title: Dabigatran abrogates brain endothelial cell permeability in response to thrombin.
abstract: Atrial fibrillation (AF) increases the risk and severity of thromboembolic stroke. Generally, antithrombotic agents increase the hemorrhagic risk of thromboembolic stroke. However, significant reductions in thromboembolism and intracerebral hemorrhage have been shown with the antithrombin dabigatran compared with warfarin. As thrombin has been implicated in microvessel injury during cerebral ischemia, we hypothesized that dabigatran decreases the risk of intracerebral hemorrhage by direct inhibition of the thrombin-mediated increase in cerebral endothelial cell permeability. Primary murine brain endothelial cells (mBECs) were exposed to murine thrombin before measuring permeability to 4-kDa fluorescein isothiocyanate-dextran. Thrombin increased mBEC permeability in a concentration-dependent manner, without significant endothelial cell death. Pretreatment of mBECs with dabigatran completely abrogated the effect of thrombin on permeability. Neither the expressions of the endothelial cell β1-integrins nor the tight junction protein claudin-5 were affected by thrombin exposure. Oxygen-glucose deprivation (OGD) also increased permeability; this effect was abrogated by treatment with dabigatran, as was the additive effect of thrombin and OGD on permeability. Taken together, these results indicate that dabigatran could contribute to a lower risk of intracerebral hemorrhage during embolism-associated ischemia from AF by protection of the microvessel permeability barrier from local thrombin challenge.
authors: Department of Medicine (Hematology), Division of Hematology, Seattle, Washington, USA.
authors: Brian Thomas
authors: BT
authors: Hawkins
authors: Department of Medicine (Hematology), Division of Hematology, Seattle, Washington, USA.
authors: Yu-Huan
authors: YH
authors: Gu
authors: Department of Medicine (Hematology), Division of Hematology, Seattle, Washington, USA.
authors: Yoshikane
authors: Y
authors: Izawa
authors: 1] Department of Medicine (Hematology), Division of Hematology, Seattle, Washington, USA [2] Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
authors: Gregory John
authors: GJ
authors: del Zoppo
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001921:Brain / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D062507:Claudin-5 / Q000032:analysis; D000069604:Dabigatran; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D019012:Integrin beta1 / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism; D010539:Permeability / Q000187:drug effects*; D013917:Thrombin / Q000378:metabolism*; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000991:Antithrombins; D001562:Benzimidazoles; D062507:Claudin-5; D019012:Integrin beta1; D015091:beta-Alanine; D013917:Thrombin; D000069604:Dabigatran; D005947:Glucose; D010100:Oxygen