{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:50:27Z","timestamp":1792673427630,"version":"4.5.0"},"reference-count":74,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1038\/s41422-025-01167-8","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T08:00:08Z","timestamp":1757664008000},"page":"840-858","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Soluble tissue factor generated by necroptosis-triggered shedding is responsible for thrombosis"],"prefix":"10.1038","volume":"35","author":[{"given":"Peixing","family":"Wan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swati","family":"Choksi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeon-Ji","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiong","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahar","family":"Foroutannejad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoshan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jichun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Lake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4849-6573","authenticated-orcid":false,"given":"Zheng-Gang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"1167_CR1","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1161\/01.ATV.0000130465.23430.74","volume":"24","author":"N Mackman","year":"2004","unstructured":"Mackman, N. Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler. Thromb. Vasc. Biol. 24, 1015\u20131022 (2004).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"1167_CR2","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1161\/ATVBAHA.117.309846","volume":"38","author":"SP Grover","year":"2018","unstructured":"Grover, S. P. & Mackman, N. Tissue factor: an essential mediator of hemostasis and trigger of thrombosis. Arterioscler. Thromb. Vasc. Biol. 38, 709\u2013725 (2018).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"1167_CR3","first-page":"1087","volume":"134","author":"TA Drake","year":"1989","unstructured":"Drake, T. A., Morrissey, J. H. & Edgington, T. S. Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am. J. Pathol. 134, 1087\u20131097 (1989).","journal-title":"Am. J. Pathol."},{"key":"1167_CR4","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/0092-8674(87)90669-6","volume":"50","author":"JH Morrissey","year":"1987","unstructured":"Morrissey, J. H., Fakhrai, H. & Edgington, T. S. Molecular cloning of the cDNA for tissue factor, the cellular receptor for the initiation of the coagulation protease cascade. Cell 50, 129\u2013135 (1987).","journal-title":"Cell"},{"key":"1167_CR5","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1161\/01.ATV.15.5.612","volume":"15","author":"GC Parry","year":"1995","unstructured":"Parry, G. C. & Mackman, N. Transcriptional regulation of tissue factor expression in human endothelial cells. Arterioscler. Thromb. Vasc. Biol. 15, 612\u2013621 (1995).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"1167_CR6","doi-asserted-by":"publisher","first-page":"2764","DOI":"10.1182\/blood-2004-09-3567","volume":"105","author":"S Butenas","year":"2005","unstructured":"Butenas, S., Bouchard, B. A., Brummel-Ziedins, K. E., Parhami-Seren, B. & Mann, K. G. Tissue factor activity in whole blood. Blood 105, 2764\u20132770 (2005).","journal-title":"Blood"},{"key":"1167_CR7","doi-asserted-by":"publisher","first-page":"12077","DOI":"10.1073\/pnas.0504526102","volume":"102","author":"A Hezi-Yamit","year":"2005","unstructured":"Hezi-Yamit, A. et al. Synergistic induction of tissue factor by coagulation factor Xa and TNF: evidence for involvement of negative regulatory signaling cascades. Proc. Natl. Acad. Sci. USA 102, 12077\u201312082 (2005).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"1167_CR8","doi-asserted-by":"crossref","unstructured":"Mechelke, T., Wittig, F., Ramer, R. & Hinz, B. Interleukin-1beta induces tissue factor expression in A549 cells via EGFR-dependent and -independent mechanisms. Int. J. Mol. Sci. 22, 6606 (2021).","DOI":"10.3390\/ijms22126606"},{"key":"1167_CR9","doi-asserted-by":"publisher","first-page":"e0158377","DOI":"10.1371\/journal.pone.0158377","volume":"11","author":"SA Ansari","year":"2016","unstructured":"Ansari, S. A., Pendurthi, U. R., Sen, P. & Rao, L. V. The role of putative phosphatidylserine-interactive residues of tissue factor on its coagulant activity at the cell surface. PLoS One\u00a011, e0158377 (2016).","journal-title":"PLoS One"},{"key":"1167_CR10","doi-asserted-by":"publisher","first-page":"S54","DOI":"10.1016\/j.thromres.2014.03.022","volume":"133","author":"HM Spronk","year":"2014","unstructured":"Spronk, H. M., ten Cate, H. & van der Meijden, P. E. Differential roles of tissue factor and phosphatidylserine in activation of coagulation. Thromb. Res. 133, S54\u2013S56 (2014).","journal-title":"Thromb. Res."},{"key":"1167_CR11","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1161\/ATVBAHA.109.200964","volume":"31","author":"JI Zwicker","year":"2011","unstructured":"Zwicker, J. I., Trenor, C. C. 3rd, Furie, B. C. & Furie, B. Tissue factor-bearing microparticles and thrombus formation. Arterioscler. Thromb. Vasc. Biol. 31, 728\u2013733 (2011).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"1167_CR12","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.1016\/j.immuni.2019.04.003","volume":"50","author":"CQ Wu","year":"2019","unstructured":"Wu, C. Q. et al. Inflammasome activation triggers blood clotting and host death through pyroptosis. Immunity 50, 1401\u20131411.e4 (2019).","journal-title":"Immunity"},{"key":"1167_CR13","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1160\/TH06-09-0524","volume":"97","author":"P Censarek","year":"2007","unstructured":"Censarek, P., Bobbe, A., Grandoch, M., Schror, K. & Weber, A. A. Alternatively spliced human tissue factor (asHTF) is not pro-coagulant. Thromb. Haemost. 97, 11\u201314 (2007).","journal-title":"Thromb. Haemost."},{"key":"1167_CR14","doi-asserted-by":"publisher","first-page":"3998","DOI":"10.1021\/bi00131a015","volume":"31","author":"E Waxman","year":"1992","unstructured":"Waxman, E. et al. Tissue factor and its extracellular soluble domain: the relationship between intermolecular association with factor VIIa and enzymatic activity of the complex. Biochemistry\u00a031, 3998\u20134003 (1992).","journal-title":"Biochemistry"},{"key":"1167_CR15","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1097\/MBC.0b013e328333b084","volume":"21","author":"P Sen","year":"2010","unstructured":"Sen, P., Neuenschwander, P. F., Pendurthi, U. R. & Rao, L. V. Analysis of factor VIIa binding to relipidated tissue factor by surface plasmon resonance. Blood Coagul. Fibrinolysis 21, 376\u2013379 (2010).","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"1167_CR16","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/S1473-3099(07)70265-7","volume":"8","author":"T van der Poll","year":"2008","unstructured":"van der Poll, T. & Opal, S. M. Host-pathogen interactions in sepsis. Lancet Infect. Dis. 8, 32\u201343 (2008).","journal-title":"Lancet Infect. Dis."},{"key":"1167_CR17","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1182\/blood-2013-09-526277","volume":"123","author":"S Antoniak","year":"2014","unstructured":"Antoniak, S. & Mackman, N. Multiple roles of the coagulation protease cascade during virus infection. Blood 123, 2605\u20132613 (2014).","journal-title":"Blood"},{"key":"1167_CR18","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1055\/s-0038-1657303","volume":"49","author":"B Osterud","year":"1983","unstructured":"Osterud, B. & Flaegstad, T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: Related to an unfavourable prognosis. Thromb. Haemost. 49, 5\u20137 (1983).","journal-title":"Thromb. Haemost."},{"key":"1167_CR19","doi-asserted-by":"publisher","first-page":"S77","DOI":"10.1097\/00003246-200009001-00017","volume":"28","author":"SM Opal","year":"2000","unstructured":"Opal, S. M. Phylogenetic and functional relationships between coagulation and the innate immune response. Crit. Care Med. 28, S77\u2013S80 (2000).","journal-title":"Crit. Care Med."},{"key":"1167_CR20","doi-asserted-by":"publisher","first-page":"2311","DOI":"10.1073\/pnas.96.5.2311","volume":"96","author":"PLA Giesen","year":"1999","unstructured":"Giesen, P. L. A. et al. Blood-borne tissue factor: Another view of thrombosis. Proc. Natl. Acad. Sci. USA 96, 2311\u20132315 (1999).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"1167_CR21","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1126\/science.1172308","volume":"325","author":"DW Zhang","year":"2009","unstructured":"Zhang, D. W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332\u2013336 (2009).","journal-title":"Science"},{"key":"1167_CR22","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1038\/82732","volume":"1","author":"N Holler","year":"2000","unstructured":"Holler, N. et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1, 489\u2013495 (2000).","journal-title":"Nat. Immunol."},{"key":"1167_CR23","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1016\/j.cell.2009.05.021","volume":"137","author":"S He","year":"2009","unstructured":"He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 137, 1100\u20131111 (2009).","journal-title":"Cell"},{"key":"1167_CR24","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.cell.2011.11.031","volume":"148","author":"L Sun","year":"2012","unstructured":"Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213\u2013227 (2012).","journal-title":"Cell"},{"key":"1167_CR25","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1038\/cr.2016.87","volume":"26","author":"ZY Cai","year":"2016","unstructured":"Cai, Z. Y. et al. Activation of cell-surface proteases promotes necroptosis, inflammation and cell migration. Cell Res. 26, 886\u2013900 (2016).","journal-title":"Cell Res."},{"key":"1167_CR26","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/j.chom.2012.01.016","volume":"11","author":"JW Upton","year":"2012","unstructured":"Upton, J. W., Kaiser, W. J. & Mocarski, E. S. DAI\/ZBP1\/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. Cell Host Microbe\u00a011, 290\u2013297 (2012).","journal-title":"Cell Host Microbe"},{"key":"1167_CR27","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1016\/j.immuni.2011.09.020","volume":"35","author":"L Duprez","year":"2011","unstructured":"Duprez, L. et al. RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35, 908\u2013918 (2011).","journal-title":"Immunity"},{"key":"1167_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23004-3","volume":"12","author":"JY Baik","year":"2021","unstructured":"Baik, J. Y. et al. ZBP1 not RIPK1 mediates tumor necroptosis in breast cancer. Nat. Commun. 12, 2666 (2021).","journal-title":"Nat. Commun."},{"key":"1167_CR29","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1016\/j.cell.2009.05.037","volume":"137","author":"Y Cho","year":"2009","unstructured":"Cho, Y. et al. Phosphorylation-driven sssembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112\u20131123 (2009).","journal-title":"Cell"},{"key":"1167_CR30","doi-asserted-by":"publisher","first-page":"11007","DOI":"10.1073\/pnas.1514730112","volume":"112","author":"L Meng","year":"2015","unstructured":"Meng, L., Jin, W. & Wang, X. RIP3-mediated necrotic cell death accelerates systematic inflammation and mortality. Proc. Natl. Acad. Sci. USA 112, 11007\u201311012 (2015).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"1167_CR31","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.thromres.2020.04.041","volume":"191","author":"FA Klok","year":"2020","unstructured":"Klok, F. A. et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb. Res. 191, 148\u2013150 (2020).","journal-title":"Thromb. Res"},{"key":"1167_CR32","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1161\/CIRCRESAHA.121.319117","volume":"129","author":"M Koupenova","year":"2021","unstructured":"Koupenova, M. et al. SARS-CoV-2 initiates programmed cell death in platelets. Circ. Res. 129, 631\u2013646 (2021).","journal-title":"Circ. Res"},{"key":"1167_CR33","doi-asserted-by":"crossref","unstructured":"Li, S. et al. Clinical and pathological investigation of patients with severe COVID-19. JCI Insight 5, 138070 (2020).","DOI":"10.1172\/jci.insight.138070"},{"key":"1167_CR34","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00496-6","volume":"8","author":"Q Xu","year":"2017","unstructured":"Xu, Q. et al. The cytoplasmic nuclear receptor RARgamma controls RIP1 initiated cell death when cIAP activity is inhibited. Nat. Commun. 8, 425 (2017).","journal-title":"Nat. Commun."},{"key":"1167_CR35","doi-asserted-by":"publisher","first-page":"2064","DOI":"10.1172\/JCI96147","volume":"128","author":"M Zelic","year":"2018","unstructured":"Zelic, M. et al. RIP kinase 1-dependent endothelial necroptosis underlies systemic inflammatory response syndrome. J. Clin. Invest. 128, 2064\u20132075 (2018).","journal-title":"J. Clin. Invest"},{"key":"1167_CR36","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1016\/j.immuni.2019.11.005","volume":"51","author":"XY Yang","year":"2019","unstructured":"Yang, X. Y. et al. Bacterial endotoxin activates the coagulation cascade through Gasdermin D-dependent phosphatidylserine exposure. Immunity 51, 983\u2013996.e6 (2019).","journal-title":"Immunity"},{"key":"1167_CR37","doi-asserted-by":"publisher","first-page":"26059","DOI":"10.1074\/jbc.M115.649509","volume":"290","author":"N Schumacher","year":"2015","unstructured":"Schumacher, N. et al. Shedding of endogenous interleukin-6 receptor (IL-6R) is governed by A disintegrin and metalloproteinase (ADAM) proteases while a full-length IL-6R isoform localizes to circulating microvesicles. J. Biol. Chem. 290, 26059\u201326071 (2015).","journal-title":"J. Biol. Chem."},{"key":"1167_CR38","doi-asserted-by":"publisher","first-page":"D624","DOI":"10.1093\/nar\/gkx1134","volume":"46","author":"ND Rawlings","year":"2018","unstructured":"Rawlings, N. D. et al. The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database. Nucleic Acids Res. 46, D624\u2013D632 (2018).","journal-title":"Nucleic Acids Res"},{"key":"1167_CR39","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1111\/j.1538-7836.2005.01680.x","volume":"4","author":"VY Bogdanov","year":"2006","unstructured":"Bogdanov, V. Y. et al. Identification and characterization of murine alternatively spliced tissue factor. J. Thromb. Haemost. 4, 158\u2013167 (2006).","journal-title":"J. Thromb. Haemost."},{"key":"1167_CR40","doi-asserted-by":"publisher","first-page":"3219","DOI":"10.1182\/blood.V89.9.3219","volume":"89","author":"RF Kelley","year":"1997","unstructured":"Kelley, R. F. et al. A soluble tissue factor mutant is a selective anticoagulant and antithrombotic agent. Blood 89, 3219\u20133227 (1997).","journal-title":"Blood"},{"key":"1167_CR41","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1055\/s-0038-1648376","volume":"67","author":"A Tripodi","year":"1992","unstructured":"Tripodi, A., Arbini, A., Chantarangkul, V. & Mannucci, P. M. Recombinant tissue factor as substitute for conventional thromboplastin in the prothrombin time test. Thromb. Haemost. 67, 42\u201345 (1992).","journal-title":"Thromb. Haemost."},{"key":"1167_CR42","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1007\/s12250-014-3530-y","volume":"29","author":"Z Yang","year":"2014","unstructured":"Yang, Z. et al. Coronavirus MHV-A59 infects the lung and causes severe pneumonia in C57BL\/6 mice. Virol. Sin. 29, 393\u2013402 (2014).","journal-title":"Virol. Sin."},{"key":"1167_CR43","doi-asserted-by":"crossref","unstructured":"K\u00f6rner, R. W., Majjouti, M., Alcazar, M. A. A. & Mahabir, E. Of mice and men: the Coronavirus MHV and mouse models as a translational approach to understand SARS-CoV-2. Viruses 12, 880 (2020).","DOI":"10.3390\/v12080880"},{"key":"1167_CR44","first-page":"S9","volume":"9","author":"B Osterud","year":"1998","unstructured":"Osterud, B. Tissue factor expression by monocytes: regulation and pathophysiological roles. Blood Coagul. Fibrinolysis\u00a09, S9\u2013S14 (1998).","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"1167_CR45","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1007\/s00432-019-03073-0","volume":"146","author":"F Ender","year":"2020","unstructured":"Ender, F. et al. Tissue factor activity on microvesicles from cancer patients. J. Cancer Res Clin. Oncol. 146, 467\u2013475 (2020).","journal-title":"J. Cancer Res Clin. Oncol."},{"key":"1167_CR46","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1111\/j.1538-7836.2009.03448.x","volume":"7","author":"JG Wang","year":"2009","unstructured":"Wang, J. G., Manly, D., Kirchhofer, D., Pawlinski, R. & Mackman, N. Levels of microparticle tissue factor activity correlate with coagulation activation in endotoxemic mice. J. Thromb. Haemost. 7, 1092\u20131098 (2009).","journal-title":"J. Thromb. Haemost."},{"key":"1167_CR47","doi-asserted-by":"publisher","first-page":"1604","DOI":"10.1182\/blood-2004-03-1095","volume":"106","author":"I Del Conde","year":"2005","unstructured":"Del Conde, I., Shrimpton, C. N., Thiagarajan, P. & Lopez, J. A. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 106, 1604\u20131611 (2005).","journal-title":"Blood"},{"key":"1167_CR48","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1007\/s10495-019-01589-x","volume":"25","author":"X Xia","year":"2020","unstructured":"Xia, X., Lei, L., Wang, S., Hu, J. & Zhang, G. Necroptosis and its role in infectious diseases. Apoptosis 25, 169\u2013178 (2020).","journal-title":"Apoptosis"},{"key":"1167_CR49","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1165\/rcmb.2022-0039LE","volume":"67","author":"K Ruskowski","year":"2022","unstructured":"Ruskowski, K. et al. Persistently elevated plasma concentrations of RIPK3, MLKL, HMGB1, and RIPK1 in patients with COVID-19 in the intensive care unit. Am. J. Respir. Cell Mol. Biol. 67, 405\u2013408 (2022).","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"1167_CR50","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/s41422-022-00775-y","volume":"33","author":"S Li","year":"2023","unstructured":"Li, S. et al. SARS-CoV-2 Z-RNA activates the ZBP1-RIPK3 pathway to promote virus-induced inflammatory responses. Cell Res. 33, 201\u2013214 (2023).","journal-title":"Cell Res"},{"key":"1167_CR51","doi-asserted-by":"crossref","unstructured":"Li, S. F. et al. SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation. Signal Transduct. Target. Ther. 5, 235 (2020).","DOI":"10.1038\/s41392-020-00334-0"},{"key":"1167_CR52","doi-asserted-by":"publisher","first-page":"5543","DOI":"10.1182\/blood-2012-01-402156","volume":"119","author":"JG Wang","year":"2012","unstructured":"Wang, J. G. et al. Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer. Blood 119, 5543\u20135552 (2012).","journal-title":"Blood"},{"key":"1167_CR53","doi-asserted-by":"publisher","first-page":"3671","DOI":"10.1158\/0008-5472.CAN-15-3100","volume":"76","author":"NS Key","year":"2016","unstructured":"Key, N. S. et al. Thrombosis in cancer: research priorities identified by a national cancer institute\/national heart, lung, and blood institute strategic working group. Cancer Res. 76, 3671\u20133675 (2016).","journal-title":"Cancer Res"},{"key":"1167_CR54","doi-asserted-by":"publisher","first-page":"2411","DOI":"10.1016\/j.jacc.2017.09.024","volume":"70","author":"JI Weitz","year":"2017","unstructured":"Weitz, J. I., Fredenburgh, J. C. & Eikelboom, J. W. A test in context: D-dimer. J. Am. Coll. Cardiol. 70, 2411\u20132420 (2017).","journal-title":"J. Am. Coll. Cardiol."},{"key":"1167_CR55","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1159\/000213677","volume":"41","author":"K Hager","year":"1995","unstructured":"Hager, K. & Platt, D. Fibrin degeneration product concentrations (D-dimers) in the course of ageing. Gerontology 41, 159\u2013165 (1995).","journal-title":"Gerontology"},{"key":"1167_CR56","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1056\/NEJM198711263172201","volume":"317","author":"JB Kruskal","year":"1987","unstructured":"Kruskal, J. B., Commerford, P. J., Franks, J. J. & Kirsch, R. E. Fibrin and fibrinogen-related antigens in patients with stable and unstable coronary artery disease. N. Engl. J. Med. 317, 1361\u20131365 (1987).","journal-title":"N. Engl. J. Med"},{"key":"1167_CR57","doi-asserted-by":"publisher","first-page":"64s","DOI":"10.1378\/chest.119.1_suppl.64S","volume":"119","author":"J Hirsh","year":"2001","unstructured":"Hirsh, J. et al. Heparin and low-molecular-weight heparin - Mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 119, 64s\u201394s (2001).","journal-title":"Chest"},{"key":"1167_CR58","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-023-01604-9","volume":"25","author":"Z Liu","year":"2023","unstructured":"Liu, Z. et al. Tumor necroptosis-mediated shedding of cell surface proteins promotes metastasis of breast cancer by suppressing anti-tumor immunity. Breast Cancer Res. 25, 10 (2023).","journal-title":"Breast Cancer Res"},{"key":"1167_CR59","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1007\/978-1-4939-8754-2_12","volume":"1857","author":"M Zelic","year":"2018","unstructured":"Zelic, M. & Kelliher, M. A. Analyzing necroptosis using an RIPK1 kinase inactive mouse model of TNF shock. Methods Mol. Biol. 1857, 125\u2013134 (2018).","journal-title":"Methods Mol. Biol."},{"key":"1167_CR60","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2012.176","volume":"3","author":"N Takahashi","year":"2012","unstructured":"Takahashi, N. et al. Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death Dis. 3, e437 (2012).","journal-title":"Cell Death Dis."},{"key":"1167_CR61","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1038\/cr.2013.75","volume":"23","author":"Y Zhang","year":"2013","unstructured":"Zhang, Y. et al. ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor-associated macrophages. Cell Res. 23, 898\u2013914 (2013).","journal-title":"Cell Res"},{"key":"1167_CR62","doi-asserted-by":"publisher","first-page":"101457","DOI":"10.1016\/j.xpro.2022.101457","volume":"3","author":"JY Baik","year":"2022","unstructured":"Baik, J. Y., Wan, P. & Liu, Z. G. Examining MLKL phosphorylation to detect necroptosis in murine mammary tumors. STAR Protoc. 3, 101457 (2022).","journal-title":"STAR Protoc."},{"key":"1167_CR63","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1038\/laban.432","volume":"43","author":"A Sharma","year":"2014","unstructured":"Sharma, A. et al. Safety and blood sample volume and quality of a refined retro-orbital bleeding technique in rats using a lateral approach. Lab Anim. 43, 63\u201366 (2014).","journal-title":"Lab Anim."},{"key":"1167_CR64","doi-asserted-by":"publisher","first-page":"321\u2013&","DOI":"10.1093\/ajcp\/39.3_ts.321","volume":"39","author":"GF Meissner","year":"1963","unstructured":"Meissner, G. F. & Moehring, C. M. Standard clotting time - a method based on use of whole venous blood in capillary tubes. Am. J. Clin. Pathol. 39, 321\u2013& (1963).","journal-title":"Am. J. Clin. Pathol."},{"key":"1167_CR65","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-014-0241-y","volume":"12","author":"DF Stroncek","year":"2014","unstructured":"Stroncek, D. F. et al. Counter-flow elutriation of clinical peripheral blood mononuclear cell concentrates for the production of dendritic and T cell therapies. J. Transl. Med. 12, 241 (2014).","journal-title":"J. Transl. Med"},{"key":"1167_CR66","doi-asserted-by":"crossref","unstructured":"Clarke, E. V., Benoit, M. E. & Tenner, A. J. Purification of human monocytes and lymphocyte populations by counter current elutriation- a short protocol. Bio. Protoc. 3, 981 (2013).","DOI":"10.21769\/BioProtoc.981"},{"key":"1167_CR67","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1038\/nature11929","volume":"495","author":"J Hoggatt","year":"2013","unstructured":"Hoggatt, J. et al. Differential stem- and progenitor-cell trafficking by prostaglandin E2. Nature 495, 365\u2013369 (2013).","journal-title":"Nature"},{"key":"1167_CR68","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.thromres.2019.07.011","volume":"182","author":"L Vallier","year":"2019","unstructured":"Vallier, L. et al. Increasing the sensitivity of the human microvesicle tissue factor activity assay. Thromb. Res. 182, 64\u201374 (2019).","journal-title":"Thromb. Res"},{"key":"1167_CR69","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1038\/labinvest.2010.59","volume":"90","author":"JA Caldwell","year":"2010","unstructured":"Caldwell, J. A., Dickhout, J. G., Al-Hashimi, A. A. & Austin, R. C. Development of a continuous assay for the measurement of tissue factor procoagulant activity on intact cells. Lab. Invest. 90, 953\u2013962 (2010).","journal-title":"Lab. Invest"},{"key":"1167_CR70","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1111\/jth.15087","volume":"19","author":"F Birkle","year":"2021","unstructured":"Birkle, F. & Morrissey, J. H. A serine loop in tissue factor mediates substrate selectivity by the tissue factor-factor VIIa complex. J. Thromb. Haemost. 19, 75\u201384 (2021).","journal-title":"J. Thromb. Haemost."},{"key":"1167_CR71","doi-asserted-by":"publisher","first-page":"21489","DOI":"10.1016\/S0021-9258(20)80565-1","volume":"268","author":"PF Neuenschwander","year":"1993","unstructured":"Neuenschwander, P. F., Fiore, M. M. & Morrissey, J. H. Factor-Vii autoactivation proceeds via interaction of distinct protease-cofactor and zymogen-cofactor complexes - implications of a 2-dimensional enzyme-kinetic mechanism. J. Biol. Chem. 268, 21489\u201321492 (1993).","journal-title":"J. Biol. Chem."},{"key":"1167_CR72","doi-asserted-by":"crossref","unstructured":"Sun, F., Xiao, G. & Qu, Z. Murine bronchoalveolar lavage. Bio. Protoc. 7, 2287 (2017).","DOI":"10.21769\/BioProtoc.2287"},{"key":"1167_CR73","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1128\/JCM.37.2.427-429.1999","volume":"37","author":"E De Brauwer","year":"1999","unstructured":"De Brauwer, E., Jacobs, J., Nieman, F., Bruggeman, C. & Drent, M. Test characteristics of acridine orange, gram, and may-grunwald-giemsa stains for enumeration of intracellular organisms in bronchoalveolar lavage fluid. J. Clin. Microbiol. 37, 427\u2013429 (1999).","journal-title":"J. Clin. Microbiol"},{"key":"1167_CR74","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1002\/cpmo.26","volume":"7","author":"F Daubeuf","year":"2017","unstructured":"Daubeuf, F. et al. A fast, easy, and customizable eight-color flow cytometric method for analysis of the cellular content of bronchoalveolar lavage fluid in the mouse. Curr. Protoc. Mouse Biol. 7, 88\u201399 (2017).","journal-title":"Curr. Protoc. Mouse Biol."}],"container-title":["Cell Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41422-025-01167-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41422-025-01167-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41422-025-01167-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T02:02:49Z","timestamp":1762394569000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41422-025-01167-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,12]]},"references-count":74,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["1167"],"URL":"https:\/\/doi.org\/10.1038\/s41422-025-01167-8","relation":{},"ISSN":["1748-7838"],"issn-type":[{"value":"1748-7838","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,12]]},"assertion":[{"value":"17 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}