{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T23:18:19Z","timestamp":1787872699068,"version":"build-2784847793"},"reference-count":38,"publisher":"Georg Thieme Verlag KG","issue":"09","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Thromb Haemost"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:p>Congenital fibrinogen deficiencies are rare coagulopathies which are treated by fibrinogen concentrates. This trial investigated the pharmacokinetic\/pharmacodynamic (PK\/PD) parameters, and surrogate efficacy and safety of a new human fibrinogen concentrate (HFC), BT524, in patients with congenital afibrinogenemia or severe hypofibrinogenemia.<\/jats:p>\n                  <jats:p>This prospective, multi-national, open-label, single-arm PK\/PD trial evaluated PK\/PD parameters of HFC (part 1; phase I) and HFC as on-demand treatment or prophylaxis for bleeding events (part 2; phase III). In part 1, patients received a single-dose of HFC (70\u2009mg\/kg body weight [BW]). PK\/PD parameters were calculated using a PK\/PD model and non-compartmental analysis. Fibrinogen antigen (FiAg) levels were determined over 14 days by immunonephelometry and fibrinogen activity (FiAc) by Clauss assay. The efficacy variable was mean change in maximum clot firmness (MCF) analyzed by thromboelastometry. Safety parameters were evaluated for 49 days.<\/jats:p>\n                  <jats:p>A total of 27 patients (n\u2009=\u200915 adults, n\u2009=\u200912 children) were treated with HFC. For FiAg, mean (SD) PK parameters were: Cmax 1.81 (0.42) g\/L, AUC0-\u221e 173 (45.4) g*h\/L, and t1\/2 67.9 (15.3) h. For FiAc, they were Cmax 1.26 (0.4) g\/L, AUC0-\u221e 104 (33.5) g*h\/L, and t1\/2 60.3 (13.3) h. In adults, MCF significantly increased 1\u2009h after HFC infusion (11.1 (5.1) mm; P\u2009&lt;\u20090.0001; 95% CI: 9.33\u201314.47). In pediatrics, mean increase in range was 9.3 to 16.5\u2009mm. Treatment-related adverse events were rare, with one mild increase in fibrin D-dimer. No thromboembolic events, hypersensitivity, or allergic reactions were observed.<\/jats:p>\n                  <jats:p>HFC effectively increased FiAg levels and FiAc, improved clot firmness, and showed a favorable safety and tolerability profile in adult and pediatric patients with congenital fibrinogen deficiency.<\/jats:p>","DOI":"10.1055\/a-2715-2994","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T22:57:38Z","timestamp":1760741858000},"page":"919-929","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacokinetics, Hemostatic Efficacy, and Safety of a New Human Fibrinogen Concentrate in Adult and Pediatric Patients with Congenital Fibrinogen Deficiency"],"prefix":"10.1055","volume":"126","author":[{"given":"Claudia","family":"Djambas Khayat","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hotel Dieu de France Hospital Beirut, Saint Joseph University, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal","family":"El-Beshlawy","sequence":"additional","affiliation":[{"name":"Pediatric Hospital CU, Egyptian Thalassemia Association, El Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balkis","family":"Meddeb","sequence":"additional","affiliation":[{"name":"Hospital Aziza Othmana, Tunis, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abderrahim","family":"Khelif","sequence":"additional","affiliation":[{"name":"Hospital Farhat Hached, Faculte de Medecine Ibn El Jazzar, Sousse University, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4506-0061","authenticated-orcid":false,"given":"Wolfgang","family":"Miesbach","sequence":"additional","affiliation":[{"name":"Department of Haemostasis\/Haemophilia Centre, Medical Clinic 2, University Hospital Frankfurt, Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Adolf","sequence":"additional","affiliation":[{"name":"National Research Center, Pediatric Hematology Department, El Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Boehm","sequence":"additional","affiliation":[{"name":"Biotest AG, Dreieich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Aigner","sequence":"additional","affiliation":[{"name":"Biotest AG, Dreieich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salomon","family":"Abraha","sequence":"additional","affiliation":[{"name":"Biotest AG, Dreieich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Bohlaender","sequence":"additional","affiliation":[{"name":"Biotest AG, Dreieich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Schuettrumpf","sequence":"additional","affiliation":[{"name":"Biotest AG, Dreieich, Germany"},{"name":"Grifols, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"issue":"S 01","key":"ref1","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/jth.12229","article-title":"Fibrin(ogen) and thrombotic disease","volume":"11","author":"R A Ari\u00ebns","year":"2013","journal-title":"J Thromb Haemost"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/bs.acc.2024.03.004","article-title":"Fibrinogen: structure, abnormalities and laboratory assays","volume":"120","author":"B G\u00fcven","year":"2024","journal-title":"Adv Clin Chem"},{"issue":"08","key":"ref3","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1111\/j.1538-7836.2005.01365.x","article-title":"Fibrinogen and fibrin structure and functions","volume":"3","author":"M W Mosesson","year":"2005","journal-title":"J Thromb Haemost"},{"issue":"09","key":"ref4","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1111\/jth.14216","article-title":"Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH","volume":"16","author":"A Casini","year":"2018","journal-title":"J Thromb Haemost"},{"issue":"08","key":"ref5","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1055\/s-0042-1756187","article-title":"One hundred years of congenital fibrinogen disorders","volume":"48","author":"A Casini","year":"2022","journal-title":"Semin Thromb Hemost"},{"issue":"04","key":"ref6","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1111\/jth.14727","article-title":"Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients","volume":"18","author":"T Lissitchkov","year":"2020","journal-title":"J Thromb Haemost"},{"issue":"11","key":"ref7","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.3390\/diagnostics11112140","article-title":"Congenital afibrinogenemia and hypofibrinogenemia: laboratory and genetic testing in rare bleeding disorders with life-threatening clinical manifestations and challenging management","volume":"11","author":"T Simurda","year":"2021","journal-title":"Diagnostics (Basel)"},{"issue":"06","key":"ref8","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1111\/j.1365-2516.2008.01831.x","article-title":"Rare inherited disorders of fibrinogen","volume":"14","author":"S S Acharya","year":"2008","journal-title":"Haemophilia"},{"issue":"06","key":"ref9","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1055\/s-0033-1349222","article-title":"Congenital fibrinogen disorders: an update","volume":"39","author":"P de Moerloose","year":"2013","journal-title":"Semin Thromb Hemost"},{"issue":"02","key":"ref10","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1055\/s-0041-1732467","article-title":"The role of fibrin(ogen) in wound healing and infection control","volume":"48","author":"K J Kearney","year":"2022","journal-title":"Semin Thromb Hemost"},{"issue":"22","key":"ref11","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.1182\/blood.2020009472","article-title":"Clinical phenotype, fibrinogen supplementation, and health-related quality of life in patients with afibrinogenemia","volume":"137","author":"A Casini","year":"2021","journal-title":"Blood"},{"issue":"09","key":"ref12","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1111\/j.1538-7836.2011.04424.x","article-title":"Fibrinogen replacement therapy for congenital fibrinogen deficiency","volume":"9","author":"L Bornikova","year":"2011","journal-title":"J Thromb Haemost"},{"issue":"05","key":"ref13","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1111\/trf.12431","article-title":"Fibrinogen as a therapeutic target for bleeding: a review of critical levels and replacement therapy","volume":"54","author":"J H Levy","year":"2014","journal-title":"Transfusion"},{"issue":"08","key":"ref14","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1182\/blood.2024025712","article-title":"How I treat quantitative fibrinogen disorders","volume":"145","author":"A Casini","year":"2025","journal-title":"Blood"},{"issue":"02","key":"ref15","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.tmrv.2019.10.005","article-title":"Selection of blood, blood components, and blood products as essential medicines in 105 low- and middle-income countries","volume":"34","author":"W T Samukange","year":"2020","journal-title":"Transfus Med Rev"},{"issue":"S 02","key":"ref16","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1016\/S0049-3848(13)70004-5","article-title":"Epidemiology and treatment of congenital fibrinogen deficiency","volume":"130","author":"F Peyvandi","year":"2012","journal-title":"Thromb Res"},{"issue":"10","key":"ref17","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1517\/14712590903193051","article-title":"Fibrinogen concentrate\u2014a potential universal hemostatic agent","volume":"9","author":"C Fenger-Eriksen","year":"2009","journal-title":"Expert Opin Biol Ther"},{"issue":"04","key":"ref18","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1160\/TH14-06-0514","article-title":"Safety of fibrinogen concentrate: analysis of more than 27 years of pharmacovigilance data","volume":"113","author":"C Solomon","year":"2015","journal-title":"Thromb Haemost"},{"issue":"12","key":"ref21","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1111\/j.1538-7836.2009.03633.x","article-title":"Pharmacokinetics and safety of fibrinogen concentrate","volume":"7","author":"M J Manco-Johnson","year":"2009","journal-title":"J Thromb Haemost"},{"issue":"03","key":"ref22","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1213\/ane.0b013e3181966675","article-title":"The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia","volume":"108","author":"T Lang","year":"2009","journal-title":"Anesth Analg"},{"issue":"07","key":"ref23","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1080\/00365513.2020.1818283","article-title":"FIBTEM clot firmness parameters correlate well with the fibrinogen concentration measured by the Clauss assay in patients and healthy subjects","volume":"80","author":"J J de Vries","year":"2020","journal-title":"Scand J Clin Lab Invest"},{"issue":"07","key":"ref24","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s00228-008-0493-7","article-title":"How many subjects are necessary for population pharmacokinetic experiments? Confidence interval approach","volume":"64","author":"K Ogungbenro","year":"2008","journal-title":"Eur J Clin Pharmacol"},{"issue":"06","key":"ref25","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1111\/hae.14619","article-title":"Analysis of fibrinogen concentrate pharmacokinetics and dosing for bleeds and surgery in adults, adolescents, and children with congenital afibrinogenaemia and hypofibrinogenaemia","volume":"28","author":"C Djambas Khayat","year":"2022","journal-title":"Haemophilia"},{"issue":"01","key":"ref26","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1097\/MBC.0000000000001182","article-title":"Pharmacokinetics, efficacy and safety of a novel fibrinogen concentrate in pediatric patients with congenital afibrinogenemia","volume":"34","author":"C D Khayat","year":"2023","journal-title":"Blood Coagul Fibrinolysis"},{"issue":"02","key":"ref27","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/jth.13923","article-title":"Pharmacokinetics, clot strength and safety of a new fibrinogen concentrate: randomized comparison with active control in congenital fibrinogen deficiency","volume":"16","author":"C Ross","year":"2018","journal-title":"J Thromb Haemost"},{"issue":"06","key":"ref28","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1055\/s-0040-1710015","article-title":"Pharmacology, efficacy and safety of a triple-secured fibrinogen concentrate in children less than or equal to 12 years with afibrinogenaemia","volume":"120","author":"C Djambas Khayat","year":"2020","journal-title":"Thromb Haemost"},{"issue":"04","key":"ref29","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1111\/jth.14392","article-title":"Clinical pharmacology, efficacy and safety study of a triple-secured fibrinogen concentrate in adults and adolescent patients with congenital fibrinogen deficiency","volume":"17","author":"C Djambas Khayat","year":"2019","journal-title":"J Thromb Haemost"},{"issue":"02","key":"ref30","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/hae.14230","article-title":"Efficacy and safety of fibrinogen concentrate for on-demand treatment of bleeding and surgical prophylaxis in paediatric patients with congenital fibrinogen deficiency","volume":"27","author":"C Djambas Khayat","year":"2021","journal-title":"Haemophilia"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.thromres.2020.12.026","article-title":"Pharmacokinetics, surrogate efficacy and safety evaluations of a new human plasma-derived fibrinogen concentrate (FIB Grifols) in adult patients with congenital afibrinogenemia","volume":"199","author":"C R Ross","year":"2021","journal-title":"Thromb Res"},{"issue":"01","key":"ref32","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1111\/ijlh.14201","article-title":"International council for standardisation in haematology recommendations on fibrinogen assays, thrombin clotting time and related tests in the investigation of bleeding disorders","volume":"46","author":"I Mackie","year":"2024","journal-title":"Int J Lab Hematol"},{"issue":"02","key":"ref34","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1111\/bcp.14147","article-title":"Population pharmacokinetics of a triple-secured fibrinogen concentrate administered to afibrinogenaemic patients: observed age- and body weight-related differences and consequences for dose adjustment in children","volume":"86","author":"A Bellon","year":"2020","journal-title":"Br J Clin Pharmacol"},{"issue":"09","key":"ref35","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.1002\/jps.23574","article-title":"A pharmacokinetic standard for babies and adults","volume":"102","author":"N Holford","year":"2013","journal-title":"J Pharm Sci"},{"issue":"04","key":"ref36","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s10238-017-0454-5","article-title":"The use of frozen plasma samples in thromboelastometry","volume":"17","author":"C Schoergenhofer","year":"2017","journal-title":"Clin Exp Med"},{"issue":"03","key":"ref38","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.transci.2004.08.003","article-title":"Efficacy and tolerability of a pasteurised human fibrinogen concentrate in patients with congenital fibrinogen deficiency","volume":"32","author":"W Kreuz","year":"2005","journal-title":"Transfus Apher Sci"},{"issue":"08","key":"ref39","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/rth2.12433","article-title":"Fibrinogen concentrate for bleeding in patients with congenital fibrinogen deficiency: observational study of efficacy and safety for prophylaxis and treatment","volume":"4","author":"J Lasky","year":"2020","journal-title":"Res Pract Thromb Haemost"},{"issue":"02","key":"ref41","doi-asserted-by":"crossref","first-page":"e260","DOI":"10.1097\/MPH.0000000000001812","article-title":"Blood, sweat, and fears: a novel mutation associated with anaphylaxis and nonresponse in a patient with afibrinogenemia","volume":"43","author":"E Hsieh","year":"2021","journal-title":"J Pediatr Hematol Oncol"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"100793","DOI":"10.1016\/j.blre.2020.100793","article-title":"Heterogeneity of congenital afibrinogenemia, from epidemiology to clinical consequences and management","volume":"48","author":"A Casini","year":"2021","journal-title":"Blood Rev"},{"issue":"06","key":"ref44","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1159\/000516339","article-title":"Congenital fibrinogen deficiency in India and role of human fibrinogen concentrate","volume":"144","author":"M J John","year":"2021","journal-title":"Acta Haematol"}],"container-title":["Thrombosis and Haemostasis"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2715-2994.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T22:41:45Z","timestamp":1787870505000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2715-2994"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,17]]},"references-count":38,"journal-issue":{"issue":"09","published-online":{"date-parts":[[2026,8,27]]},"published-print":{"date-parts":[[2026,9]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2715-2994","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0340-6245","2567-689X"],"issn-type":[{"value":"0340-6245","type":"print"},{"value":"2567-689X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,17]]}}}