Division of Hematology/Oncology, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
Institute of Cardiology, Jagiellonian University, Kraków, Poland.
J Thromb Haemost. 2021 Mar;19(3):814-821. doi: 10.1111/jth.15206. Epub 2020 Dec 27.
Overweight and obesity are significant risk factors for deep vein thrombosis (DVT). Cellular fibronectin containing extra domain A (Fn-EDA), an endogenous ligand for toll-like-receptor 4 (TLR4), contributes to thrombo-inflammation. The role of Fn-EDA in the modulation of DVT is not elucidated yet.
To determine whether Fn-EDA promotes DVT in the context of diet-induced obesity.
Wild-type (WT) and Fn-EDA-deficient mice were either fed control or high-fat (HF) diet for 12 weeks. DVT was induced by inferior vena cava (IVC) stenosis and evaluated after 48 hours. Cellular Fn-EDA levels in the plasma of venous thromboembolism (VTE) patients were measured by sandwich ELISA.
We found that cellular Fn-EDA levels were significantly elevated in VTE patients' plasma and positively correlated with body mass index. HF diet-fed WT mice exhibited increased DVT susceptibility compared with control diet-fed WT mice. In contrast, HF diet-fed Fn-EDA-deficient mice exhibited significantly reduced thrombus weight and decreased incidence (%) of DVT compared with HF diet-fed WT mice concomitant with reduced neutrophil content and citrullinated histone H3-positive cells (a marker of NETosis) in IVC thrombus. Exogenous cellular Fn-EDA potentiated NETosis in neutrophils stimulated with thrombin-activated platelets via TLR4. Genetic deletion of TLR4 in Fn-EDA mice (constitutively express Fn-EDA in plasma and tissues), but not in Fn-EDA-deficient mice, reduced DVT compared with respective controls.
These results demonstrate a previously unknown role of Fn-EDA in the DVT exacerbation, which may be an essential mechanism promoting DVT in the setting of diet-induced obesity.
超重和肥胖是深静脉血栓形成（DVT）的重要危险因素。含有额外结构域 A 的细胞纤维连接蛋白（Fn-EDA）是 Toll 样受体 4（TLR4）的内源性配体，有助于血栓炎症。Fn-EDA 在调节 DVT 中的作用尚未阐明。
确定 Fn-EDA 是否在饮食诱导肥胖的情况下促进 DVT。
野生型（WT）和 Fn-EDA 缺陷型小鼠分别喂食对照或高脂肪（HF）饮食 12 周。通过下腔静脉（IVC）狭窄诱导 DVT，并在 48 小时后进行评估。通过夹心 ELISA 测量静脉血栓栓塞（VTE）患者血浆中的细胞 Fn-EDA 水平。
我们发现 VTE 患者血浆中的细胞 Fn-EDA 水平显着升高，并且与体重指数呈正相关。与对照饮食喂养的 WT 小鼠相比，HF 饮食喂养的 WT 小鼠表现出增加的 DVT 易感性。相比之下，HF 饮食喂养的 Fn-EDA 缺陷型小鼠与 HF 饮食喂养的 WT 小鼠相比，血栓重量显着降低，DVT 发生率（%）降低，同时 IVC 血栓中的中性粒细胞含量和瓜氨酸化组蛋白 H3 阳性细胞（NETosis 的标志物）减少。外源性细胞 Fn-EDA 通过 TLR4 增强了凝血酶激活血小板刺激的中性粒细胞的 NETosis。在 Fn-EDA 小鼠（在血浆和组织中持续表达 Fn-EDA）中而不是在 Fn-EDA 缺陷型小鼠中遗传缺失 TLR4 与各自的对照相比，减少了 DVT。
这些结果表明 Fn-EDA 在 DVT 加重中的作用以前未知，这可能是促进饮食诱导肥胖患者中 DVT 的重要机制。
