Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD using PRO-RBDD (Prospective Rare Bleeding Disorders Database). Clinical phenotypes, laboratory, and genetic features were investigated using retrospective data from the PRO-RBDD. Patients were classified from asymptomatic to grade 3 based on their bleeding severity. In addition, FGA, FGB, and FGG were sequenced to find causative variants. A total of 166 CFD cases from 16 countries were included, of whom 123 (30 afibrinogenemia, 33 hypofibrinogenemia, 55 dysfibrinogenemia, and 5 hypodysfibrinogenemia) were well characterized. Considering the previously established factor activity and antigen level thresholds, bleeding severity was correctly identified in 58% of the cases. The rates of thrombotic events among afibrinogenemic and hypofibrinogenemic patients were relatively similar (11% and 10%, respectively) and surprisingly higher than in dysfibrinogenemic cases. The rate of spontaneous abortions among 68 pregnancies was 31%, including 86% in dysfibrinogenemic women and 14% with hypofibrinogenemia. Eighty-six patients received treatment (69 on-demand and/or 17 on prophylaxis), with fibrinogen concentrates being the most frequently used product. Genetic analysis was available for 91 cases and 41 distinct variants were identified. Hotspot variants (FGG, p.Arg301Cys/His and FGA, p.Arg35Cys/His) were present in 51% of dysfibrinogenemia. Obstetric complications were commonly observed in dysfibrinogenemia. This large multicenter study provided a comprehensive insight into the clinical, laboratory, and genetic history of patients with CFDs. We conclude that bleeding severity grades were in agreement with the established factor activity threshold in nearly half of the cases with quantitative defects.

Center for Benign Haematology Thrombosis and Haemostasis Van Creveldkliniek University Medical Center Utrecht Utrecht University Utrecht The Netherlands

Clinical Hematology National Institute of Blood Diseases and Bone Marrow Transplantation Karachi Pakistan

Coagulation Centre Rhein Ruhr Duisburg Germany

Department of Biological Hematology CHU Montpellier Université de Montpellier Montpellier France

Department of Biomedical Sciences Humanitas University Milan Italy

Department of Genetic Medicine and Development Faculty of Medicine University of Geneva Geneva Switzerland

Department of Haematology Guys and St Thomas' NHS Foundation Trust London United Kingdom

Department of Hematology Radboud University Medical Center Nijmegen The Netherlands

Department of Paediatrics Haematology and Biochemistry University Hospital Brno and Masaryk University Brno Czech Republic

Department of Pathophysiology and Transplantation Università degli Studi di Milano Milan Italy

Department of Pediatric Hematology Radboud University Medical Center Nijmegen The Netherlands

Division of Angiology and Hemostasis Faculty of Medicine Geneva University Hospitals Geneva Switzerland

Division of Pediatric Hematology Oncology Department of Pediatrics Weill Cornell Medicine New York NY

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa Milan Italy

Haemophilia Centre Haemostasis Unit Aghia Sophia Children's Hospital Athens Greece

Hemostasis Department Blood Transfusion Institute of Serbia Belgrade Serbia

Indiana Hemophilia and Thrombosis Center Indianapolis IN

IRCCS Humanitas Research Hospital Milan Italy

Pediatric Hematology Department Istinye University Istanbul Turkey

School of Cellular and Molecular Medicine University of Bristol Bristol United Kingdom

Sheffield Haemophilia and Thrombosis Centre Royal Hallamshire Hospital Sheffield United Kingdom

University of Health Sciences Kartal Health Application and Research Center Pediatric Hematology and Oncology Clinic Istanbul Turkey

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Tennent GA, Brennan SO, Stangou AJ, O'Grady J, Hawkins PN, Pepys MB. Human plasma fibrinogen is synthesized in the liver. Blood. 2007;109(5):1971–1974. PubMed

Medved L, Weisel J, Fibrinogen and Factor XIII Subcommittee of Scientific Standardization Committee of International Society on Thrombosis and Haemostasis Recommendations for nomenclature on fibrinogen and fibrin. J Thromb Haemost. 2009;7(2):355–359. PubMed PMC

Menegatti M, Peyvandi F. Treatment of rare factor deficiencies other than hemophilia. Blood. 2019;133(5):415–424. PubMed

Casini A, Undas A, Palla R, Thachil J, De Moerloose P, Subcommittee on Factor XIII and Fibrinogen Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16(9):1887–1890. PubMed

Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and treatment. Blood. 2015;125(13):2052–2061. PubMed

Paraboschi EM, Duga S, Asselta R. Fibrinogen as a pleiotropic protein causing human diseases: the mutational burden of Aα, Bβ, and γ chains. Int J Mol Sci. 2017;18(12):2711. PubMed PMC

Acharya S, Dimichele D. Rare inherited disorders of fibrinogen. Haemophilia. 2008;14(6):1151–1158. PubMed

Casini A, de Moerloose P, Neerman-Arbez M. Clinical features and management of congenital fibrinogen deficiencies. Semin Thromb Hemost. 2016;42(4):366–374. PubMed

Castaman G, Lunardi M, Rigo L, Mastroeni V, Bonoldi E, Rodeghiero F. Severe spontaneous arterial thrombotic manifestations in patients with inherited hypo-and afibrinogenemia. Haemophilia. 2009;15(2):533–537. PubMed

Santoro C, Massaro F, Venosi S, et al. Severe thrombotic complications in congenital afibrinogenemia: a pathophysiological and management dilemma. Semin Thromb Hemost. 2016;42(5):577–582. PubMed

Simurda T, Caccia S, Asselta R, et al. Congenital hypofibrinogenemia associated with a novel heterozygous nonsense mutation in the globular C-terminal domain of the γ-chain (p. Glu275Stop) J Thromb Thrombolysis. 2020;50(1):233–236. PubMed

Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Thromb Haemost. 1995;73(1):151–161. PubMed

Zhou J, Ding Q, Chen Y, et al. Clinical features and molecular basis of 102 Chinese patients with congenital dysfibrinogenemia. Blood Cells Mol Dis. 2015;55(4):308–315. PubMed

Casini A, Blondon M, Lebreton A, et al. Natural history of patients with congenital dysfibrinogenemia. Blood. 2015;125(3):553–561. PubMed PMC

Snir A, Brenner B, Paz B, Ohel G, Lanir N. The role of fibrin matrices and tissue factor in early-term trophoblast proliferation and spreading. Thromb Res. 2013;132(4):477–483. PubMed

Iwaki T, Castellino FJ. Maternal fibrinogen is necessary for embryonic development. Curr Drug Targets. 2005;6(5):535–539. PubMed

Iwaki T, Sandoval-Cooper MJ, Paiva M, Kobayashi T, Ploplis VA, Castellino FJ. Fibrinogen stabilizes placental-maternal attachment during embryonic development in the mouse. Am J Pathol. 2002;160(3):1021–1034. PubMed PMC

Peyvandi F, Palla R, Menegatti M, et al. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost. 2012;10(4):615–621. PubMed

Rodeghiero F, Tosetto A, Abshire T, et al. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost. 2010;8(9):2063–2065. PubMed

Rodeghiero F, Castaman G, Tosetto A, et al. The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multicenter study. J Thromb Haemost. 2005;3(12):2619–2626. PubMed

Palla R, Siboni SM, Menegatti M, Musallam KM, Peyvandi F, European Network of Rare Bleeding Disorders EN-RBD group Establishment of a bleeding score as a diagnostic tool for patients with rare bleeding disorders. Thromb Res. 2016;148:128–134. PubMed

Šrámek A, Eikenboom JC, Briët E, Vandenbroucke JP, Rosendaal FR. Usefulness of patient interview in bleeding disorders. Arch Intern Med. 1995;155(13):1409–1415. PubMed

Asselta R, Duga S, Tenchini ML. The molecular basis of quantitative fibrinogen disorders. J Thromb Haemost. 2006;4(10):2115–2129. PubMed

Hanss M, Biot F. A database for human fibrinogen variants. Ann N Y Acad Sci. 2001;936(1):89–90. PubMed

Casini A, Blondon M, Tintillier V, et al. Mutational epidemiology of congenital fibrinogen disorders. Thromb Haemost. 2018;118(11):1867–1874. PubMed

Simurda T, Zolkova J, Snahnicanova Z, et al. Identification of two novel fibrinogen Bβ chain mutations in two Slovak families with quantitative fibrinogen disorders. Int J Mol Sci. 2017;19(1):100. PubMed PMC

Mohsenian S, Seidizadeh O, Mirakhorli M, Jazebi M, Azarkeivan A. Clinical and molecular characterization of Iranian patients with congenital fibrinogen disorders. Transfus Apher Sci. 2021;60(6) PubMed

Makris M, Calizzani G, Fischer K, et al. The European Haemophilia Network (EUHANET) Blood Transfus. 2014;12(suppl 3):s515–s518. PubMed PMC

Menegatti M, Palla R, Bucciarelli P, Peyvandi F. Minimal factor XIII activity level to prevent major spontaneous bleeds: reply. J Thromb Haemost. 2017;15(11):2280–2282. PubMed

Neerman-Arbez M, de Moerloose P, Casini A. Laboratory and genetic investigation of mutations accounting for congenital fibrinogen disorders. Semin Thromb Hemost. 2016;42(4):356–365. PubMed

Mohsenian S, Seidizadeh O, Palla R, et al. Diagnostic utility of bleeding assessment tools in congenital fibrinogen deficiencies. Haemophilia. 2023;29(3):827–835. PubMed

Saes JL, Verhagen MJ, Meijer K, et al. Bleeding severity in patients with rare bleeding disorders: real-life data from the RBiN study. Blood Adv. 2020;4(20):5025–5034. PubMed PMC

Sumitha E, Jayandharan G, Arora N, et al. Molecular basis of quantitative fibrinogen disorders in 27 patients from I ndia. Haemophilia. 2013;19(4):611–618. PubMed

Lak M, Keihani M, Elahi F, Peyvandi F, Mannucci PM. Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia. Br J Haematol. 1999;107(1):204–206. PubMed

Casini A, Neerman-Arbez M, De Moerloose P. Heterogeneity of congenital afibrinogenemia, from epidemiology to clinical consequences and management. Blood Rev. 2021;48 PubMed

Valiton V, Hugon-Rodin J, Fontana P, Neerman-Arbez M, Casini A. Obstetrical and postpartum complications in women with hereditary fibrinogen disorders: a systematic literature review. Haemophilia. 2019;25(5):747–754. PubMed

Brunclikova M, Simurda T, Zolkova J, et al. Heterogeneity of genotype–phenotype in congenital hypofibrinogenemia—a review of case reports associated with bleeding and thrombosis. J Clin Med. 2022;11(4):1083. PubMed PMC

Marchi R, Walton BL, McGary CS, et al. Dysregulated coagulation associated with hypofibrinogenaemia and plasma hypercoagulability: implications for identifying coagulopathic mechanisms in humans. Thromb Haemost. 2012;108(3):516–526. PubMed PMC

Neerman-Arbez M, Casini A. Clinical consequences and molecular bases of low fibrinogen levels. Int J Mol Sci. 2018;19(1):192. PubMed PMC

Mosesson MW. Update on antithrombin I (fibrin) Thromb Haemost. 2007;98(1):105–108. PubMed

Korte W, Poon M-C, Iorio A, Makris M. Thrombosis in inherited fibrinogen disorders. Transfus Med Hemother. 2017;44(2):70–76. PubMed PMC

Hugon-Rodin J, Carrière C, Claeyssens S, et al. Obstetrical complications in hereditary fibrinogen disorders: the Fibrinogest study. J Thromb Haemost. 2023;21(8):2126–2136. PubMed

Tziomalos K, Vakalopoulou S, Perifanis V, Garipidou V. Treatment of congenital fibrinogen deficiency: overview and recent findings. Vasc Health Risk Manag. 2009;5:843–848. PubMed PMC

Nagler M, Kremer Hovinga JA, Alberio L, et al. Thromboembolism in patients with congenital afibrinogenaemia. Thromb Haemost. 2016;116(4):722–732. PubMed

Solomon C, Gröner A, Ye J, Pendrak I. Safety of fibrinogen concentrate: analysis of more than 27 years of pharmacovigilance data. Thromb Haemost. 2015;113(4):759–771. PubMed

Davis RL, Homer VM, George PM, Brennan SO. A deep intronic mutation in FGB creates a consensus exonic splicing enhancer motif that results in afibrinogenemia caused by aberrant mRNA splicing, which can be corrected in vitro with antisense oligonucleotide treatment. Hum Mutat. 2009;30(2):221–227. PubMed

Apweiler R, Bairoch A, Wu CH, et al. UniProt: the universal protein knowledgebase. Nucleic Acids Res. 2004;32(database issue):D115–D119. PubMed PMC

Siebenlist KR, Mosesson M, Meh D, DiOrio J, Albrecht R, Olson J. Coexisting dysfibrinogenemia (gammaR275C) and factor V Leiden deficiency associated with thromboembolic disease (fibrinogen Cedar Rapids) Blood Coagul Fibrinolysis. 2000;11(3):293–304. PubMed

Castaman G, Giacomelli SH, Biasoli C, Contino L, Radossi P. Risk of bleeding and thrombosis in inherited qualitative fibrinogen disorders. Eur J Haematol. 2019;103(4):379–384. PubMed

Blombäck M, Blombäck B, Mammen E, Prasad A. Fibrinogen Detroit—a molecular defect in the N-terminal disulphide knot of human fibrinogen? Nature. 1968;218(5137):134–137. PubMed

Tiscia GL, Margaglione M. Human fibrinogen: molecular and genetic aspects of congenital disorders. Int J Mol Sci. 2018;19(6):1597. PubMed PMC

De Moerloose P, Casini A, Neerman-Arbez M. Congenital fibrinogen disorders: an update. Semin Thromb Hemost. 2013;39(6):585–595. PubMed