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

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.

Factor VIII Activity in Relation to the Type of Thrombosis and Patient's Risk Factors for Thrombosis, Age, and Comorbidity.

OBJECTIVE: Elevated factor VIII has been shown to be an independent risk factor for deep venous thrombosis and pulmonary embolism. It has been suggested that increased factor VIII levels by itself is insufficient to cause thrombosis; however, increased factor VIII with other risk factors could increase the risk of thrombosis. The aim of the study was to evaluate the factor VIII level with regard to the type of thrombosis and patient's risk factors such as age or comorbidity. MATERIALS AND METHODS: In total, 441 patients who were referred for thrombophilia testing from the period of January 2010 to December 2020 were included in the study. The patients who developed the first thrombosis before the age of 50 were eligible for the study. The patients' data that were used in statistical analyses were collected from our thrombophilia register. RESULTS: The number of the subjects with increased factor VIII over 1.5 IU/mL is equal regardless of the thrombosis type. Factor VIII activity already begins to increase over 40 years old and reaches the mean values of 1.45 IU/mL close to the cut-off (1.5 IU/mL), showing a statistically significant difference compared to those under 40, P = .001. Comorbidities other than thyroid disease or malignancy had no influence on the increase of factor VIII. In the mentioned conditions, the average factor VIII of 1.82 (0.79) and 1.65 (0.43) was obtained, respectively. CONCLUSION: Factor VIII activity is significantly affected by age. Thrombosis type and comorbid diseases other than thyroid disease and malignancy had no effect on factor VIII.