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GM132443"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Histones are cationic nuclear proteins that are essential for the structure and functions of eukaryotic chromatin. However, extracellular histones trigger inflammatory responses and contribute to death in sepsis by unknown mechanisms. We recently reported that inflammasome activation and pyroptosis trigger coagulation activation through a tissue-factor (TF)-dependent mechanism. We used a combination of various deficient mice to elucidate the molecular mechanism of histone-induced coagulation. We showed that histones trigger coagulation activation in vivo, as evidenced by coagulation parameters and fibrin deposition in tissues. However, histone-induced coagulopathy was neither dependent on intracellular inflammasome pathways involving caspase 1\/11 and gasdermin D (GSDMD), nor on cell surface receptor TLR2- and TLR4-mediated host immune response, as the deficiency of these genes in mice did not protect against histone-induced coagulopathy. The incubation of histones with macrophages induced lytic cell death and phosphatidylserine (PS) exposure, which is required for TF activity, a key initiator of coagulation. The neutralization of TF diminished the histone-induced coagulation. Our findings revealed lytic cell death as a novel mechanism of histone-induced coagulation activation and thrombosis.<\/jats:p>","DOI":"10.3390\/ijms23126800","type":"journal-article","created":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T09:51:11Z","timestamp":1655545871000},"page":"6800","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death"],"prefix":"10.3390","volume":"23","author":[{"given":"Yan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China"},{"name":"Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A & M University, College Station, TX 76549, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7725-7881","authenticated-orcid":false,"given":"Congqing","family":"Wu","sequence":"additional","affiliation":[{"name":"Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Surgery, College of Medicine, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Arts and Sciences, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7433-3129","authenticated-orcid":false,"given":"Ankit","family":"Pandeya","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Arts and Sciences, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A & M University, College Station, TX 76549, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8483-9975","authenticated-orcid":false,"given":"Jian","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Arts and Sciences, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Kirchhofer","sequence":"additional","affiliation":[{"name":"Department of Early Discovery Biochemistry, Genentech Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy P.","family":"Wood","sequence":"additional","affiliation":[{"name":"Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan S.","family":"Smyth","sequence":"additional","affiliation":[{"name":"Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9936-7149","authenticated-orcid":false,"given":"Yinan","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A & M University, College Station, TX 76549, USA"},{"name":"Department of Chemistry, College of Arts and Sciences, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Li","sequence":"additional","affiliation":[{"name":"Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A & M University, College Station, TX 76549, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1182\/blood.V122.21.457.457","article-title":"Histone-Induced Lung Injury and Coagulation Activation Are Reduced by C-Reactive Protein in the Acute Phase Response","volume":"122","author":"Abrams","year":"2013","journal-title":"Blood"},{"key":"ref_2","first-page":"2884","article-title":"Extracellular histones induce erythrocyte fragility and anemia","volume":"130","author":"Kordbacheh","year":"2017","journal-title":"J. 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