Department of Pathology and Molecular Medicine (A.M., C.N.D., K.N., L.L.S., D.L.), Queen's University, Kingston, ON, Canada.
Cancer Research Institute (J.M.), Queen's University, Kingston, ON, Canada.
Arterioscler Thromb Vasc Biol. 2020 Dec;40(12):2860-2874. doi: 10.1161/ATVBAHA.120.314690. Epub 2020 Sep 24.
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.
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.
肥胖症的特征是慢性低度炎症，随之而来的是高凝状态，与静脉血栓栓塞的发生率增加有关。VWF（血管性血友病因子）血浆浓度和促凝功能增加是静脉血栓栓塞的独立危险因素，在肥胖患者中升高。在这里，我们使用小鼠模型探索 VWF 在肥胖相关静脉血栓形成中的病理生物学作用。
我们首先表明，与同窝对照相比，饮食诱导肥胖的小鼠具有更高的 VWF 血浆水平和 FVIII（因子 VIII）活性。升高的 VWF 水平似乎是由于合成增加和清除受损所致。使用下腔静脉狭窄的深静脉血栓形成模型评估饮食诱导的肥胖相关静脉血栓形成。饮食诱导肥胖的小鼠形成了更大的富含 VWF、红细胞和白细胞的静脉血栓。给予多克隆抗 VWF 抗体或抗 VWF A1 结构域纳米抗体可预防肥胖介导的血栓形成。延迟给药（下腔静脉狭窄后 3 小时）也可减少饮食诱导肥胖小鼠的血栓重量。
这项研究表明 VWF 在肥胖症的复杂血栓炎症状态中起着关键作用。它为靶向血栓性疾病中的 VWF 特异性相互作用增加了越来越多的理由。
