Comparative In Vitro Study of Various α2-Adrenoreceptor Agonist Drugs for Ticagrelor Reversal

Guillaume Porta Bonete,Tiphaine Belleville-Rolland,Christilla Bachelot-Loza,Anne Godier,Pascale Gaussem,Anne-Céline Martin,Alexandre Leuci,Sonia Poirault-Chassac

doi:10.3390/jcm9030809

Abstract

Ticagrelor, an antiplatelet adenosine diphosphate (ADP)-P2Y12 receptor antagonist, increases the risk of bleeding. Its management is challenging because platelet transfusion is ineffective and no specific antidote is currently available. Epinephrine, a vasopressor catecholamine prescribed during shock, restores platelet functions inhibited by ticagrelor through stimulation of α2A-adrenoreceptors. It subsequently inhibits cyclic adenosine monophosphate (cAMP) pathway and PI3K signaling. However, since epinephrine may expose a patient to deleterious hemodynamic effects, we hypothesized that other α2-adrenoreceptor agonist drugs used in clinical practice with fewer side effects could reverse the antiplatelet effects of ticagrelor. We compared in vitro the efficacy of clonidine, dexmedetomidine, brimonidine, and norepinephrine with epinephrine to restore ADP- and PAR-1-AP-induced washed platelet aggregation inhibited by ticagrelor, as well as resulting platelet cAMP levels. In ticagrelor-free samples, none of the α2-adrenoreceptor agonists induced aggregation by itself but all of them potentiated ADP-induced aggregation. Compared with epinephrine, norepinephrine, and brimonidine partially restored ADP- and fully restored PAR-1-AP-induced aggregation inhibited by ticagrelor while clonidine and dexmedetomidine were ineffective. Indeed, this lack of effect resulted from a lower decrease in cAMP concentration elicited by these partial α2-adrenoreceptor agonists, clonidine, and dexmedetomidine, compared with full α2-agonists. Our results support the development of specific full and systemic α2-adrenoreceptor agonists for ticagrelor reversal.

Highlights

Ticagrelor is a direct-acting, selective, and reversible antagonist of the platelet adenosine diphosphate (ADP) P2Y12 receptor that is recommended for the treatment of acute coronary syndromes [1]
We recently showed that epinephrine, a vasopressor agent used to treat shock, is able in vitro to restore platelet functions inhibited by ticagrelor
The α subunit of Gz-protein binds to adenylate cyclase and inhibits the synthesis of the second messenger cyclic adenosine monophosphate, which plays a central role in platelet inhibition, while the dissociated βγ subunit activates phosphoinositide 3-kinase (PI3K) pathway [10,11]

Summary

Introduction

Ticagrelor is a direct-acting, selective, and reversible antagonist of the platelet adenosine diphosphate (ADP) P2Y12 receptor that is recommended for the treatment of acute coronary syndromes [1]. We recently showed that epinephrine, a vasopressor agent used to treat shock, is able in vitro to restore platelet functions inhibited by ticagrelor. Epinephrine acts through stimulation of α2A-adrenoreceptors coupled with Gz-protein on the platelet membrane surface. In combination with ADP stimulating the P2Y1 receptor signaling and subsequent Ca2+ mobilization, epinephrine induces aggregation of ticagrelor-treated platelets through inhibition of the cAMP pathway and activation of the PI3K pathway. We hypothesized that other α2-adrenoreceptor agonist drugs used in clinical practice in various settings with fewer side effects and less hemodynamic impact could have platelet-activating properties and be of interest to reverse the antiplatelet effects of ticagrelor

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