von Willebrand Factor Is a Critical Mediator of Deep Vein Thrombosis in a Mouse Model of Diet-Induced Obesity

Arterioscler Thromb Vasc Biol. 2020 Dec;40(12):2860-2874. doi: 10.1161/ATVBAHA.120.314690. Epub 2020 Sep 24.

Abstract

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.

Keywords: deep vein thrombosis; murine model; obesity; von Willebrand factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS13 Protein / genetics
  • ADAMTS13 Protein / metabolism
  • Animals
  • Diet, High-Fat*
  • Disease Models, Animal
  • Female
  • Fibrinolytic Agents / pharmacology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / complications*
  • Obesity / metabolism
  • Signal Transduction
  • Single-Domain Antibodies / pharmacology
  • Vena Cava, Inferior / drug effects
  • Vena Cava, Inferior / metabolism*
  • Vena Cava, Inferior / pathology
  • Venous Thrombosis / etiology*
  • Venous Thrombosis / metabolism
  • Venous Thrombosis / pathology
  • Venous Thrombosis / prevention & control
  • von Willebrand Factor / antagonists & inhibitors
  • von Willebrand Factor / genetics
  • von Willebrand Factor / metabolism*

Substances

  • Fibrinolytic Agents
  • Single-Domain Antibodies
  • von Willebrand Factor
  • ADAMTS13 protein, mouse
  • ADAMTS13 Protein

Grants and funding