{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T23:43:57Z","timestamp":1792539837139,"version":"4.5.0"},"reference-count":37,"publisher":"National Academy of Sciences","issue":"21","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,5,21]]},"abstract":"<jats:p>\n                    Deep vein thrombosis and pulmonary embolism are major health problems associated with high mortality. Recently, DNA-based neutrophil extracellular traps (NETs) resulting from the release of decondensed chromatin, were found to be part of the thrombus scaffold and to promote coagulation. However, the significance of nuclear decondensation and NET generation in thrombosis is largely unknown. To address this, we adopted a stenosis model of deep vein thrombosis and analyzed venous thrombi in peptidylarginine deiminase 4 (PAD4)-deficient mice that cannot citrullinate histones, a process required for chromatin decondensation and NET formation. Intriguingly, less than 10% of\n                    <jats:italic>\n                      PAD4\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice produced a thrombus 48 h after inferior vena cava stenosis whereas 90% of wild-type mice did. Neutrophils were abundantly present in thrombi formed in both groups, whereas extracellular citrullinated histones were seen only in thrombi from wild-type mice. Bone marrow chimera experiments indicated that PAD4 in hematopoietic cells was the source of the prothrombotic effect in deep vein thrombosis. Thrombosis could be rescued by infusion of wild-type neutrophils, suggesting that neutrophil PAD4 was important and sufficient. Endothelial activation and platelet aggregation were normal in\n                    <jats:italic>\n                      PAD4\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice, as was hemostatic potential determined by bleeding time and platelet plug formation after venous injury. Our results show that PAD4-mediated chromatin decondensation in the neutrophil is crucial for pathological venous thrombosis and present neutrophil activation and PAD4 as potential drug targets for deep vein thrombosis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1301059110","type":"journal-article","created":{"date-parts":[[2013,5,7]],"date-time":"2013-05-07T00:00:47Z","timestamp":1367884847000},"page":"8674-8679","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":494,"title":["Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice"],"prefix":"10.1073","volume":"110","author":[{"given":"Kimberly","family":"Martinod","sequence":"first","affiliation":[{"name":"Immunology Graduate Program, Division of Medical Sciences, Harvard Medical School, Boston, MA 02115;"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Demers","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115;"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias A.","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115;"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siu Ling","family":"Wong","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115;"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Brill","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115;"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen","family":"Gallant","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Hu","sequence":"additional","affiliation":[{"name":"Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802; 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