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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$a Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database / $c S. Mohsenian, R. Palla, M. Menegatti, A. Cairo, A. Lecchi, A. Casini, M. Neerman-Arbez, R. Asselta, S. Scardo, SM. Siboni, J. Blatny, O. Zapletal, JF. Schved, M. Giansily-Blaizot, S. Halimeh, MA. Daoud, H. Platokouki, H. Pergantou, REG. Schutgens, M. Van Haaften-Spoor, P. Brons, B. Laros-van Gorkom, E. Van Pinxten, M. Borhany, N. Fatima, D. Mikovic, M. Saracevic, GN. Özdemir, Y. Ay, M. Makris, C. Lockley, A. Mumford, A. Harvey, S. Austin, A. Shapiro, A. Williamson, C. McGuinn, I. Goldberg, P. De Moerloose, F. Peyvandi

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$a 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.

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