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Comparative In Vitro Study of Various ?2-Adrenoreceptor Agonist Drugs for Ticagrelor Reversal.

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 ?2A-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 ?2-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 ?2-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 ?2-adrenoreceptor agonists, clonidine, and dexmedetomidine, compared with full ?2-agonists. Our results support the development of specific full and systemic ?2-adrenoreceptor agonists for ticagrelor reversal.

SUBMITTER: Porta Bonete G

PROVIDER: S-EPMC7141185 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Porta Bonete Guillaume G Godier Anne A Gaussem Pascale P Belleville-Rolland Tiphaine T Leuci Alexandre A Poirault-Chassac Sonia S Bachelot-Loza Christilla C Martin Anne-Céline AC

Journal of clinical medicine 20200316 3

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 PI3 ...[more]

PMID: 32188130

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Project description:BackgroundCatecholamine infusion elicits an increase in clotting factors and this increase has been attributed to stimulation of ?2-adrenorecptors (?2AR). Accordingly, we tested the hypothesis that inhalation of a short-acting selective ?2AR agonist can induce a procoagulant state in healthy individuals.MethodsWe recruited 23 healthy volunteers (nine females; mean age: 26±0.8 years; body mass index: 24.7±0.5 kg/m2) and randomly allocated them into two groups, the ?2AR arm (seventeen subjects) and the saline arm (six subjects). Hemodynamics, plasma norepinephrine concentration, and procoagulant, anticoagulant, and fibrinolytic profiles of each participant were determined using specific assays before and after inhalation of either 2 mL nebulized normal saline or a mixture of 1 mL saline and 1 mL of salbutamol (5 mg salbutamol sulfate), a selective ?2AR agonist, which were delivered by a nebulizer over ten minutes.ResultsSaline inhalation had no effect on the procoagulant, anticoagulant and fibrinolytic profiles of the six healthy volunteer in the study's saline arm. Salbutamol inhalation caused (a) a significant increase in the activity or levels of the procoagulant factors; FVIII increased by 11±3% (p = 0.04), von Willebrand factor increased by 7±1% (p = 0.03), and (b) a significant decrease in the activated partial prothrombin time from 27.4±0.4 seconds to 25.5 ±0.5 seconds (p<0.001) in the 17 volunteers in the study's ?2AR arm. D-dimer and prothrombin fragments F1+2 were elevated by 200 ±90% and 505.0 ±300.0%, respectively. In addition, the activity of the anticoagulant protein C pathway (demonstrated by the protein C Global assay) decreased from 1.0±0.08 to 0.82±0.06 (p<0.001). Although plasma levels of tissue plasminogen activator decreased, all other indices of the fibrinolytic system did not change following salbutamol inhalation.ConclusionWe found that a single inhalation of salbutamol, a short-acting ?2AR agonist, activates the clotting system without affecting the fibrinolytic system. This induction of a procoagulant state in healthy subjects warrants further investigation in patients treated with these agents.

Dataset Information

Comparative In Vitro Study of Various ?2-Adrenoreceptor Agonist Drugs for Ticagrelor Reversal.

Publications

Comparative <i>In Vitro</i> Study of Various α<sub>2</sub>-Adrenoreceptor Agonist Drugs for Ticagrelor Reversal.

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