von Willebrand Factor Is a Critical Mediator of Deep Vein Thrombosis in a Mouse Model of Diet-Induced Obesity
| Autor: | Kate Nesbitt, Laura L. Swystun, Alison Michels, Peter J. Lenting, Charlotte Kawecki, Jeffrey Mewburn, Courtney Dwyer, David Lillicrap |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Deep vein ADAMTS13 Protein Inflammation Vena Cava Inferior 030204 cardiovascular system & hematology Diet High-Fat 03 medical and health sciences 0302 clinical medicine Mediator Von Willebrand factor Fibrinolytic Agents hemic and lymphatic diseases Internal medicine von Willebrand Factor Medicine Animals Obesity Risk factor Mice Knockout Venous Thrombosis biology business.industry Single-Domain Antibodies medicine.disease Thrombosis Mice Inbred C57BL Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure cardiovascular system biology.protein Female medicine.symptom Cardiology and Cardiovascular Medicine business Venous thromboembolism Signal Transduction |
| Zdroj: | Arteriosclerosis, thrombosis, and vascular biology. 40(12) |
| ISSN: | 1524-4636 |
| Popis: | Objective: Obesity is characterized by chronic low-grade inflammation and consequentially a hypercoagulable state, associating with an increased incidence of venous thromboembolism. Increased VWF (von Willebrand factor) plasma concentration and procoagulant function are independent risk factors for venous thromboembolism and are elevated in obese patients. Here, we explore the pathobiological role of VWF in obesity-associated venous thrombosis using murine models. Approach and Results: We first showed that diet-induced obese mice have increased VWF plasma levels and FVIII (factor VIII) activity compared with littermate controls. Elevated VWF levels appeared to be because of both increased synthesis and impaired clearance. Diet-induced obesity-associated venous thrombosis was assessed using the inferior vena cava-stenosis model of deep vein thrombosis. Diet-induced obese mice developed larger venous thrombi that were rich in VWF, erythrocytes, and leukocytes. Administering a polyclonal anti-VWF antibody or an anti-VWF A1 domain nanobody was protective against obesity-mediated thrombogenicity. Delayed administration (3 hours post–inferior vena cava stenosis) similarly reduced thrombus weight in diet-induced obese mice. Conclusions: This study demonstrates the critical role of VWF in the complex, thrombo-inflammatory state of obesity. It adds to the growing rationale for targeting VWF-specific interactions in thrombotic disease. |
| Databáze: | OpenAIRE |
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