{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:59:17Z","timestamp":1790618357713,"version":"4.1.0"},"reference-count":128,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T00:00:00Z","timestamp":1683763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"U.S. Food and Drug Administration, Center for Biologics Evaluation"},{"name":"Research project 05010 (AGS)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Factor VIII (FVIII) is an important component of blood coagulation as its congenital deficiency results in life-threatening bleeding. Current prophylactic therapy of the disease (hemophilia A) is based on 3\u20134 intravenous infusions of therapeutic FVIII per week. This poses a burden on patients, demanding reduction of infusion frequency by using FVIII with extended plasma half-life (EHL). Development of these products requires understanding FVIII plasma clearance mechanisms. This paper overviews (i) an up-to-date state of the research in this field and (ii) current EHL FVIII products, including recently approved efanesoctocog alfa, for which the plasma half-life exceeds a biochemical barrier posed by von Willebrand factor, complexed with FVIII in plasma, which results in ~1 per week infusion frequency. We focus on the EHL FVIII products\u2019 structure and function, in particular related to the known discrepancy in results of one-stage clotting (OC) and chromogenic substrate (CS) assays used to assign the products\u2019 potency, dosing, and for clinical monitoring in plasma. We suggest a possible root cause of these assays\u2019 discrepancy that is also pertinent to EHL factor IX variants used to treat hemophilia B. Finally, we discuss approaches in designing future EHL FVIII variants, including those to be used for hemophilia A gene therapy.<\/jats:p>","DOI":"10.3390\/ijms24108584","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T04:29:01Z","timestamp":1683779341000},"page":"8584","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Plasma Clearance of Coagulation Factor VIII and Extension of Its Half-Life for the Therapy of Hemophilia A: A Critical Review of the Current State of Research and Practice"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6124-9713","authenticated-orcid":false,"given":"Andrey G.","family":"Sarafanov","sequence":"first","affiliation":[{"name":"Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"545","DOI":"10.3324\/haematol.2019.232132","article-title":"Hemophilia therapy: The future has begun","volume":"105","author":"Mannucci","year":"2020","journal-title":"Haematologica"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1182\/hematology.2022000388","article-title":"Gene therapy for hemophilia","volume":"2022","author":"Nathwani","year":"2022","journal-title":"Hematol. 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