title: Increased risk of hemorrhagic transformation in ischemic stroke occurring during warfarin anticoagulation: an experimental study in mice.
abstract: OBJECTIVE
  The prevalence of long-term oral anticoagulant therapy is rising. Treatment options for patients who have an ischemic stroke under oral anticoagulant therapy are limited, and clinical data on the risk of hemorrhagic transformation (HT) in this condition are scarce. We therefore aimed to establish a mouse model of ischemic stroke occurring during oral anticoagulant therapy to assess the frequency and characteristics of HT.
  
  
  METHODS
  C57BL/6 mice (n=59) were pretreated with warfarin. Untreated mice (n=32) served as controls. We performed a 3-hour transient filament occlusion of the right middle cerebral artery. In a first set of animals, ischemic lesion size and HT were evaluated macroscopically at 24 hours after middle cerebral artery occlusion. In a second set of mice, quantitative analysis of HT was performed at different time points after middle cerebral artery occlusion and in animals with different international normalized ratio levels using a photometric hemoglobin assay.
  
  
  RESULTS
  Oral anticoagulant therapy at the onset of ischemia led to HT in all anticoagulated mice, whereas only 14% of the control mice showed HT. Mean HT blood volume 24 hours after middle cerebral artery occlusion was 0.3±0.4 μL in controls, 4.2±1.7 μL in mice anticoagulated to a mean international normalized ratio of 1.9±0.5 (P<0.05 versus controls), and 5.2±2.7 μL in mice with an international normalized ratio of 2.9±0.9 (P<0.001 versus controls). Anticoagulated mice euthanized at the time point of reperfusion had less HT than mice euthanized after 21 hours of reperfusion (1.6±0.5 μL versus 5.9±3.6 μL, P<0.05).
  
  
  CONCLUSIONS
  We present a mouse model of ischemic stroke occurring during oral anticoagulant therapy. Warfarin pretreatment dramatically increases the risk of HT 24 hours after middle cerebral artery occlusion. Reperfusion injury seems to be a critical component in this condition.
authors.affiliation: University Hospital, Goethe University Frankfurt am Main, Department of Neurology, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. w.pfeilschifter@med.uni-frankfurt.de
authors.forename: Waltraud
authors.initials: W
authors.lastname: Pfeilschifter
authors.forename: Daniel
authors.initials: D
authors.lastname: Spitzer
authors.forename: Bozena
authors.initials: B
authors.lastname: Czech-Zechmeister
authors.forename: Helmuth
authors.initials: H
authors.lastname: Steinmetz
authors.forename: Christian
authors.initials: C
authors.lastname: Foerch
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000097:blood / Q000633:toxicity*; D002545:Brain Ischemia / Q000097:blood / Q000150:complications* / Q000188:drug therapy*; D002543:Cerebral Hemorrhage / Q000097:blood / Q000139:chemically induced*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000097:blood / Q000139:chemically induced; D012307:Risk Factors; D020521:Stroke / Q000097:blood / Q000188:drug therapy*; D014859:Warfarin / Q000097:blood / Q000633:toxicity*
chemical_list: D000925:Anticoagulants; D014859:Warfarin