{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T07:05:11Z","timestamp":1789110311262,"version":"build-2803163510"},"reference-count":36,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,9,30]],"date-time":"2023-09-30T00:00:00Z","timestamp":1696032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health, Labor and Welfare of Japan","award":["21FC1008"],"award-info":[{"award-number":["21FC1008"]}]},{"name":"Ministry of Health, Labor and Welfare of Japan","award":["23fk0410037s0203"],"award-info":[{"award-number":["23fk0410037s0203"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["21FC1008"],"award-info":[{"award-number":["21FC1008"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["23fk0410037s0203"],"award-info":[{"award-number":["23fk0410037s0203"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Regular prophylactic therapy has become an increasingly common treatment for severe hemophilia. Therefore, hypercoagulability\u2014a potential risk factor of thrombosis\u2014is a cause for concern in hemophilic patients treated with a high dose of FVIII concentrate. In clot waveform analysis (CWA)-thrombin time (TT), a small amount of thrombin activates clotting factor VIII (FVIII) instead of fibrinogen, resulting in FVIII measurements using CWA-TT with a small amount of thrombin. Methods: The coagulation ability of patients treated with FVIII concentrate or emicizumab was evaluated using activated partial thromboplastin time (APTT), TT and a small amount of tissue factor-induced FIX activation assay (sTF\/FIXa) using CWA. Results: The FVIII activity based on CWA-TT was significantly greater than that based on the CWA-APTT or chromogenic assay. FVIII or FVIII-like activities based on the three assays in plasma without emicizumab were closely correlated; those in plasma with emicizumab based on CWA-TT and chromogenic assays were also closely correlated. CWA-APTT and CWA-TT showed different patterns in patients treated with FVIII concentrates compared to those treated with emicizumab. In particular, CWA-TT in patients treated with FVIII concentrate showed markedly higher peaks in platelet-rich plasma than in platelet-poor plasma. CWA-APTT showed lower coagulability in hemophilic patients treated with FVIII concentrate than in healthy volunteers, whereas CWA-sTF\/FIXa did not. In contrast, CWA-TT showed hypercoagulability in hemophilic patients treated with FVIII concentrate. Conclusions: CWA-TT can be used to evaluate the thrombin bursts that cause hypercoagulability in patients treated with emicizumab. Although routine APTT evaluations demonstrated low coagulation ability in patients treated with FVIII concentrate, CWA-TT showed hypercoagulability in these patients, suggesting that the evaluation of coagulation ability may be useful when using multiple assays.<\/jats:p>","DOI":"10.3390\/jcm12196320","type":"journal-article","created":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T04:39:30Z","timestamp":1696221570000},"page":"6320","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Evaluation of Clot Waveform Analyses for Assessing Hypercoagulability in Patients Treated with Factor VIII Concentrate"],"prefix":"10.3390","volume":"12","author":[{"given":"Takeshi","family":"Matsumoto","sequence":"first","affiliation":[{"name":"Department of Transfusion Medicine and Cell Therapy, Mie University Hospital, Tsu 514-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9021-8633","authenticated-orcid":false,"given":"Hideo","family":"Wada","sequence":"additional","affiliation":[{"name":"Department of General and Laboratory Medicine, Mie Prefectural General Medical Center, Yokkaichi 510-0885, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuya","family":"Shiraki","sequence":"additional","affiliation":[{"name":"Department of General and Laboratory Medicine, Mie Prefectural General Medical Center, Yokkaichi 510-0885, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Suzuki","sequence":"additional","affiliation":[{"name":"The Emergency and Critical Care Center, Mie University Hospital, Tsu 514-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiki","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu 514-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5426-9422","authenticated-orcid":false,"given":"Isao","family":"Tawara","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu 514-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideto","family":"Shimpo","sequence":"additional","affiliation":[{"name":"Mie Prefectural General Medical Center, Yokkaichi 510-0885, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motomu","family":"Shimaoka","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu 514-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,30]]},"reference":[{"key":"ref_1","first-page":"583","article-title":"Treatment of haemophilia: From replacement to gene therapy","volume":"157","year":"2021","journal-title":"Med. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1053\/j.seminhematol.2015.10.006","article-title":"Factor VIII\/factor IX prophylaxis for severe hemophilia","volume":"53","author":"Carcao","year":"2016","journal-title":"Semin. Hematol."},{"key":"ref_3","unstructured":"National Hemophilia Foundation (2023, June 22). MASAC Document 267-MASAC Recommendation Concerning Prophylaxis for Hemophilia A and B with and without Inhibitors. Available online: http:\/\/www.hemophilia.org\/NHFWeb\/MainPgs\/MainNHF.aspx?menuid=57&contentid=1007."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1056\/NEJMoa067659","article-title":"Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia","volume":"357","author":"Abshire","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1365-2516.2009.02155.x","article-title":"Longer-acting factor VIII to overcome limitations in haemophilia management: The PEGylated liposomes formulation issue","volume":"16","author":"Cerbone","year":"2010","journal-title":"Haemophilia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1056\/NEJMoa2209226","article-title":"Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia, A","volume":"388","author":"Chowdary","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/s40265-023-01866-9","article-title":"Efanesoctocog Alfa: First Approval","volume":"83","author":"Keam","year":"2023","journal-title":"Drugs"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1056\/NEJMoa1703068","article-title":"Emicizumab Prophylaxis in Hemophilia A with Inhibito","volume":"377","author":"Oldenburg","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1056\/NEJMoa1803550","article-title":"Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors","volume":"379","author":"Mahlangu","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1111\/jth.14135","article-title":"Routine measurements of factor VIII activity and inhibitor titer in the presence of emicizumab utilizing anti-idiotype monoclonal antibodies","volume":"16","author":"Nogami","year":"2018","journal-title":"J. Thromb. Haemost."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1007\/978-1-0716-3175-1_39","article-title":"Chromogenic Factor VIII Assay for Patients with Hemophilia A and on Emicizumab Therapy","volume":"2663","author":"Yacoub","year":"2023","journal-title":"Methods Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1111\/jth.14784","article-title":"Laboratory testing in hemophilia: Impact of factor and non-factor replacement therapy on coagulation assays","volume":"18","author":"Peyvandi","year":"2020","journal-title":"Thromb. Haemost."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/hae.13907","article-title":"Laboratory measurement of factor replacement therapies in the treatment of congenital haemophilia: A United Kingdom Haemophilia Centre Doctors\u2019 Organisation guideline","volume":"26","author":"Gray","year":"2020","journal-title":"Haemophilia."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/ejh.13423","article-title":"Factor VIII and IX assays for post-infusion monitoring in hemophilia patients: Guidelines from the French BIMHO group (GFHT)","volume":"105","author":"Jeanpierre","year":"2020","journal-title":"Eur. J. Haematol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1076029620912027","DOI":"10.1177\/1076029620912027","article-title":"Update on the Clot Waveform Analysis","volume":"26","author":"Wada","year":"2020","journal-title":"Clin. Appl. Thromb. Hemost."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wada, H., Ichikawa, Y., Ezaki, E., Matsumoto, T., Yamashita, Y., Shiraki, K., Shimaoka, M., and Shimpo, H. (2021). The reevaluation of thrombin time using a clot waveform analysis. J. Clin. Med., 10.","DOI":"10.3390\/jcm10214840"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wada, H., Shiraki, K., Matsumoto, T., Suzuki, K., Yamashita, Y., Tawara, I., Shimpo, H., and Shimaoka, M. (2022). A Clot Waveform Analysis of Thrombin Time Using a Small Amount of Thrombin Is Useful for Evaluating the Clotting Activity of Plasma Independent of the Presence of Emicizumab. J. Clin. Med., 11.","DOI":"10.3390\/jcm11206142"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.thromres.2020.06.018","article-title":"Effects of platelet and phospholipids on clot formation activated by a small amount of tissue factor","volume":"193","author":"Wada","year":"2020","journal-title":"Thromb. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1111\/jth.14190","article-title":"Modified clot waveform analysis to measure plasma coagulation potential in the presence of the anti-factor IXa\/factor X bispecific antibody emicizumab: Comment","volume":"16","author":"Matsumoto","year":"2018","journal-title":"J. Thromb. Haemost."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/hae.14676","article-title":"Prophylaxis use of clotting factor replacement products in people with non-severe haemophilia: A review of the literature","volume":"29","author":"Iorio","year":"2023","journal-title":"Haemophilia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1111\/hae.14679","article-title":"Emicizumab dose up-titration in case of suboptimal bleeding control in people with haemophilia, A","volume":"29","author":"Schmitt","year":"2023","journal-title":"Haemophilia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/bjh.18379","article-title":"Current and future therapies for haemophilia-Beyond factor replacement therapies","volume":"200","author":"Nogami","year":"2023","journal-title":"Br. J. Haematol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2166334","DOI":"10.1080\/16078454.2023.2166334","article-title":"Expert opinion paper on the treatment of hemophilia a with emicizumab","volume":"28","author":"Coll","year":"2023","journal-title":"Hematology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/bs.acc.2022.12.001","article-title":"Emicizumab monitoring and impact on coagulation testing","volume":"113","author":"Nardi","year":"2023","journal-title":"Adv. Clin. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7615","DOI":"10.1038\/s41598-023-32143-0","article-title":"Platelet function suggests cardioembolic aetiology in cryptogenic stroke","volume":"13","author":"Dev","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1111\/j.1365-2141.2012.09134.x","article-title":"Elevated factor VIII levels and risk of venous thrombosis","volume":"157","author":"Jenkins","year":"2012","journal-title":"Br. J. Haematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.ejim.2014.12.015","article-title":"Factor V Leiden mutation and high FVIII are associated with an increased risk of VTE in women with breast cancer during adjuvant tamoxifen-results from a prospective, single center, case control study","volume":"26","author":"Kovac","year":"2015","journal-title":"Eur. J. Intern. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Badescu, M.C., Ciocoiu, M., Rezus, E., Badulescu, O.V., Tanase, D.M., Ouatu, A., Dima, N., Ganceanu-Rusu, A.R., Popescu, D., and Seritean Isac, P.N. (2021). Current Therapeutic Approach to Acute Myocardial Infarction in Patients with Congenital Hemophilia. Life, 11.","DOI":"10.3390\/life11101072"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.2217\/cer-2021-0120","article-title":"Estimating the risk of thrombotic events in people with congenital hemophilia A using US claims data","volume":"10","author":"Faghmous","year":"2021","journal-title":"J. Comp. Eff. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/ijlh.13335","article-title":"Impact of variation in reagent combinations for one-stage clotting assay on assay discrepancy in nonsevere haemophilia A","volume":"43","author":"Suzuki","year":"2021","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1111\/jth.15741","article-title":"Efanesoctocog alfa elicits functional clot formation that is indistinguishable to that of recombinant factor VIII","volume":"20","author":"Demers","year":"2022","journal-title":"Thromb. Haemost."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1080\/17474086.2023.2223925","article-title":"Efanesoctocog alfa for the prevention and treatment of bleeding in patients with hemophilia A","volume":"16","author":"Konkle","year":"2023","journal-title":"Expert. Rev. Hematol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1055\/s-0040-1716542","article-title":"Emicizumab Augments Thrombus Formation in Whole Blood from Patients with Hemophilia A under High Shear Flow Conditions","volume":"121","author":"Yaoi","year":"2021","journal-title":"Thromb. Haemost."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1007\/s12185-016-2108-x","article-title":"A combined approach using global coagulation assays quickly differentiates coagulation disorders with prolonged aPTT and low levels of FVIII activity","volume":"105","author":"Matsumoto","year":"2017","journal-title":"Int. J. Hematol."},{"key":"ref_35","first-page":"592","article-title":"Clot Waveform Analysis for Monitoring Hemostasis","volume":"49","author":"Nogami","year":"2022","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1161\/01.ATV.0000031340.68494.34","article-title":"Platelets and thrombin generation","volume":"22","author":"Monroe","year":"2002","journal-title":"Arterioscler. Thromb. Vasc. Biol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/19\/6320\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:03:17Z","timestamp":1760130197000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/19\/6320"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,30]]},"references-count":36,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["jcm12196320"],"URL":"https:\/\/doi.org\/10.3390\/jcm12196320","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,30]]}}}