title: Thrombolysis with recombinant tissue plasminogen activator under dabigatran anticoagulation in experimental stroke.
abstract: OBJECTIVE
  Anticoagulation with dabigatran etexilate (DE) has a favorable risk-to-benefit profile for the prevention of ischemic events in patients with atrial fibrillation compared to warfarin. Whereas warfarin constitutes a strong contraindication for thrombolysis, it is unclear whether patients anticoagulated with DE can be thrombolysed. We compared the risk of thrombolysis-associated hemorrhagic transformation (HT) after pretreatment with DE or warfarin in a mouse model of ischemic stroke.
  
  
  METHODS
  Thirty-nine C57BL/6 mice were pretreated orally with 75 mg/kg DE, 112.5mg/kg DE, 2mg/kg warfarin, or saline. We performed right middle cerebral artery occlusion for 3 hours, administered recombinant tissue plasminogen activator (rt-PA) directly before reperfusion, and assessed neurological deficit and HT blood volume after 24 hours.
  
  
  RESULTS
  Warfarin anticoagulation increased HT secondary to rt-PA treatment as compared to nonanticoagulated controls (6.9 ± 5.5 μl vs 0.8 ± 0.6 μl, p < 0.05). In contrast, the rate of HT after pretreatment with 75 mg/kg DE, which led to plasma levels comparable to the highest plasma levels observed in participants of the RE-LY trial, did not differ significantly from controls (1.6 ± 0.8; p > 0.05 vs control). However, a high-dose group receiving 112.5mg/kg DE showed a considerable extent of HT (9.2 ± 5.6 μl, p < 0.01).
  
  
  CONCLUSIONS
  Our experimental data suggest that the risk of thrombolysis-associated HT may not be increased under DE pretreatment with standard doses leading to plasma levels of up to 400 ng/ml, a concentration that was not exceeded in the majority of DE trial patients. At higher DE plasma levels, however, the risk of severe HT rises considerably, emphasizing the need for a readily available assay of DE anticoagulant activity.
authors.affiliation: Department of Neurology, Division of Vascular Medicine, University Hospital, Goethe University Frankfurt, Germany. w.pfeilschifter@med.uni-frankfurt.de
authors.forename: Waltraud
authors.initials: W
authors.lastname: Pfeilschifter
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Bohmann
authors.forename: Peter
authors.initials: P
authors.lastname: Baumgarten
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Edelgard
authors.initials: E
authors.lastname: Lindhoff-Last
authors.forename: Helmuth
authors.initials: H
authors.lastname: Steinmetz
authors.forename: Christian
authors.initials: C
authors.lastname: Foerch
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000453:epidemiology; D000069604:Dabigatran; D004195:Disease Models, Animal; D004347:Drug Interactions; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020521:Stroke / Q000150:complications / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000009:adverse effects; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects; D015091:beta-Alanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
chemical_list: D000925:Anticoagulants; D001562:Benzimidazoles; D005343:Fibrinolytic Agents; D015091:beta-Alanine; D014859:Warfarin; D010959:Tissue Plasminogen Activator; D000069604:Dabigatran