title: Warfarin anticoagulation exacerbates the risk of hemorrhagic transformation after rt-PA treatment in experimental stroke: therapeutic potential of PCC.
abstract: BACKGROUND
  Oral anticoagulant therapy (OAT) with warfarin is the standard of stroke prevention in patients with atrial fibrillation. Approximately 30% of patients with cardioembolic strokes are on OAT at the time of symptom onset. We investigated whether warfarin exacerbates the risk of thrombolysis-associated hemorrhagic transformation (HT) in a mouse model of ischemic stroke.
  
  
  METHODS
  62 C57BL/6 mice were used for this study. To achieve effective anticoagulation, warfarin was administered orally. We performed right middle cerebral artery occlusion (MCAO) for 3 h and assessed functional deficit and HT blood volume after 24 h.
  
  
  RESULTS
  In non-anticoagulated mice, treatment with rt-PA (10 mg/kg i.v.) after 3 h MCAO led to a 5-fold higher degree of HT compared to vehicle-treated controls (4.0±0.5 µl vs. 0.8±0.1, p<0.001). Mice on warfarin revealed larger amounts of HT after rt-PA treatment in comparison to non-anticoagulated mice (9.2±3.2 µl vs. 2.8±1.0, p<0.05). The rapid reversal of anticoagulation by means of prothrombin complex concentrates (PCC, 100 IU/kg) at the end of the 3 h MCAO period, but prior to rt-PA administration, neutralized the exacerbated risk of HT as compared to sham-treated controls (3.8±0.7 µl vs. 15.0±3.8, p<0.001).
  
  
  CONCLUSIONS
  In view of the vastly increased risk of HT, it seems to be justified to withhold tPA therapy in effectively anticoagulated patients with acute ischemic stroke. The rapid reversal of anticoagulation with PCC prior to tPA application reduces the risk attributed to warfarin pretreatment and may constitute an interesting therapeutic option.
authors: Department of Neurology, Goethe University Hospital, Frankfurt am Main, Germany. w.pfeilschifter@med.uni-frankfurt.de
authors: Waltraud
authors: W
authors: Pfeilschifter
authors: Daniel
authors: D
authors: Spitzer
authors: Josef
authors: J
authors: Pfeilschifter
authors: Helmuth
authors: H
authors: Steinmetz
authors: Christian
authors: C
authors: Foerch
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D011516:Prothrombin / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D011994:Recombinant Proteins; D014859:Warfarin; D011516:Prothrombin; D010959:Tissue Plasminogen Activator