{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:11:04Z","timestamp":1790244664911,"version":"4.1.0"},"reference-count":72,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Broxmeyer Fellowship in Clinical Thrombosis"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Balancing thrombotic and bleeding risk remains the central challenge of anticoagulation, and clinically significant bleeding continues to limit even direct oral anticoagulants, especially in high-bleeding-risk patients. Factor XI (FXI) and activated FXI (FXIa) inhibitors are a mechanistically novel class that seeks to uncouple thrombosis from hemostasis; FXI amplifies clot formation through the intrinsic pathway but contributes little to physiologic hemostasis. This state-of-the-art review examines three classes of FXI\/FXIa inhibitors (antisense oligonucleotides, monoclonal antibodies, and small-molecule inhibitors) that are in advanced phase II and III clinical trials, and synthesizes currently available evidence across six indications, including primary thromboprophylaxis in high-bleed-risk orthopedic surgery, primary thromboprophylaxis in end-stage renal disease, stroke prevention in atrial fibrillation, acute coronary syndromes, secondary stroke prevention, and treatment of cancer-associated venous thromboembolism. A pattern emerges, where FXI\/FXIa inhibition offers a favorable safety profile across multiple settings and high-risk subgroups, yet clear efficacy has so far been established only in secondary prevention of noncardioembolic ischemic stroke over existing antiplatelet strategies. Although unlikely to completely replace current anticoagulants, these agents may offer important therapeutic options for selected high-risk populations. Ongoing phase II and III trials will further define their potential advantages in areas of unmet clinical need.<\/jats:p>","DOI":"10.3390\/jcm15197431","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T09:07:54Z","timestamp":1790240874000},"page":"7431","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Factor XI and XIa Inhibitors: A State-of-the-Art Review Across Clinical Indications"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4845-0901","authenticated-orcid":false,"given":"Ermioni","family":"Oikonomou","sequence":"first","affiliation":[{"name":"Institute of Health System Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell Health at Lenox Hill Hospital, New York, NY 10075, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Goldin","sequence":"additional","affiliation":[{"name":"Institute of Health System Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell Health at Lenox Hill Hospital, New York, NY 10075, USA"},{"name":"Donald and Barbara Zucker School of Medicine at Hofstra, Northwell, Hempstead, NY 11549, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3175-461X","authenticated-orcid":false,"given":"Alex C.","family":"Spyropoulos","sequence":"additional","affiliation":[{"name":"Institute of Health System Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell Health at Lenox Hill Hospital, New York, NY 10075, USA"},{"name":"Donald and Barbara Zucker School of Medicine at Hofstra, Northwell, Hempstead, NY 11549, USA"},{"name":"Elmezzi Graduate School of Molecular Medicine, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/S0140-6736(20)32658-1","article-title":"Venous thromboembolism","volume":"398","author":"Khan","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1093\/europace\/euac020","article-title":"Assessment and mitigation of bleeding risk in atrial fibrillation and venous thromboembolism: A Position Paper from the ESC Working Group on Thrombosis, in collaboration with the European Heart Rhythm Association, the Association for Acute CardioVascular Care and the Asia-Pacific Heart Rhythm Society","volume":"24","author":"Gorog","year":"2022","journal-title":"Europace"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.thromres.2022.08.015","article-title":"Challenging clinical scenarios for therapeutic anticoagulation: A practical approach","volume":"218","author":"Martens","year":"2022","journal-title":"Thromb. 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