{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T17:06:30Z","timestamp":1786727190574,"version":"build-2736575974"},"reference-count":40,"publisher":"American Society of Hematology","issue":"16","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,4,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Factor IXa (FIXa) plays a pivotal role in coagulation by contributing to FX activation via the intrinsic pathway. Although antithrombin (AT) and other plasma inhibitors are thought to regulate FIXa procoagulant function, the impact of FIXa inhibition on thrombin generation and clot formation in\u00a0vivo remains unclear. Here, we generated FIXa variants with altered reactivity to plasma inhibitors that target the FIXa active site but maintain procoagulant function when bound to its cofactor, FVIIIa. We found that selected FIXa variants (eg, FIXa-V16L) have a prolonged activity half-life in the plasma due, in part, to AT resistance. Studies using hemophilia B mice have shown that delayed FIXa inhibition has a major impact on reducing the bleeding phenotype and promoting thrombus formation following administration of FIX protein. Overall, these results demonstrate that the regulation of FIXa inhibition contributes in a major way to the spatial and temporal control of coagulation at the site of vascular injury. Our findings provide novel insights into the physiological regulation of FIXa, enhance our understanding of thrombus formation in\u00a0vivo via the intrinsic pathway, and suggest that altering FIXa inhibition could have therapeutic benefits.<\/jats:p>","DOI":"10.1182\/blood.2022018083","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T21:25:05Z","timestamp":1675286705000},"page":"2022-2032","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":7,"title":["Factor IXa variants resistant to plasma inhibitors enhance clot formation in\u00a0vivo"],"prefix":"10.1182","volume":"141","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3468-8600","authenticated-orcid":false,"given":"Lacramioara","family":"Ivanciu","sequence":"first","affiliation":[{"name":"1Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"},{"name":"2Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valder R.","family":"Arruda","sequence":"additional","affiliation":[{"name":"1Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"},{"name":"2Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0585-4537","authenticated-orcid":false,"given":"Rodney M.","family":"Camire","sequence":"additional","affiliation":[{"name":"1Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"},{"name":"2Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"1","key":"2023110216020948500_bib1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1182\/blood.V76.1.1.1","article-title":"Surface-dependent reactions of the vitamin K-dependent enzyme complexes","volume":"76","author":"Mann","year":"1990","journal-title":"Blood"},{"issue":"222","key":"2023110216020948500_bib2","first-page":"1","article-title":"Introduction: blood coagulation","volume":"222","author":"Mann","year":"1993","journal-title":"Methods Enzymol"},{"issue":"19","key":"2023110216020948500_bib3","doi-asserted-by":"crossref","first-page":"12481","DOI":"10.1016\/S0021-9258(18)98924-6","article-title":"Structural basis for the decreased procoagulant activity of human factor VIII compared to the porcine homolog","volume":"266","author":"Lollar","year":"1991","journal-title":"J\u00a0Biol Chem"},{"issue":"30","key":"2023110216020948500_bib4","doi-asserted-by":"crossref","first-page":"20139","DOI":"10.1016\/S0021-9258(18)54901-2","article-title":"Activated protein C-catalyzed inactivation of human factor VIII and factor VIIIa. 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