Off‐target effects of oral anticoagulants – vascular effects of vitamin K antagonist and non‐vitamin K antagonist oral anticoagulant dabigatran etexilate
| Autor: | Marc R. Dweck, Danyel Jennen, Matthias Bauwens, Rick H. van Gorp, Joanne van Ryn, Jan Bucerius, Vincent Brandenburg, Ingrid Dijkgraaf, Felix M. Mottaghy, Chris P. M. Reutelingsperger, Peter Leenders, Jacco J. Briedé, Leon J. Schurgers, Vanessa Bröker, Henri M. H. Spronk |
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| Přispěvatelé: | RS: Carim - B02 Vascular aspects thrombosis and Haemostasis, Biochemie, RS: Carim - B01 Blood proteins & engineering, Beeldvorming, RS: Carim - B04 Clinical thrombosis and Haemostasis, Toxicogenomics, RS: GROW - R1 - Prevention, RS: Carim - B06 Imaging, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience |
| Rok vydání: | 2021 |
| Předmět: |
Vitamin K
medicine.drug_class VASCULAR BIOLOGY 030204 cardiovascular system & hematology Pharmacology Dabigatran Mice 03 medical and health sciences 0302 clinical medicine Thrombin Atrial Fibrillation Matrix gla protein medicine Animals Humans vascular smooth muscle cells oxidative stress NOAC biology business.industry VKA Warfarin Anticoagulants Atherosclerosis/drug therapy Hematology Extracellular vesicle Vitamin K antagonist medicine.disease Thrombosis 3. Good health vascular calcification biology.protein Original Article Female atherosclerosis business medicine.drug Calcification |
| Zdroj: | Journal of Thrombosis and Haemostasis, 19(5), 1348-1363. Wiley Journal of Thrombosis and Haemostasis |
| ISSN: | 1538-7836 1538-7933 |
| DOI: | 10.1111/jth.15289 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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