title: Secondary intracerebral hemorrhage due to early initiation of oral anticoagulation after ischemic stroke: an experimental study in mice.
abstract: OBJECTIVE
  The uncertain risk of secondary intracerebral hemorrhage (sICH) frequently keeps clinicians from initiating oral anticoagulation (OAC) early after ischemic cardioembolic stroke. The goal of this experimental study was to determine the risk of sICH depending on the timing of OAC initiation relative to stroke onset and to address the role of hematogenous macrophages for repair processes preventing OAC-associated sICH.
  
  
  METHODS
  C57BL/6 mice were subjected to transient middle cerebral artery occlusion. Subgroups were treated with either the vitamin K antagonist (VKA) phenprocoumon or the direct thrombin inhibitor dabigatran etexilate. Hematogenous macrophages were depleted using intraperitoneal injections of clodronate-filled liposomes.
  
  
  RESULTS
  Time to therapeutic OAC was 48 hours with VKA and 0.5 hours with dabigatran etexilate treatment. In VKA-treated mice, the risk of sICH was high if effective OAC was already present at stroke onset or achieved within 48 hours after ischemia. With more delayed OAC, the risk of sICH rapidly decreased. Compared with VKA treatment, effective anticoagulation with dabigatran etexilate was associated with a significantly reduced extent of sICH, either if present at stroke onset or if achieved 48 hours later. Partial depletion of macrophages greatly increased the extent of OAC-associated sICH in the subacute stage of 3 to 4 days after ischemia.
  
  
  CONCLUSIONS
  Our findings suggest that repair mechanisms involving hematogenous macrophages rapidly decrease the risk of OAC-associated sICH in the first days after ischemic stroke. The lower risk of sICH under dabigatran etexilate compared with VKA treatment may facilitate early initiation of OAC after cardioembolic stroke.
authors.affiliation: Department of Neurology, Heinrich-Heine-University, Medical Faculty, Moorenstr. 5, 40225 Düsseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gliem
authors.forename: Derik
authors.initials: D
authors.lastname: Hermsen
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.forename: Sebastian
authors.initials: S
authors.lastname: Jander
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology; D000069604:Dabigatran; D004195:Disease Models, Animal; D020766:Intracranial Embolism / Q000188:drug therapy / Q000453:epidemiology / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010644:Phenprocoumon / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012307:Risk Factors; D020521:Stroke / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D013997:Time Factors
chemical_list: D000925:Anticoagulants; D001562:Benzimidazoles; D011725:Pyridines; D000069604:Dabigatran; D010644:Phenprocoumon