Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
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
_version_ 1783717316371939328
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
work_keys_str_mv AT vangorprickh offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate
AT dijkgraafingrid offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate
AT brokervanessa offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate
AT bauwensmatthias offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate
AT leenderspeter offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate
AT jennendanyel offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate
AT dweckmarcr offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate
AT buceriusjan offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate
AT briedejaccoj offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate
AT vanrynjoanne offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate
AT brandenburgvincent offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate
AT mottaghyfelix offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate
AT spronkhenrimh offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate
AT reutelingspergerchrisp offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate
AT schurgersleonj offtargeteffectsoforalanticoagulantsvasculareffectsofvitaminkantagonistandnonvitaminkantagonistoralanticoagulantdabigatranetexilate