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Off‐target effects of oral anticoagulants – vascular effects of vitamin K antagonist and non‐vitamin K antagonist oral anticoagulant dabigatran etexilate
INTRODUCTION: Vitamin K antagonists (VKA) and non‐vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off‐target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcifica...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252511/ https://www.ncbi.nlm.nih.gov/pubmed/33687782 http://dx.doi.org/10.1111/jth.15289 |
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author | van Gorp, Rick H. Dijkgraaf, Ingrid Bröker, Vanessa Bauwens, Matthias Leenders, Peter Jennen, Danyel Dweck, Marc R. Bucerius, Jan Briedé, Jacco J. van Ryn, Joanne Brandenburg, Vincent Mottaghy, Felix Spronk, Henri M. H. Reutelingsperger, Chris P. Schurgers, Leon J. |
author_facet | van Gorp, Rick H. Dijkgraaf, Ingrid Bröker, Vanessa Bauwens, Matthias Leenders, Peter Jennen, Danyel Dweck, Marc R. Bucerius, Jan Briedé, Jacco J. van Ryn, Joanne Brandenburg, Vincent Mottaghy, Felix Spronk, Henri M. H. Reutelingsperger, Chris P. Schurgers, Leon J. |
author_sort | van Gorp, Rick H. |
collection | PubMed |
description | INTRODUCTION: Vitamin K antagonists (VKA) and non‐vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off‐target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup. MATERIAL AND METHODS: Female Apoe (−/−) mice (age 12 weeks) were fed Western‐type diet as control or supplemented with dabigatran etexilate or warfarin for 6 or 18 weeks. Vascular calcification was measured in whole aortic arches using µCT and [(18)F]‐NaF. Atherosclerotic burden was assessed by (immuno)histochemistry. Additionally, in vitro effects of warfarin, thrombin, and dabigatran on primary vascular smooth muscle cells (VSMC) were assessed. RESULTS: Short‐term treatment with warfarin promoted formation of atherosclerotic lesions with a pro‐inflammatory phenotype, and more rapid plaque progression compared with control and dabigatran. In contrast, dabigatran significantly reduced plaque progression compared with control. Long‐term warfarin treatment significantly increased both presence and activity of plaque calcification compared with control and dabigatran. Calcification induced by warfarin treatment was accompanied by increased presence of uncarboxylated matrix Gla protein. In vitro, both warfarin and thrombin significantly increased VSMC oxidative stress and extracellular vesicle release, which was prevented by dabigatran. CONCLUSION: Warfarin aggravates atherosclerotic disease activity, increasing plaque inflammation, active calcification, and plaque progression. Dabigatran lacks undesired vascular side effects and reveals beneficial effects on atherosclerosis progression and calcification. The choice of anticoagulation impacts atherosclerotic disease by differential off target effect. Future clinical studies should test whether this beneficial effect also applies to patients. |
format | Online Article Text |
id | pubmed-8252511 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82525112021-07-09 Off‐target effects of oral anticoagulants – vascular effects of vitamin K antagonist and non‐vitamin K antagonist oral anticoagulant dabigatran etexilate van Gorp, Rick H. Dijkgraaf, Ingrid Bröker, Vanessa Bauwens, Matthias Leenders, Peter Jennen, Danyel Dweck, Marc R. Bucerius, Jan Briedé, Jacco J. van Ryn, Joanne Brandenburg, Vincent Mottaghy, Felix Spronk, Henri M. H. Reutelingsperger, Chris P. Schurgers, Leon J. J Thromb Haemost VASCULAR BIOLOGY INTRODUCTION: Vitamin K antagonists (VKA) and non‐vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off‐target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup. MATERIAL AND METHODS: Female Apoe (−/−) mice (age 12 weeks) were fed Western‐type diet as control or supplemented with dabigatran etexilate or warfarin for 6 or 18 weeks. Vascular calcification was measured in whole aortic arches using µCT and [(18)F]‐NaF. Atherosclerotic burden was assessed by (immuno)histochemistry. Additionally, in vitro effects of warfarin, thrombin, and dabigatran on primary vascular smooth muscle cells (VSMC) were assessed. RESULTS: Short‐term treatment with warfarin promoted formation of atherosclerotic lesions with a pro‐inflammatory phenotype, and more rapid plaque progression compared with control and dabigatran. In contrast, dabigatran significantly reduced plaque progression compared with control. Long‐term warfarin treatment significantly increased both presence and activity of plaque calcification compared with control and dabigatran. Calcification induced by warfarin treatment was accompanied by increased presence of uncarboxylated matrix Gla protein. In vitro, both warfarin and thrombin significantly increased VSMC oxidative stress and extracellular vesicle release, which was prevented by dabigatran. CONCLUSION: Warfarin aggravates atherosclerotic disease activity, increasing plaque inflammation, active calcification, and plaque progression. Dabigatran lacks undesired vascular side effects and reveals beneficial effects on atherosclerosis progression and calcification. The choice of anticoagulation impacts atherosclerotic disease by differential off target effect. Future clinical studies should test whether this beneficial effect also applies to patients. John Wiley and Sons Inc. 2021-03-28 2021-05 /pmc/articles/PMC8252511/ /pubmed/33687782 http://dx.doi.org/10.1111/jth.15289 Text en © 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | VASCULAR BIOLOGY van Gorp, Rick H. Dijkgraaf, Ingrid Bröker, Vanessa Bauwens, Matthias Leenders, Peter Jennen, Danyel Dweck, Marc R. Bucerius, Jan Briedé, Jacco J. van Ryn, Joanne Brandenburg, Vincent Mottaghy, Felix Spronk, Henri M. H. Reutelingsperger, Chris P. Schurgers, Leon J. Off‐target effects of oral anticoagulants – vascular effects of vitamin K antagonist and non‐vitamin K antagonist oral anticoagulant dabigatran etexilate |
title | Off‐target effects of oral anticoagulants – vascular effects of vitamin K antagonist and non‐vitamin K antagonist oral anticoagulant dabigatran etexilate |
title_full | Off‐target effects of oral anticoagulants – vascular effects of vitamin K antagonist and non‐vitamin K antagonist oral anticoagulant dabigatran etexilate |
title_fullStr | Off‐target effects of oral anticoagulants – vascular effects of vitamin K antagonist and non‐vitamin K antagonist oral anticoagulant dabigatran etexilate |
title_full_unstemmed | Off‐target effects of oral anticoagulants – vascular effects of vitamin K antagonist and non‐vitamin K antagonist oral anticoagulant dabigatran etexilate |
title_short | Off‐target effects of oral anticoagulants – vascular effects of vitamin K antagonist and non‐vitamin K antagonist oral anticoagulant dabigatran etexilate |
title_sort | off‐target effects of oral anticoagulants – vascular effects of vitamin k antagonist and non‐vitamin k antagonist oral anticoagulant dabigatran etexilate |
topic | VASCULAR BIOLOGY |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252511/ https://www.ncbi.nlm.nih.gov/pubmed/33687782 http://dx.doi.org/10.1111/jth.15289 |
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