{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T02:36:54Z","timestamp":1787798214478,"version":"build-2784847793"},"reference-count":42,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T00:00:00Z","timestamp":1725840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Direct oral anticoagulants (DOACs) are increasingly used for the treatment of thrombosis. While inhibitors of factor IIa and factor Xa have shown effectiveness, the risk of bleeding remains a significant concern. Recently, direct factor XIa inhibitors\u2014including asundexian and milvexian\u2014have emerged as potential anticoagulation therapies, based on clinical observations that patients with factor XIa deficiencies seldom present with spontaneous bleeding tendencies. The interferences associated with DOACs in routine and specialised coagulation assays are well-described; however, the interferences associated with emerging FXIa inhibitors are largely uncharacterised. Here, we briefly report the impact of asundexian and milvexian in routine coagulation assays using in vitro plasma-based systems. Asundexian and milvexian induce concentration-dependent prolongations in APTT-based assays with curvilinear regressions, which may be suitable for the measurement of pharmacodynamic effects at peak levels ex vivo. We also report differential sensitivities of APTT-based assays\u2014particularly at higher FXIa inhibitor concentrations\u2014highlighting the clinical need for an extensive evaluation of interferences associated with FXIa inhibitors in coagulation assays.<\/jats:p>","DOI":"10.3390\/diagnostics14171991","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T05:59:08Z","timestamp":1725861548000},"page":"1991","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Laboratory Evaluation of Interferences Associated with Factor XIa Inhibitors Asundexian and Milvexian in Routine Coagulation Assays"],"prefix":"10.3390","volume":"14","author":[{"given":"Gavin T.","family":"Buckley","sequence":"first","affiliation":[{"name":"Department of Haematology, Cork University Hospital, Wilton, T12 DC4A Cork, Ireland"},{"name":"EOLAS Research Group, Cork University Hospital, Wilton, T12 DC4A Cork, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2245-1227","authenticated-orcid":false,"given":"Maeve P.","family":"Crowley","sequence":"additional","affiliation":[{"name":"Department of Haematology, Cork University Hospital, Wilton, T12 DC4A Cork, Ireland"},{"name":"EOLAS Research Group, Cork University Hospital, Wilton, T12 DC4A Cork, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3817-3658","authenticated-orcid":false,"given":"James V.","family":"Harte","sequence":"additional","affiliation":[{"name":"Department of Haematology, Cork University Hospital, Wilton, T12 DC4A Cork, Ireland"},{"name":"EOLAS Research Group, Cork University Hospital, Wilton, T12 DC4A Cork, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2137288","DOI":"10.1001\/jamanetworkopen.2021.37288","article-title":"Clinician Trends in Prescribing Direct Oral Anticoagulants for US Medicare Beneficiaries","volume":"4","author":"Wheelock","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e234059","DOI":"10.1001\/jamanetworkopen.2023.4059","article-title":"Trends in the Use of Oral Anticoagulants for Adults with Venous Thromboembolism in the US, 2010\u20132020","volume":"6","author":"Iyer","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1056\/NEJMoa1107039","article-title":"Apixaban versus Warfarin in Patients with Atrial Fibrillation","volume":"365","author":"Granger","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1056\/NEJMoa1310907","article-title":"Edoxaban versus Warfarin in Patients with Atrial Fibrillation","volume":"369","author":"Giugliano","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1056\/NEJMoa1009638","article-title":"Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation","volume":"365","author":"Patel","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.7326\/M21-1094","article-title":"Long-Term Risk for Major Bleeding during Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism","volume":"174","author":"Khan","year":"2021","journal-title":"Ann. Intern. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.1111\/jth.15415","article-title":"Risks Associated with Discontinuation of Oral Anticoagulation in Newly Diagnosed Patients with Atrial Fibrillation: Results from the GARFIELD-AF Registry","volume":"19","author":"Cools","year":"2021","journal-title":"J. Thromb. Haemost."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1055\/s-0037-1615947","article-title":"A Cell-based Model of Hemostasis","volume":"85","author":"Hoffman","year":"2001","journal-title":"Thromb. Haemost."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41572-021-00278-x","article-title":"Haemophilia","volume":"7","author":"Berntorp","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.jacc.2021.06.010","article-title":"Factor XI Inhibition to Uncouple Thrombosis from Hemostasis","volume":"78","author":"Hsu","year":"2021","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1111\/j.1538-7836.2012.04653.x","article-title":"Coagulation Factor Activity and Clinical Bleeding Severity in Rare Bleeding Disorders: Results from the European Network of Rare Bleeding Disorders","volume":"10","author":"Peyvandi","year":"2012","journal-title":"J. Thromb. Haemost."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1182\/blood.2023020721","article-title":"Factor XI deficiency: Phenotypic Age-Related Considerations and Clinical Approach towards Bleeding Risk Assessment","volume":"143","author":"Barg","year":"2024","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1182\/blood-2016-09-742262","article-title":"Factor XI Deficiency Is Associated with Lower Risk for Cardiovascular and Venous Thromboembolism Events","volume":"129","author":"Preis","year":"2017","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1056\/NEJM200003093421004","article-title":"High Levels of Coagulation Factor XI as a Risk Factor for Venous Thrombosis","volume":"342","author":"Meijers","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/S1474-4422(23)00403-9","article-title":"Safety and Efficacy of Factor XIa Inhibition with Milvexian for Secondary Stroke Prevention (AXIOMATIC-SSP): A Phase 2, International, Randomised, Double-Blind, Placebo-Controlled, Dose-Finding Trial","volume":"23","author":"Sharma","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1056\/NEJMoa2113194","article-title":"Milvexian for the Prevention of Venous Thromboembolism","volume":"385","author":"Weitz","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1161\/CIRCULATIONAHA.122.061612","article-title":"A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction","volume":"146","author":"Rao","year":"2022","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/S0140-6736(22)01588-4","article-title":"Factor XIa Inhibition with Asundexian after Acute Non-Cardioembolic Ischaemic Stroke (PACIFIC-Stroke): An International, Randomised, Double-Blind, Placebo-Controlled, Phase 2b Trial","volume":"400","author":"Shoamanesh","year":"2022","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1016\/S0140-6736(22)00456-1","article-title":"Safety of the Oral Factor XIa Inhibitor Asundexian Compared with Apixaban in Patients with Atrial Fibrillation (PACIFIC-AF): A Multicentre, Randomised, Double-Blind, Double-Dummy, Dose-Finding Phase 2 Study","volume":"399","author":"Piccini","year":"2022","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"598","DOI":"10.2174\/1389200218666170417124035","article-title":"Laboratory Monitoring or Measurement of Direct Oral Anticoagulants (DOACs): Advantages, Limitations and Future Challenges","volume":"18","author":"Favaloro","year":"2017","journal-title":"Curr. Drug Metab."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Dunois, C. (2021). Laboratory Monitoring of Direct Oral Anticoagulants (DOACs). Biomedicines, 9.","DOI":"10.3390\/biomedicines9050445"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10760296241241524","DOI":"10.1177\/10760296241241524","article-title":"Challenges to Laboratory Monitoring of Direct Oral Anticoagulants","volume":"30","author":"Qiao","year":"2024","journal-title":"Clin. Appl. Thromb."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1160\/TH10-06-0342","article-title":"Effects of the Oral, Direct Thrombin Inhibitor Dabigatran on Five Common Coagulation Assays","volume":"105","author":"Lindahl","year":"2011","journal-title":"Thromb. Haemost."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1111\/jth.12649","article-title":"Effects of the Oral, Direct Factor Xa Inhibitor Apixaban on Routine Coagulation Assays and Anti-FXa Assays","volume":"12","author":"Hillarp","year":"2014","journal-title":"J. Thromb. Haemost."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1111\/j.1538-7836.2010.04098.x","article-title":"Effects of the Oral, Direct Factor Xa Inhibitor Rivaroxaban on Commonly Used Coagulation Assays","volume":"9","author":"Hillarp","year":"2011","journal-title":"J. Thromb. Haemost."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1080\/00365513.2018.1522664","article-title":"Effects of the Oral, Direct Factor Xa Inhibitor Edoxaban on Routine Coagulation Assays, Lupus Anticoagulant and Anti-Xa Assays","volume":"78","author":"Hillarp","year":"2018","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1111\/cts.13148","article-title":"First-in-Human Study of Milvexian, an Oral, Direct, Small Molecule Factor XIa Inhibitor","volume":"15","author":"Perera","year":"2022","journal-title":"Clin. Transl. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3447","DOI":"10.1111\/bcp.15230","article-title":"Pharmacokinetics, Pharmacodynamics and Safety of BAY 2433334, a Novel Activated Factor XI Inhibitor, in Healthy Volunteers: A Randomized Phase 1 Multiple-Dose Study","volume":"88","author":"Kubitza","year":"2022","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1182\/hematology.2021000241","article-title":"Direct Oral Anticoagulant (DOAC) Interference in Hemostasis Assays","volume":"2021","author":"Moser","year":"2021","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1093\/ajcp\/aqac013","article-title":"An Analysis of the Sensitivity of the Activated Partial Thromboplastin Time (APTT) Assay, as Used in a Large Laboratory Network, to Coagulation Factor Deficiencies","volume":"158","author":"Do","year":"2022","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"022","DOI":"10.1055\/s-0038-1677018","article-title":"How to Optimize Activated Partial Thromboplastin Time (APTT) Testing: Solutions to Establishing and Verifying Normal Reference Intervals and Assessing APTT Reagents for Sensitivity to Heparin, Lupus Anticoagulant, and Clotting Factors","volume":"45","author":"Favaloro","year":"2019","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1007\/s40262-022-01110-9","article-title":"Single-Dose Pharmacokinetics of Milvexian in Participants with Mild or Moderate Hepatic Impairment Compared with Healthy Participants","volume":"61","author":"Perera","year":"2022","journal-title":"Clin. Pharmacokinet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s13318-023-00838-4","article-title":"Metabolism and Disposition of the Novel Oral Factor XIa Inhibitor Asundexian in Rats and in Humans","volume":"48","author":"Piel","year":"2023","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Perera, V., Wang, Z., Lubin, S., Christopher, L.J., Chen, W., Xu, S., Seiffert, D., DeSouza, M., and Murthy, B. (2022). Effects of Rifampin on the Pharmacokinetics and Pharmacodynamics of Milvexian, a Potent, Selective, Oral Small Molecule Factor XIa Inhibitor. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-25936-2"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1160\/TH12-12-0898","article-title":"Impact of Apixaban on Routine and Specific Coagulation Assays: A Practical Laboratory Guide","volume":"110","author":"Douxfils","year":"2013","journal-title":"Thromb. Haemost."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1160\/th15-05-0415","article-title":"Edoxaban: Impact on Routine and Specific Coagulation Assays. A Practical Laboratory Guide","volume":"115","author":"Douxfils","year":"2016","journal-title":"Thromb. Haemost."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1055\/s-0038-1657772","article-title":"Betrixaban: Impact on Routine and Specific Coagulation Assays\u2014A Practical Laboratory Guide","volume":"118","author":"Siriez","year":"2018","journal-title":"Thromb. Haemost."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1160\/TH11-11-0804","article-title":"Impact of Dabigatran on a Large Panel of Routine or Specific Coagulation Assays","volume":"107","author":"Douxfils","year":"2012","journal-title":"Thromb. Haemost."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/j.thromres.2012.09.004","article-title":"Assessment of the Impact of Rivaroxaban on Coagulation Assays: Laboratory Recommendations for the Monitoring of Rivaroxaban and Review of the Literature","volume":"130","author":"Douxfils","year":"2012","journal-title":"Thromb. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1055\/s-0038-1661531","article-title":"The Reliability of Activated Partial Thromboplastin Time Methods and the Relationship to Lipid Composition and Ultrastructure","volume":"55","author":"Stevenson","year":"1986","journal-title":"Thromb. Haemost."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1046\/j.1365-2257.1998.00122.x","article-title":"Assessment of Actin FS and Actin FSL Sensitivity to Specific Clotting Factor Deficiencies","volume":"20","author":"Lawrie","year":"1998","journal-title":"Clin. Lab. Haematol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1111\/ijlh.12528","article-title":"Comparison of the Effect of the Anti-Xa Direct Oral Anticoagulants Apixaban, Edoxaban, and Rivaroxaban on Coagulation assays","volume":"38","author":"Gosselin","year":"2016","journal-title":"Int. J. Lab. Hematol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/14\/17\/1991\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:52:04Z","timestamp":1760111524000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/14\/17\/1991"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,9]]},"references-count":42,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["diagnostics14171991"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics14171991","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,9]]}}}