Epinephrine restores platelet functions inhibited by ticagrelor: A mechanistic approach

Eur J Pharmacol. 2020 Jan 5;866:172798. doi: 10.1016/j.ejphar.2019.172798. Epub 2019 Nov 15.

Abstract

Ticagrelor, an antagonist of the platelet adenosine diphosphate (ADP)-P2Y12 receptor is recommended for patients with acute coronary syndromes. However, ticagrelor exposes to a risk of bleeding, the management of which is challenging because platelet transfusion is ineffective, and no antidote is yet available. We hypothesized that the vasopressor drug epinephrine could counter the antiplatelet effects of ticagrelor and restore platelet functions. We assessed in vitro the efficiency of epinephrine in restoring platelet aggregation inhibited by ticagrelor and investigated the underlying mechanisms. Washed platelet aggregation and secretion were measured upon stimulation by epinephrine alone or in combination with ADP, in the presence or absence of ticagrelor. Mechanistic investigations used P2Y1 and phosphoinositide 3-kinase (PI3K) inhibitors and included vasodilator-stimulated phosphoprotein (VASP) and Akt phosphorylation assays as well as measurement of Ca2+ mobilisation. We found that epinephrine restored ADP-induced platelet aggregation, but not dense granule release. Epinephrine alone failed to induce aggregation whereas it fully induced VASP dephosphorylation and Akt phosphorylation regardless of the presence of ticagrelor. In the presence of ticagrelor, blockage of the P2Y1 receptor prevented restoration of platelet aggregation by the combination of epinephrine and ADP, as well as intracellular Ca2+ mobilisation. In combination with ADP, epinephrine induced platelet aggregation of ticagrelor-treated platelets through inhibition of the cAMP pathway and activation of the PI3K pathway, thus enabling the P2Y1 receptor signalling and subsequent Ca2+ mobilisation. This proof-of-concept study needs to be challenged in vivo for the management of bleeding in ticagrelor-treated patients.

Keywords: Antiplatelet agent; Epinephrine; Reversal; Signalling pathway; Ticagrelor.

MeSH terms

  • Blood Platelets / cytology
  • Blood Platelets / drug effects*
  • Blood Platelets / physiology*
  • Cell Adhesion Molecules / metabolism
  • Epinephrine / pharmacology*
  • Humans
  • Microfilament Proteins / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Platelet Aggregation / drug effects
  • Receptors, Purinergic P2Y1 / metabolism
  • Signal Transduction / drug effects
  • Ticagrelor / pharmacology*

Substances

  • Cell Adhesion Molecules
  • Microfilament Proteins
  • Phosphoproteins
  • Receptors, Purinergic P2Y1
  • vasodilator-stimulated phosphoprotein
  • Ticagrelor
  • Epinephrine