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

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.

• Authors: Clémentine Puech, Xavier Delavenne, Zhiguo He, Valérie Forest, Patrick Mismetti, Nathalie Perek
• Journal: Brain research (Brain Res) Vol. 1719 Pg. 57-63 (09 15 2019) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 31121158 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Anticoagulants
• Antigens, CD
• Cadherins
• Pyrazoles
• Pyridones
• Receptor, PAR-1
• TJP1 protein, human
• Zonula Occludens-1 Protein
• cadherin 5
• apixaban
• Warfarin
• Heparin
• Rivaroxaban
• Protein Serine-Threonine Kinases
• Thrombin

Topics

• Administration, Oral
• Anticoagulants (metabolism, pharmacology)
• Antigens, CD (metabolism)
• Blood-Brain Barrier (drug effects)
• Cadherins (metabolism)
• Cell Line
• Cerebral Hemorrhage (drug therapy)
• Endothelial Cells (drug effects, metabolism)
• Heparin
• Humans
• Protein Serine-Threonine Kinases (metabolism)
• Pyrazoles
• Pyridones
• Receptor, PAR-1 (metabolism)
• Rivaroxaban
• Thrombin (metabolism)
• Warfarin
• Zonula Occludens-1 Protein (metabolism)