelor treatment was associated with a significant increase in both P2Y12 and, unexpectedly, TP platelet surface expression as assessed by flow cytometry. This was recapitulated ex vivo using healthy donor platelets, and further explored through co-expression of tagged P2Y12 and TPα in HEK293T cells where enhanced surface expression of each receptor was observed, compared to single receptor transfectants. This appeared specific, since no such enhancement was seen upon substitution of P2Y12 with the similarly Gαi-coupled µOR. Finally, tagged, overexpressed P2Y12 and TP receptors were demonstrated to interact in reciprocal co-immunoprecipitation experiments indicating dimerization.
Conclusion(s): These data suggest co-trafficking of P2Y12 and TP receptors, that can be modulated through inhibition of P2Y12 by ticagrelor. They highlight the complex relationship between P2Y12 and TP receptor biology helping to inform the debate on DAPT versus monotherapy.
To cite this abstract in AMA style:Keith M, Hutchinson J, Khalil J, Aungraheeta M, Mundell S. Ticagrelor enhances platelet TP receptor surface expression in patients due to P2Y12 / TP dimerization [abstract]. https://abstracts.isth.org/abstract/ticagrelor-enhances-platelet-tp-receptor-surface-expression-in-patients-due-to-p2y12-tp-dimerization/. Accessed March 4, 2024.
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