title: In Models of Intracerebral Hemorrhage, Rivaroxaban is Superior to Warfarin to Limit Blood Brain Barrier Disruption and Hematoma Expansion.
abstract: Intracerebral hemorrhage (ICH) during oral anticoagulation therapy with an oral vitamin K epoxidase reductase such as warfarin is a life-threatening complication. However, whether direct oral anticoagulants (DOACs) are associated with larger hematoma volume and higher mortality rates remains controversial. We evaluated the hematoma volume and pathophysiology of ICH during anticoagulation with warfarin or rivaroxaban, an orally active direct factor Xa inhibitor.
  
  
  
  Mice were orally pretreated with rivaroxaban (10 or 30 mg/kg), warfarin (4 mg/kg), or vehicle. ICH was induced by intrastriatal collagenase-injection. Hematoma volume and neurological deficits 24 h after ICH induction were significantly decreased in the rivaroxaban-pretreated group in comparison with the warfarin-pretreated group. Rivaroxaban did not increase the hematoma volume relative to that observed for vehicle, and improved survival rate 7 days after ICH induction compared with warfarin.
  
  
  
  We evaluated blood-brain barrier (BBB) permeability 6 h after ICH induction using Evans blue spectrophotometry. Evans blue extravasation was significantly reduced in the rivaroxaban group compared with the warfarin group. To investigate the mechanism underlying hematoma expansion and BBB permeability, we focused on thrombin, a clot-derived factor and one of the major contributors to ICH-induced brain injury. To investigate the effects of anticoagulant agents on thrombin-induced injuries, human brain endothelial cells were used in membrane permeability assays. Rivaroxaban, but not warfarin, significantly mitigated the thrombin-induced increase in membrane permeability.
  
  
  
  These findings indicate that rivaroxaban decreases BBB disruption after ICH, and limits early hematoma expansion in these experimental models compared with warfarin. Our study suggests that rivaroxaban has advantages over warfarin with respect to ICH, an important complication during long-term anticoagulation therapy.
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu. Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Sawada
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu. Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ono
authors.affiliation: Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu. Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Egashira
authors.affiliation: Department of Neurosurgery, Hyogo College of Medicine, Hyogo. Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Takagi
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu. Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu. Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.affiliation: Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu. Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Iwama
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196. Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D004195:Disease Models, Animal; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects; D065427:Factor Xa Inhibitors / Q000627:therapeutic use*; D006406:Hematoma / Q000188:drug therapy* / Q000209:etiology; D017879:Isothiocyanates / Q000493:pharmacokinetics; D051379:Mice; D009460:Neurologic Examination; D010539:Permeability / Q000187:drug effects; D000069552:Rivaroxaban / Q000627:therapeutic use*; D016896:Treatment Outcome; D014859:Warfarin / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D017879:Isothiocyanates; C037152:isothiocyanic acid; D014859:Warfarin; D000069552:Rivaroxaban
keywords: Intracerebral hemorrhage; anticoagulant therapy; blood-brain barrier permeability; rivaroxaban; thrombin; warfarin