Wan Peixing, Choksi Swati, Park Yeon-Ji, Chen Xin, Yan Jiong, Foroutannejad Sahar, Liu Zhaoshan, Chen Jichun, Lake Ross, Liu Chengyu, Liu Zheng-Gang
National Cancer Institute; National Institutes of Health, Laboratory of Cellular and Molecular Biology, Bethesda, MD, USA.
National Heart, Lung, and Blood Institute; National Institutes of Health, Transgenic Core, Bethesda, MD, USA.
Cell Res. 2025 Sep 12. doi: 10.1038/s41422-025-01167-8.
Tissue factor (TF) is a cell surface protein critical for normal hemostasis and pathological thrombosis. Necroptosis is a form of regulated necrosis associated with different diseases. Here, we reported the identification of the first functional soluble tissue factor (sTF) in mediating blood coagulation, shed from the membrane full-length TF (flTF) by proteases, ADAMs, during necroptosis. By generating sTF-specific antibody and transgenic mice carrying knockin mutations at the ADAM cleavage site of TF (T211V212 mutated to E211E212), we demonstrated that this sTF is responsible for necroptosis-related thrombosis in inflammation and viral infection mouse models. Importantly, we showed that eliminating necroptosis or the cleavage of the flTF blocked the production of sTF and prevented thrombosis in mice. We also detected sTF in the plasma of human COVID-19 patients and showed that SARS-CoV-2 pseudovirus induced sTF production. Our findings demonstrated that the sTF plays a major role in thrombosis under necroptosis-related pathological conditions and provided a diagnostic marker and potential therapies for treating thrombosis without affecting hemostasis.
组织因子（TF）是一种对正常止血和病理性血栓形成至关重要的细胞表面蛋白。坏死性凋亡是一种与多种疾病相关的程序性坏死形式。在此，我们报告了首次鉴定出在介导血液凝固中起作用的可溶性组织因子（sTF），它是在坏死性凋亡过程中由蛋白酶ADAMs从膜全长TF（flTF）上脱落产生的。通过生成sTF特异性抗体以及构建在TF的ADAM切割位点携带敲入突变（T211V212突变为E211E212）的转基因小鼠，我们证明了这种sTF在炎症和病毒感染小鼠模型中导致坏死性凋亡相关的血栓形成。重要的是，我们表明消除坏死性凋亡或flTF的切割可阻断sTF的产生并预防小鼠血栓形成。我们还在人类COVID-19患者的血浆中检测到了sTF，并表明SARS-CoV-2假病毒可诱导sTF产生。我们的研究结果表明，sTF在坏死性凋亡相关的病理条件下的血栓形成中起主要作用，并为治疗血栓形成提供了一种诊断标志物和潜在疗法，且不影响止血功能。
