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Direct oral anticoagulants are associated with limited damage of endothelial cells of the blood-brain barrier mediated by the thrombin/PAR-1 pathway.

Authors
  • Puech, Clémentine1
  • Delavenne, Xavier2
  • He, Zhiguo3
  • Forest, Valérie4
  • Mismetti, Patrick5
  • Perek, Nathalie6
  • 1 INSERM, U1059 Sainbiose, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; Université de Lyon, Saint-Etienne F-42023, France. Electronic address: [email protected] , (France)
  • 2 INSERM, U1059 Sainbiose, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; Université de Lyon, Saint-Etienne F-42023, France; Laboratoire de Pharmacologie Toxicologie, CHU Saint-Etienne, F-42055 Saint-Etienne, France. , (France)
  • 3 Université de Lyon, Saint-Etienne F-42023, France; EA 2521, Biologie, Ingénierie et Imagerie de la Greffe de Cornée (BIIGC), Saint-Etienne, France. , (France)
  • 4 Mines Saint-Etienne, Univ Lyon, Univ Jean Monnet, INSERM, U 1059 Sainbiose, Centre CIS, F-42023 Saint-Etienne, France. , (France)
  • 5 INSERM, U1059 Sainbiose, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; Université de Lyon, Saint-Etienne F-42023, France; Unité de Recherche Clinique Innovation et Pharmacologie, CHU de Saint-Etienne, F-42055 Saint Etienne, France. , (France)
  • 6 INSERM, U1059 Sainbiose, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; Université de Lyon, Saint-Etienne F-42023, France. , (France)
Type
Published Article
Journal
Brain research
Publication Date
May 20, 2019
Volume
1719
Pages
57–63
Identifiers
DOI: 10.1016/j.brainres.2019.05.024
PMID: 31121158
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Anticoagulant therapy presents iatrogenic effects such as intracerebral hemorrhage (ICH). The latest anticoagulants on the market, direct oral anticoagulants (DOACs) such as apixaban, dabigatran and rivaroxaban, are reported to cause less ICH than other anticoagulants. Next to the ICH area, the thrombin is accumulated and the blood-brain barrier (BBB) is opened. The effects of thrombin on the BBB are largely mediated by the protease activated receptor (PAR) family, especially the PAR-1 isoform. Our hypothesis is that DOACs may limit the effects of thrombin on endothelial cells (of the BBB) alteration by a mechanism probably involving PAR-1 activation. To test this hypothesis in vitro, we used HBEC-5i human brain endothelial cells as a human BBB model. The effects of thrombin under warfarin, heparin, rivaroxaban, apixaban, and dabigatran treatment on endothelial cells were then investigated by measuring of permeability and junction proteins: ZO-1 and VE-cadherin expressions and PAR-1 cleavage. Depending on the anticoagulant used, we observed three profiles of response of the endothelial cells after thrombin exposure: i) dabigatran treatment allowed maintaining the tightness of the endothelial monolayer; ii) other DOACs limited thrombin-induced alteration of the endothelial monolayer; and iii) pretreatment with warfarin and heparin did not protect from thrombin-induced BBB breakdown. Pretreatment with DOACs clearly limited the impact of thrombin on PAR-1 cleavage in our model, contrary to other anticoagulants, associated with ZO-1 and VE-cadherin expressions. In conclusion, DOACs seem to limit the alteration of the monolayer of endothelial cells of the BBB mediated by the thrombin/PAR-1 pathway. Copyright © 2019 Elsevier B.V. All rights reserved.

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