PB0176 - Congenital hypofibrinogenemia due to large heterozygous deletion including FGA, FGB and FGG diagnosed in a patient with recurrent venous thrombosis and factor V Leiden mutation

Background: Congenital fibrinogen disorders are a group of defects affecting either the quantity (afibrinogenemia and hypofibrinogenemia), the quality (dysfibrinogenaemia) or both (hypodysfibrinogenemia) of fibrinogen.

Aims: We present a unique case of a 77-year-old male patient with recurrent venous thrombosis diagnosed with moderate hypofibrinogenemia.

Methods: Hypodysfibrinogenemia was diagnosed based on proportional decreased functional (2.5 µmol/L) and antigenic fibrinogen (2.7 µmol/L) levels. Definitive diagnosis of congenital hypofibrinogenemia was done by genotyping using whole exome sequencing, which identified a large heterozygous deletion on the long arm of chromosome 4, including FGA, FGB and FGG. Thrombophilia investigation revealed a heterozygous factor V Leiden (FVL) mutation. In order to elaborate on the genotype-phenotype associations, fibrin structure assays were conducted, which revealed a polymerization defect, increased fibrin fiber thickness, and fibrin mass-to-length ratio, but normal clot lysis analysis.

Results: The patient experienced one provoked (following shoulder alloplasty) and one spontaneous deep-vein thrombosis (DVT) at the ages of 65 and 71, respectively, accompanied by compromised wound healing. Due to the high recurrence risk of thrombosis, he was placed on long term anticoagulant therapy with rivaroxaban (20 mg/daily). The patient experienced once bleeding in the form of a hematoma in an infected knee prosthesis, which was drained under the coverage of human fibrinogen concentrate and Tranexamic acid. The elder son of the patient, aged 52, experienced two instances of DVT, but has not undergone investigation for hypofibrinogenemia.

Conclusion(s): This case shows that the risk of thrombosis in patients carrying the FVL mutation is not mitigated by moderate congenital hypofibrinogenemia, attributable to the large deletion encompassing FGB, FGA and FGG. These findings suggest that coinheritance of FVL, which is associated with increased thrombin generation, may synergistically interact with reduced thrombin clearance in patients with low fibrinogen level and thereby probably shifting haemostatic balance towards a prothrombotic state.