Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2024 Mar 26;8(6):1392-1404.
doi: 10.1182/bloodadvances.2023012186.

Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database

Samin Mohsenian  1 , Roberta Palla  1 , Marzia Menegatti  2 , Andrea Cairo  2 , Anna Lecchi  2 , Alessandro Casini  3 , Marguerite Neerman-Arbez  4 , Rosanna Asselta  5   6 , Sara Scardo  2 , Simona Maria Siboni  2 , Jan Blatny  7 , Ondrej Zapletal  7 , Jean-Francois Schved  8 , Muriel Giansily-Blaizot  8 , Susan Halimeh  9 , Mohamad Ayman Daoud  9 , Helen Platokouki  10 , Helen Pergantou  10 , Roger E G Schutgens  11 , Monique Van Haaften-Spoor  11 , Paul Brons  12 , Britta Laros-van Gorkom  13 , Elise Van Pinxten  13 , Munira Borhany  14 , Naveena Fatima  14 , Danijela Mikovic  15 , Marko Saracevic  15 , Gül Nihal Özdemir  16 , Yılmaz Ay  17 , Michael Makris  18 , Caryl Lockley  18 , Andrew Mumford  19 , Andrew Harvey  19 , Steve Austin  20 , Amy Shapiro  21 , Adrianna Williamson  21 , Catherine McGuinn  21 , Ilene Goldberg  22 , Philippe De Moerloose  3 , Flora Peyvandi  1   2
Affiliations
Multicenter Study

Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database

Samin Mohsenian et al. Blood Adv. .

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: F.P. reports participation at educational meetings/symposia of Takeda/Spark and the advisory board of Sanofi, Sobi, CSL Behring, Roche, and BioMarin. R.P. reports participation and speaker fees at the educational workshop organized by Novo Nordisk. S.H. has received speaker’s honorarium from Bayer Healthcare GmbH, Baxalta Innovations (Now Shire) GmbH, Biotest AG, CSL Behring GmbH and Novartis Pharma GmbH, Novo Nordisk Pharma, GmbH, Octapharma GmbH, Pfizer Pharma, Roche Pharma AG, Swedish Orphan Biovitrum GmbH; and received research grant and attended advisory board of Bayer Healthcare GmbH, Biotest AG, CSL Behring GmbH, Novo Nordisk Pharma, GmbH, Octapharma GmbH, Chugai Pharma Germany GmbH, and Swedish Orphan Biovitrum GmbH. J.B. has received speaker’s and/or consultation fees for Novo Nordisk, Roche, Sobi, Takeda, and CSL Behring. A. Casini has received grants and fees from Octapharma, Sobi, LFB, Takeda, and Novo Nordisk. The institution of R.E.G.S. has received speaker’s fees and/or research grants from Bayer, CSL Behring, Hemab, Novartis, Novo Nordisk, Octapharma, Roche, Sobi, and Takeda. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Comparison between age at diagnosis in different groups of fibrinogen deficiencies and the association between factor activity levels and grades of severity. (A) The box plot compares the median age at diagnosis in 3 different fibrinogen deficiency groups. The solid line indicates the median. (B-C) The box plot compares the median factor activity levels between all grades of severity in quantitative (B) and qualitative (C) deficiencies. The Kruskal-Wallis test was performed to determine differences in the age at diagnosis between different subclasses of fibrinogen disorders. ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001.
Figure 2.
Figure 2.
Reported frequency of different types of bleeding symptoms. Menorrhagia was considered in women who were in fertile age, and postpartum bleeding was assessed in women who underwent labor. GI, gastrointestinal bleeding.
Figure 3.
Figure 3.
Distribution of causative variants identified in this study. Location of variants in quantitative (A) and qualitative (B) fibrinogen deficiencies.
See this image and copyright information in PMC

References

    1. 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
    1. 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. - PMC - PubMed
    1. Menegatti M, Peyvandi F. Treatment of rare factor deficiencies other than hemophilia. Blood. 2019;133(5):415–424. - PubMed
    1. 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
    1. Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and treatment. Blood. 2015;125(13):2052–2061. - PubMed

Publication types