{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:11:45Z","timestamp":1790914305156,"version":"4.1.0"},"reference-count":47,"publisher":"Georg Thieme Verlag KG","issue":"01","funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"crossref","award":["21K07804"],"award-info":[{"award-number":["21K07804"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"crossref","award":["22K15928"],"award-info":[{"award-number":["22K15928"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Thromb Haemost"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>\n            Background\u2003Bypassing agents are used for breakthrough bleedings in patients with hemophilia A with inhibitor (PwHAwI) receiving emicizumab prophylaxis. Previous study demonstrated a weak binding affinity between emicizumab and factor (F)X (K\n            d; 1.85 \u03bcM), and that this value was much greater than the plasma FX concentration (\u223c130\u2009nM). We speculated that increased FX levels could enhance coagulation potential in emicizumab-treated patients with hemophilia A (PwHA). To investigate the relationship between FX concentrations and emicizumab-driven coagulation.<\/jats:p><jats:p>\n            Methods\u2003Plasma FX (up to 1,040\u2009nM) and emicizumab (50 \u00b5g\/mL) were added to FVIII-deficient plasmas, and plasma-derived FX (520\u2009nM) or recombinant (r)FVIIa (2.2 \u00b5g\/mL) was added to plasmas from three emicizumab-treated PwHAwI. The adjusted maximum coagulation velocity (Ad|min1|) by clot waveform analysis and peak thrombin (PeakTh) by thrombin generation assay in them were evaluated. Emicizumab (3.0\u2009mg\/kg), human (h)FIX (100\u2009IU\/kg), and various doses of hFX (100\u2013500\u2009IU\/kg) were intravenously administered to HA mice. Clotting time\/clot formation time (CT\/CFT) were assessed using rotational thromboelastometry, and blood loss was estimated by a tail-clip assay.<\/jats:p><jats:p>\n            Results\u2003The addition of FX to FVIII-deficient plasma with emicizumab increased Ad|min1| and PeakTh. The coagulation parameters in emicizumab-treated PwHAwI spiked with additional FX remained within the normal range as well as the additional rFVIIa. In animal models, hFX injection shortened the CT and CT\u2009+\u2009CFT. The shorter CT and CT\u2009+\u2009CFT, and the lower blood loss were evident after 200 or 500\u2009IU\/kg hFX administration, and those indices were comparable to those in wild-type mice.<\/jats:p><jats:p>\n            Conclusion\u2003Supplementation with FX may improve emicizumab-driven hemostasis in PwHA.<\/jats:p>","DOI":"10.1055\/a-2315-8199","type":"journal-article","created":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T22:31:05Z","timestamp":1714257065000},"page":"021-032","source":"Crossref","is-referenced-by-count":9,"title":["Additional Factor X Enhances Emicizumab-Driven Coagulation Function in Patients with Hemophilia A and Hemophilia A Mice"],"prefix":"10.1055","volume":"125","author":[{"given":"Kazuki","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuto","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan"},{"name":"Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eisuke","family":"Takami","sequence":"additional","affiliation":[{"name":"Medical Affairs Section, KM Biologics Co., Ltd, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotoshi","family":"Nakano","sequence":"additional","affiliation":[{"name":"Medical Affairs Section, KM Biologics Co., Ltd, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiji","family":"Nogami","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2024,5,15]]},"reference":[{"issue":"03","key":"ref1","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1056\/NEJMoa1208024","article-title":"Factor VIII products and inhibitor development in severe hemophilia A","volume":"368","author":"S C Gouw","year":"2013","journal-title":"N Engl J Med"},{"issue":"S 01","key":"ref2","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1160\/TH16-01-0049","article-title":"The burden of inhibitors in haemophilia patients","volume":"116","author":"C E Walsh","year":"2016","journal-title":"Thromb Haemost"},{"issue":"01","key":"ref3","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/j.1365-2516.2006.01403.x","article-title":"Current use of by-passing agents in Europe in the management of acute bleeds in patients with haemophilia and inhibitors","volume":"13","author":"J Astermark","year":"2007","journal-title":"Haemophilia"},{"issue":"01","key":"ref4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1365-2516.2008.01931.x","article-title":"Differential response to bypassing agents complicates treatment in patients with haemophilia and inhibitors","volume":"15","author":"E Berntorp","year":"2009","journal-title":"Haemophilia"},{"issue":"05","key":"ref5","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1007\/s12185-014-1572-4","article-title":"Tissue factor pathway inhibitor in activated prothrombin complex concentrates (aPCC) moderates the effectiveness of therapy in some severe hemophilia A patients with inhibitor","volume":"99","author":"K Ogiwara","year":"2014","journal-title":"Int J Hematol"},{"issue":"04","key":"ref6","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1111\/j.0042-9007.2003.00365.x","article-title":"A novel therapeutic approach combining human plasma-derived Factors VIIa and X for haemophiliacs with 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Shirahata","year":"2013","journal-title":"Haemophilia"},{"issue":"01","key":"ref9","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/hae.13050","article-title":"A phase III clinical trial of a mixture agent of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors","volume":"23","author":"Y Shinkoda","year":"2017","journal-title":"Haemophilia"},{"issue":"10","key":"ref10","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1038\/nm.2942","article-title":"A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model","volume":"18","author":"T Kitazawa","year":"2012","journal-title":"Nat Med"},{"issue":"02","key":"ref11","doi-asserted-by":"crossref","first-page":"e57479","DOI":"10.1371\/journal.pone.0057479","article-title":"Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor 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