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

Authors	MOHSENIAN Samin PALLA Roberta MENEGATTI Marzia CAIRO Andrea LECCHI Anna CASINI Alessandro NEERMAN-ARBEZ Marguerite ASSELTA Rosanna SCARDO Sara SIBONI Simona Maria BLATNÝ Jan ZAPLETAL Ondřej SCHVED Jean-Francois GIANSILY-BLAIZOT Muriel HALIMEH Susan DAOUD Mohamad Ayman PLATOKOUKI Helen PERGANTOU Helen SCHUTGENS Roger E G MONIQUE Van Haaften-Spoor BRONS Paul GORKOM Britta Laros-van ELISE Van Pinxten BORHANY Munira FATIMA Naveena MIKOVIC Danijela SARACEVIC Marko OZDEMIR Gul Nihal AY Yilmaz MAKRIS Michael LOCKLEY Caryl MUMFORD Andrew HARVEY Andrew AUSTIN Steve SHAPIRO Amy WILLIAMSON Adrianna MCGUINN Catherine GOLDBERG Ilene DE MOERLOOSE Philippe PEYVANDI Flora
Year of publication	2024
Type	Article in Periodical
Magazine / Source	Blood advances
MU Faculty or unit	Faculty of Medicine
Citation
web	https://ashpublications.org/bloodadvances/article/8/6/1392/514755/Congenital-fibrinogen-disorders-a-retrospective
Doi	http://dx.doi.org/10.1182/bloodadvances.2023012186
Keywords	Congenital fibrinogen disorders
Description	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 dys fibrinogenemia. Obstetric complications were commonly observed in dys fibrinogenemia. 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.