Key result
Ticagrelor binding to the P2Y12 receptor was prolonged and resistant to wash-out in human platelets and cell-based assays, acting more akin to an irreversible antagonist.
Why the study?
Although ticagrelor is labeled as a reversible P2Y12 receptor antagonist, the effectiveness of platelet transfusion to manage bleeding following ticagrelor therapy remains debated.
Ticagrelor exhibits prolonged, irreversible-like binding at the P2Y12 receptor, challenging its classification as a reversible antagonist and emphasizing the need for specific reversal agents in bleeding emergencies.
Ticagrelor may show prolonged P2Y12 binding in vitro; leaves open its reversible classification and reversal needs pending clinical data.
Background: Ticagrelor is labelled as a reversible, direct-acting platelet P2Y12 receptor (P2Y12R) antagonist that is indicated clinically for the prevention of thrombotic events in patients with acute coronary syndrome (ACS). As with many antiplatelet drugs, ticagrelor therapy increases bleeding risk in patients which in emergency situations requires platelet transfusion although there is ongoing debate on its effectiveness following ticagrelor therapy. The aim of this study was to further examine the reversibility of ticagrelor at the P2Y12R. Methods: Studies were performed in human platelets with both P2Y12R-stimulated GTPase activity and platelet aggregation assessed. Cell-based bioluminescence resonance energy transfer (BRET) assays were also undertaken to assess G protein subunit activation downstream of P2Y12R activation. Results: Initial studies revealed a range of P2Y12R ligands including ticagrelor displayed inverse agonist activity at the P2Y12R. Of these only ticagrelor was resistant to wash-out. In both human platelets and cell-based assays, washing failed to reverse ticagrelor-dependent inhibition of ADP-stimulated P2Y12R function in contrast to other P2Y12R antagonists. The P2Y12R agonist 2MeSADP, which was also resistant to wash-out, was able to effectively compete with ticagrelor. In silico docking revealed that ticagrelor and 2MeSADP penetrated more deeply into the orthosteric binding pocket of the P2Y12R than other P2Y12R ligands. Conclusion: Ticagrelor binding to the P2Y12R is prolonged and more akin to that of an irreversible antagonist especially versus the endogenous P2Y12R agonist ADP. This study highlights the potential clinical need for novel ticagrelor reversal strategies in patients with spontaneous major bleeding and bleeding associated with urgent invasive procedures.
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Khalil et al. (2022) studied this question. Ticagrelor vs. Other P2Y12R antagonists was evaluated on Reversibility of ticagrelor at the P2Y12R. Ticagrelor binding to the P2Y12 receptor was prolonged and resistant to wash-out in human platelets and cell-based assays, acting more akin to an irreversible antagonist.
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