{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T07:12:20Z","timestamp":1794035540606,"version":"4.8.0"},"reference-count":117,"publisher":"American Society for Clinical Investigation","issue":"22","license":[{"start":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T00:00:00Z","timestamp":1700611200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["K99 HL156060,R35 HL150698"],"award-info":[{"award-number":["K99 HL156060,R35 HL150698"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010633","name":"Philadelphia Foundation","doi-asserted-by":"crossref","award":["Brody Family Medical Trust Fund Fellowship"],"award-info":[{"award-number":["Brody Family Medical Trust Fund Fellowship"]}],"id":[{"id":"10.13039\/100010633","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["19TPA34890056"],"award-info":[{"award-number":["19TPA34890056"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,22]]},"abstract":"<jats:p>\n                    Plasma cell-free DNA (cfDNA), a marker of disease severity in sepsis, is a recognized driver of thromboinflammation and a potential therapeutic target. In sepsis, plasma cfDNA is mostly derived from neutrophil extracellular trap (NET) degradation. Proposed NET-directed therapeutic strategies include preventing NET formation or accelerating NET degradation. However, NET digestion liberates pathogens and releases cfDNA that promote thrombosis and endothelial cell injury. We propose an alternative strategy of cfDNA and NET stabilization with chemokine platelet factor 4 (PF4, CXCL4). We previously showed that human PF4 (hPF4) enhances NET-mediated microbial entrapment. We now show that hPF4 interferes with thrombogenicity of cfDNA and NETs by preventing their cleavage to short-fragment and single-stranded cfDNA that more effectively activates the contact pathway of coagulation. In vitro, hPF4 also inhibits cfDNA-induced endothelial tissue factor surface expression and von Willebrand factor release. In vivo, hPF4 expression reduced plasma thrombin-antithrombin (TAT) levels in animals infused with exogenous cfDNA. Following lipopolysaccharide challenge,\n                    <jats:italic>\n                      Cxcl4\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    mice had significant elevation in plasma TAT, cfDNA, and cystatin C levels, effects prevented by hPF4 infusion. These results show that hPF4 interacts with cfDNA and NETs to limit thrombosis and endothelial injury, an observation of potential clinical benefit in the treatment of sepsis.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.171054","type":"journal-article","created":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T14:00:56Z","timestamp":1700575256000},"source":"Crossref","is-referenced-by-count":42,"title":["Platelet factor 4 limits neutrophil extracellular trap\u2013 and cell-free DNA\u2013induced thrombogenicity and endothelial injury"],"prefix":"10.1172","volume":"8","author":[{"given":"Anh T.P.","family":"Ngo","sequence":"first","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Skidmore","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna","family":"Oberg","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Yarovoi","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5828-9682","authenticated-orcid":true,"given":"Amrita","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nate","family":"Levine","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Bochenek","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guohua","family":"Zhao","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1990-3077","authenticated-orcid":true,"given":"Lubica","family":"Rauova","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA."},{"name":"Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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