{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T07:03:31Z","timestamp":1792047811250,"version":"4.4.0"},"reference-count":81,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Factor XII (FXII) is a central mediator at the intersection of coagulation, fibrinolysis, inflammation, and immunity. It is activated upon contact with negatively charged surfaces, triggering the intrinsic coagulation pathway and driving thrombus formation and stabilization. Beyond clotting, FXII contributes to activation of the kallikrein\u2013kinin system, generation of bradykinin, and modulation of inflammatory and immune responses. Congenital FXII deficiency does not increase bleeding risk, highlighting its unique role and making FXII inhibition an attractive strategy for anticoagulation and immune modulation with a potentially superior safety profile. Preclinical studies provide compelling evidence for this concept. In models of ischemic stroke and traumatic brain injury, FXII blockade significantly reduced infarct volume, improved neurological outcomes, and attenuated neuroinflammation without increasing hemorrhage. Similarly, in extracorporeal circulation and vascular stent implantation, FXII inhibition prevented thrombus formation and reduced fibrin deposition, achieving effects comparable to heparin but with markedly lower bleeding risk. Several classes of FXII inhibitors are currently in development, including antisense oligonucleotides, peptides, recombinant proteins, and monoclonal antibodies. Among them, Ixodes ricinus contact phase inhibitor (Ir-CPI) and recombinant human albumin-fused Infestin-4 (rHA-Infestin-4) have demonstrated strong antithrombotic efficacy in animal models. Most notably, garadacimab, a monoclonal anti-FXIIa antibody, has completed phase 3 trials and received regulatory approval for hereditary angioedema (HAE) prophylaxis, where it markedly reduces attack frequency with a favorable safety profile. This review summarizes current knowledge on FXII biology and evaluates its translational potential as a novel target for anticoagulant and anti-inflammatory therapies.<\/jats:p>","DOI":"10.3390\/ijms27073336","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T14:00:31Z","timestamp":1775570431000},"page":"3336","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Factor XII in Thrombosis and Thromboinflammation: From Molecular Biology to Clinical Translation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7315-7485","authenticated-orcid":false,"given":"Jan","family":"St\u0119pnicki","sequence":"first","affiliation":[{"name":"Department of Internal Medicine & Cardiology with the Centre for Management of Venous Thromboembolic Disease, Medical University of Warsaw, 02-005 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.","family":"Imiela","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine & Cardiology with the Centre for Management of Venous Thromboembolic Disease, Medical University of Warsaw, 02-005 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Szyma\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine & Cardiology with the Centre for Management of Venous Thromboembolic Disease, Medical University of Warsaw, 02-005 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakub","family":"Miko\u0142ajczuk","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine & Cardiology with the Centre for Management of Venous Thromboembolic Disease, Medical University of Warsaw, 02-005 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9768-0000","authenticated-orcid":false,"given":"Piotr","family":"Pruszczyk","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine & Cardiology with the Centre for Management of Venous Thromboembolic Disease, Medical University of Warsaw, 02-005 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1002\/rth2.12235","article-title":"Factor XII\u2014What\u2019s important but not commonly thought about","volume":"3","author":"Schmaier","year":"2019","journal-title":"Res. 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