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ORIGINAL ARTICLES

Soluble tissue factor generated by necroptosis-triggered shedding is responsible for thrombosis

Peixing Wan1,† , Swati Choksi1,† , Yeon-Ji Park1,† , Xin Chen1,† , Jiong Yan1 , Sahar Foroutannejad1 , Zhaoshan Liu1 , Jichun Chen2 , Ross Lake3 , Chengyu Liu2 , Zheng-Gang Liu1,*

1National Cancer Institute; National Institutes of Health, Laboratory of Cellular and Molecular Biology, Bethesda, MD, USA
2National Heart, Lung, and Blood Institute; National Institutes of Health, Transgenic Core, Bethesda, MD, USA
3National Cancer Institute; National Institutes of Health, Laboratory of Cancer Biology and Genetics, Bethesda, MD, USA
These authors contributed equally: Peixing Wan, Swati Choksi, Yeon-Ji Park, Xin Chen
* Correspondence: Zheng-Gang Liu(zgliu@helix.nih.gov)

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.

https://doi.org/10.1038/s41422-025-01167-8

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