title: Translational insights into traumatic brain injury occurring during dabigatran or warfarin anticoagulation.
abstract: To date, only limited data are available on the effects of pretreatment with novel oral anticoagulants in the event of traumatic brain injury (TBI). We determined intracerebral hemorrhage volume and functional outcome in a standardized TBI model in mice treated with warfarin or dabigatran. Additionally, we investigated whether excess concentrations of dabigatran could increase bleeding and whether this was preventable by using prothrombin complex concentrate (PCC). C57 mice were treated orally with warfarin or dabigatran; sham-treated mice served as controls. Effective anticoagulation was verified by measurement of international normalized ratio and diluted thrombin time, and TBI was induced by controlled cortical impact (CCI). Twenty-four hours after CCI, intracerebral hemorrhage volume was larger in warfarin-pretreated mice than in controls (10.1 ± 4.9 vs 4.1 ± 1.7 μL; analysis of variance post hoc P=0.001), but no difference was found between controls and dabigatran-pretreated mice (5.3 ± 1.5 μL). PCC applied 30 minutes after CCI did not reliably reduce intracerebral hemorrhage induced by excess dabigatran concentration compared with saline (10.4 ± 11.2 vs 8.7 ± 7.1 μL). Our data suggest pathophysiological differences in TBI occurring during warfarin and dabigatran anticoagulation. The reduced hemorrhage formation under dabigatran therapy could present a safety advantage compared with warfarin. An excess dabigatran concentration, however, can increase hemorrhage.
authors.affiliation: 1] Department of Neurology, Goethe University, Frankfurt am Main, Germany [2] Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jan Hendrik
authors.initials: JH
authors.lastname: Schaefer
authors.affiliation: Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Leung
authors.affiliation: 1] Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Neurology, The First Bethune Hospital of Jilin University, Changchun, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Van Cott
authors.affiliation: 1] Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Lok
authors.affiliation: 1] Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Whalen
authors.affiliation: Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: van Leyen
authors.affiliation: Department of Neurology, Goethe University, Frankfurt am Main, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Lauer
authors.affiliation: CardioMetabolic Disease Research, Boehringer Ingelheim GmbH & Co. KG, Biberach, Germany.
authors.forename: Joanne
authors.initials: J
authors.lastname: van Ryn
authors.affiliation: Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.affiliation: Department of Neurology, Goethe University, Frankfurt am Main, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Foerch
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001930:Brain Injuries / Q000097:blood* / Q000188:drug therapy*; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D000069604:Dabigatran; D006470:Hemorrhage / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015091:beta-Alanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D001562:Benzimidazoles; D001779:Blood Coagulation Factors; D015091:beta-Alanine; C025667:prothrombin complex concentrates; D014859:Warfarin; D000069604:Dabigatran