No influence of dabigatran anticoagulation on hemorrhagic transformation in an experimental model of ischemic stroke

PLoS One. 2012;7(7):e40804. doi: 10.1371/journal.pone.0040804. Epub 2012 Jul 24.

Abstract

Background: Dabigatran etexilate (DE) is a new oral direct thrombin inhibitor. Clinical trials point towards a favourable risk-to-benefit profile of DE compared to warfarin. In this study, we evaluated whether hemorrhagic transformation (HT) occurs after experimental stroke under DE treatment as we have shown for warfarin.

Methods: 44 male C57BL/6 mice were pretreated orally with 37.5 mg/kg DE, 75 mg/kg DE or saline and diluted thrombin time (dTT) and DE plasma concentrations were monitored. Ischemic stroke was induced by transient middle cerebral artery occlusion (tMCAO) for 1 h or 3 h. We assessed functional outcome and HT blood volume 24 h and 72 h after tMCAO.

Results: After 1 h tMCAO, HT blood volume did not differ significantly between mice pretreated with DE 37.5 mg/kg and controls (1.5±0.5 µl vs. 1.8±0.5 µl, p>0.05). After 3 h tMCAO, DE-anticoagulated mice did also not show an increase in HT, neither at the dose of 37.5 mg/kg equivalent to anticoagulant treatment in the therapeutic range (1.3±0.9 µl vs. control 2.3±0.5 µl, p>0.05) nor at 75 mg/kg, clearly representing supratherapeutic anticoagulation (1.8±0.8 µl, p>0.05). Furthermore, no significant increase in HT under continued anticoagulation with DE 75 mg/kg could be found at 72 h after tMCAO for 1 h (1.7±0.9 µl vs. control 1.6±0.4 µl, p>0.05).

Conclusion: Our experimental data suggest that DE does not significantly increase hemorrhagic transformation after transient focal cerebral ischemia in mice. From a translational viewpoint, this indicates that a continuation of DE anticoagulation in case of an ischemic stroke might be safe, but clearly, clinical data on this question are warranted.

MeSH terms

  • Administration, Oral
  • Animals
  • Antithrombins / administration & dosage
  • Antithrombins / pharmacokinetics
  • Antithrombins / pharmacology*
  • Benzimidazoles / administration & dosage
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology*
  • Blood Coagulation / drug effects
  • Cerebral Hemorrhage / blood*
  • Cerebral Hemorrhage / drug therapy
  • Cerebral Hemorrhage / etiology*
  • Dabigatran
  • Disease Models, Animal
  • Male
  • Mice
  • Pyridines / administration & dosage
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Stroke / blood*
  • Stroke / complications*
  • Stroke / etiology
  • Treatment Outcome
  • beta-Alanine / administration & dosage
  • beta-Alanine / analogs & derivatives*
  • beta-Alanine / pharmacokinetics
  • beta-Alanine / pharmacology

Substances

  • Antithrombins
  • Benzimidazoles
  • Pyridines
  • beta-Alanine
  • Dabigatran

Grant support

These authors have no support or funding to report.