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) and Flora Peyvandi 1) 2)
1-Department of Pathophysiology and Transplantation, Universit` a degli Studi di Milano, Milan, Italy; 2-Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milan, Italy; 3-Division of Angiology and Hemostasis, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland; 4-Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland; 5-Department of Biomedical Sciences, Humanitas University, Milan, Italy; 6-IRCCS Humanitas Research Hospital, Milan, Italy; 7-Department of Paediatrics Haematology and Biochemistry, University Hospital Brno and Masaryk University, Brno, Czech Republic; 8-Department of Biological Hematology, CHU Montpellier, Universit´ e de Montpellier, Montpellier, France; 9-Coagulation Centre Rhein-Ruhr, Duisburg, Germany; 10-Haemophilia-Centre-Haemostasis Unit, Aghia Sophia Children’s Hospital, Athens, Greece; 11-Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; 12-Department of Pediatric Hematology, Radboud University Medical Center, Nijmegen, The Netherlands; 13-Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands; 14-Clinical Hematology, National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan; 15-Hemostasis Department, Blood Transfusion Institute of Serbia, Belgrade, Serbia; 16-Pediatric Hematology Department, Istinye University, Istanbul, Turkey; 17-University of Health Sciences Kartal Health Application and Research Center, Pediatric Hematology and Oncology Clinic, Istanbul, Turkey; 18-Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, United Kingdom; 19-School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom; 20-Department of Haematology, Guys and St Thomas’ NHS Foundation Trust, London, United Kingdom; 21-Indiana Hemophilia and Thrombosis Center, Indianapolis, IN; and 22-Division of Pediatric Hematology Oncology, Department of Pediatrics, Weill Cornell Medicine, New York, NY
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.