{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:19:31Z","timestamp":1791393571002,"version":"4.3.3"},"reference-count":26,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SIFO (\u201cSociet\u00e0 Italiana di Farmacia Ospedaliera e Dei Servizi Farmaceutici Delle Aziende Sanitarie\u201d) Campania"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmacy"],"abstract":"<jats:p>The introduction of direct oral anticoagulants (DOACs), particularly factor Xa (FXa) inhibitors, has transformed the prevention and treatment of thromboembolic events. These agents have largely replaced vitamin K antagonists across most indications due to their predictable pharmacokinetics, reduced rates of intracranial bleeding, and overall ease of use. Nevertheless, a substantial residual bleeding risk remains, particularly gastrointestinal bleeding and clinically relevant non-major bleeding in elderly, frail, or polymedicated patients. Furthermore, the management of patients with severe renal dysfunction, active cancer, especially gastrointestinal or genitourinary malignancies and those requiring complex pharmacological regimens, continues to pose significant challenges. These limitations have intensified interest in targeting earlier steps of the coagulation cascade, specifically factor XI (FXI) and its activated form (FXIa). FXI occupies a unique mechanistic position: it contributes substantially to pathological thrombosis while playing only a limited role in physiological hemostasis. Genetic, observational, and mechanistic evidence consistently demonstrates that FXI deficiency confers protection against venous thromboembolism and cardiovascular events while causing minimal spontaneous bleeding. This biological paradigm has catalyzed the development of novel FXI\/FXIa inhibitors, including small-molecule agents (asundexian, milvexian) and biological therapies (abelacimab). Clinical trials such as AXIOMATIC-TKR, PACIFIC-AF, and OCEANIC-AF, and ongoing programmes including ASTER and MAGNOLIA suggest that FXI inhibition may preserve antithrombotic efficacy while substantially reducing bleeding risk. This review summarizes the current landscape of oral FXa inhibitors, outlines the biological rationale for FXI\/FXIa inhibition, and discusses the evolving clinical evidence supporting what may represent the next major advance in anticoagulant therapy.<\/jats:p>","DOI":"10.3390\/pharmacy14010019","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T15:41:56Z","timestamp":1769528516000},"page":"19","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Direct Oral Anti-Xa Anticoagulants and the Future of Factor XI\/FXIa Inhibition: A New Paradigm in Thrombosis Prevention"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4851-4276","authenticated-orcid":false,"given":"Francesca Futura","family":"Bernardi","sequence":"first","affiliation":[{"name":"Coordination of the Regional Healt System, General Directorate for Healt Protection, SIFO (\u201cSociet\u00e0 Italiana di Farmacia Ospedaliera e Dei Servizi Farmaceutici Delle Aziende Sanitarie\u201d) Campania Section, 80100 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Bianco","sequence":"additional","affiliation":[{"name":"Pozzuoli Hospital, SIFO (\u201cSociet\u00e0 Italiana di Farmacia Ospedaliera e Dei Servizi Farmaceutici Delle Aziende Sanitarie\u201d) Campania Section, 80100 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosaria","family":"Lanzillo","sequence":"additional","affiliation":[{"name":"University Hospital \u201cFederico II\u201d, SIFO (\u201cSociet\u00e0 Italiana di Farmacia Ospedaliera e Dei Servizi Farmaceutici Delle Aziende Sanitarie\u201d) Campania Section, 80100 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Diana","sequence":"additional","affiliation":[{"name":"Local Healt Unit, SIFO (\u201cSociet\u00e0 Italiana di Farmacia Ospedaliera e Dei Servizi Farmaceutici Delle Aziende Sanitarie\u201d) Campania Section, 80100 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Scarpato","sequence":"additional","affiliation":[{"name":"Monaldi Hospital, SIFO (\u201cSociet\u00e0 Italiana di Farmacia Ospedaliera e Dei Servizi Farmaceutici Delle Aziende Sanitarie\u201d) Campania Section, 80100 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Lalli","sequence":"additional","affiliation":[{"name":"Fatebenefratelli Hospital, SIFO (\u201cSociet\u00e0 Italiana di Farmacia Ospedaliera e Dei Servizi Farmaceutici Delle Aziende Sanitarie\u201d) Campania Section, 80100 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniello","family":"Corallo","sequence":"additional","affiliation":[{"name":"Local Healt Authority of Salerno, SIFO (\u201cSociet\u00e0 Italiana di Farmacia Ospedaliera e Dei Servizi Farmaceutici Delle Aziende Sanitarie\u201d) Campania Section, 84131 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7074-362X","authenticated-orcid":false,"given":"Consiglia","family":"Riccardi","sequence":"additional","affiliation":[{"name":"Regional Center of Pharmacovigilance and Pharmacoepidemiology, SIFO (\u201cSociet\u00e0 Italiana di Farmacia Ospedaliera e Dei Servizi Farmaceutici Delle Aziende Sanitarie\u201d) Campania Section, University of Campania Luigi Vanvitelly, 80100 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ugo","family":"Trama","sequence":"additional","affiliation":[{"name":"Coordination of the Regional Healt System, General Directorate for Healt Protection, SIFO (\u201cSociet\u00e0 Italiana di Farmacia Ospedaliera e Dei Servizi Farmaceutici Delle Aziende Sanitarie\u201d) Campania Section, 80100 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2812-8500","authenticated-orcid":false,"given":"Alessandro","family":"Perrella","sequence":"additional","affiliation":[{"name":"First Division of Infectious Disease, P.O. Cotugno, AO dei Colli, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Basaglia","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Parma University Hospital, 43125 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ada","family":"Maffettone","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, San Luca Vallo della Lucania, 84131 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8484-4598","authenticated-orcid":false,"given":"Pierpaolo","family":"Di Micco","sequence":"additional","affiliation":[{"name":"Interal Medicine Ward, \u201cP.O. Santa Maria delle Grazie\u201d, 80076 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0613-1074","authenticated-orcid":false,"given":"Carmine","family":"Siniscalchi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Parma University Hospital, 43125 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1161\/CIRCRESAHA.115.306841","article-title":"Global Burden of Thrombosis: Epidemiologic Aspects","volume":"118","author":"Wendelboe","year":"2016","journal-title":"Circ. 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