{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:22:17Z","timestamp":1791235337258,"version":"4.1.0"},"reference-count":20,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T00:00:00Z","timestamp":1647907200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100011096","name":"Jazz Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011096","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006260","name":"Rheumatology Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006260","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000964","name":"Arthritis National Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000964","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01\u2010HL\u2010115138"],"award-info":[{"award-number":["R01\u2010HL\u2010115138"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012051","name":"Lupus Research Alliance, Inc.","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006260","name":"Rheumatology Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006260","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Defibrotide is a heterogenous mixture of polyanionic oligonucleotides currently approved for treatment of transplant\u2010associated venoocclusive disease. While defibrotide has a known role in limiting endothelial cell activation, some studies have also demonstrated anti\u2010leukocyte properties. In a recent study, we found that neutrophil extracellular traps (NETs) play a role in the thrombotic complications of antiphospholipid syndrome (APS). In the present study, we investigated the hypothesis that defibrotide might act to mitigate APS\u2010relevant NET formation in vitro and in mouse models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used in vitro assays and a mouse model to determine the mechanisms by which defibrotide inhibits NET formation and venous thrombosis in APS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At doses ranging from 1 to 10 \u03bcg\/ml, defibrotide significantly suppressed NET formation from control neutrophils stimulated with IgG isolated from patients with APS. Defibrotide increased levels of intracellular cyclic AMP in neutrophils, and its suppressive effects on NET formation were mitigated by blocking adenosine A<jats:sub>2A<\/jats:sub> receptor or by inhibiting the cyclic AMP\u2013dependent kinase protein kinase A. Defibrotide at doses ranging from 15 to 150 mg\/kg\/day inhibited NET formation and venous thrombosis in a model of antiphospholipid antibody\u2013accelerated thrombosis\u2014an effect that was reduced in adenosine A<jats:sub>2A<\/jats:sub> receptor\u2013knockout mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study is the first to demonstrate mechanisms by which defibrotide counteracts neutrophil\u2010mediated thrombotic inflammation inherent to APS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42017","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T22:49:20Z","timestamp":1635806960000},"page":"902-907","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Defibrotide Inhibits Antiphospholipid Antibody\u2013Mediated Neutrophil Extracellular Trap Formation and Venous Thrombosis"],"prefix":"10.1002","volume":"74","author":[{"given":"Ramadan A.","family":"Ali","sequence":"first","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanea K.","family":"Estes","sequence":"additional","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex A.","family":"Gandhi","sequence":"additional","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srilakshmi","family":"Yalavarthi","sequence":"additional","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire K.","family":"Hoy","sequence":"additional","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Shi","sequence":"additional","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zuo","sequence":"additional","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7216-677X","authenticated-orcid":false,"given":"Doruk","family":"Erkan","sequence":"additional","affiliation":[{"name":"Hospital for Special Surgery, Weill Cornell Medicine  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0995-9771","authenticated-orcid":false,"given":"Jason S.","family":"Knight","sequence":"additional","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,22]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2014.05.001"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092385"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.24437"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0032366"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-209442"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1005743107"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39247"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39938"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09801-x"},{"key":"e_1_2_7_11_1","article-title":"Antineutrophil properties of natural gingerols in models of lupus. 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