title: Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran.
abstract: OBJECTIVE
  Dabigatran-etexilate (DE) recently has been approved for stroke prevention in atrial fibrillation. However, lack of effective antagonists represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with dabigatran, and to test the efficacy of different hemostatic factors in preventing hematoma growth.
  
  
  METHODS
  In C57BL/6 mice receiving DE (4.5 or 9.0 mg/kg), in vivo and in vitro coagulation assays and dabigatran plasma levels were measured repeatedly. Thirty minutes after inducing ICH by striatal collagenase injection, mice received an intravenous injection of saline, prothrombin complex concentrate (PCC; 100 U/kg), murine fresh-frozen plasma (200 μL), or recombinant human factor VIIa (8.0 mg/kg). ICH volume was quantified on brain cryosections 24 hours later.
  
  
  RESULTS
  DE substantially prolonged tail vein bleeding time and ecarin clotting time for 4 hours corresponding to dabigatran plasma levels. Intracerebral hematoma expansion was observed mainly during the first 3 hours on serial T2* MRI. Anticoagulation with high doses of DE increased the hematoma volume significantly. PCC and, less consistently, fresh-frozen plasma prevented excess hematoma expansion caused by DE, whereas recombinant human factor VIIa was ineffective. Prevention of hematoma growth and reversal of tail vein bleeding time by PCC were dose-dependent.
  
  
  CONCLUSIONS
  The study provides strong evidence that PCC and, less consistently, fresh-frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with dabigatran. The efficacy and safety of this strategy must be further evaluated in clinical studies.
authors: Department of Neurology, University Heidelberg, INF 400, 69120 Heidelberg, Germany.
authors: Wei
authors: W
authors: Zhou
authors: Sönke
authors: S
authors: Schwarting
authors: Sergio
authors: S
authors: Illanes
authors: Arthur
authors: A
authors: Liesz
authors: Moritz
authors: M
authors: Middelhoff
authors: Markus
authors: M
authors: Zorn
authors: Martin
authors: M
authors: Bendszus
authors: Sabine
authors: S
authors: Heiland
authors: Joanne
authors: J
authors: van Ryn
authors: Roland
authors: R
authors: Veltkamp
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000473:pathology; D000069604:Dabigatran; D004305:Dose-Response Relationship, Drug; D051379:Mice; D015091:beta-Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D000069604:Dabigatran