(MED-FR-11.2) Fibrinogen deficiency

Congenital fibrinogen deficiency (CFD) comprises a diverse group of fibrinogen defects, characterized by deficient or dysfunctional fibrinogen caused by mutations in the FGA, FGB, and FGG genes. The ISTH has revised the classification of CFD, considering fibrinogen levels, patient genotype, and clinical phenotype. Several types have been identified.
Accurate diagnosis is crucial for effective management. This involves routine coagulation assays and the assessment of functional fibrinogen levels (using the Clauss method or PT-derived methods) alongside antigenic fibrinogen levels. A Clauss/antigen ratio of <0.7, or a Clauss/PT-derived ratio of <0.47, serves as a screening marker for dysfibrinogenemia. Genotype is mandatory to confirm diagnosis.
Fibrinogen plays a vital role in the hemostatic cascade by acting as the substrate for fibrin clot formation, supporting platelet aggregation, and serving as a scaffold for fibrinolysis and wound healing. The hallmark of CFD includes unpredictable bleeding and thrombosis, making management particularly challenging. Treatment involves fibrinogen replacement therapy and antithrombotic drugs.
Thrombotic events, intracerebral hemorrhage, splenic rupture, and ovarian cyst rupture can be life-threatening.
In afibrinogenemia, the estimated cumulative incidence of thrombosis by age 40 is 20%, with the mean age of first venous and arterial thrombosis being 27 and 36 years, respectively.
Spontaneous splenic rupture is often associated with thrombosis. Splenectomy carries a high risk of portal vein thrombosis and should be avoided where possible; conservative management is preferred.
Intracerebral bleeding has a high prevalence (23%), with a cumulative incidence of 35% at 10 years, suggesting that primary prophylaxis may be necessary early in childhood.
Approximately 25% of patients with afibrinogenemia experience bone lesions, presenting as spontaneous recurrent skeletal pain. Clinical exams and X-rays appear often normal. MRI is the diagnostic modality of choice. Symptoms resolve following fibrinogen replacement therapy. A fibrinogen target level of 1 g/L can prevent crises over 15–21 days, and prophylaxis may help prevent bone lesions.
Pregnancy in women with CFD is a high-risk scenario, marked by an increased risk of miscarriage, bleeding, and thrombosis. A multidisciplinary approach is essential. Prophylactic fibrinogen replacement therapy is recommended, maintaining a trough fibrinogen level of 1 g/L throughout pregnancy and 1.5 g/L at delivery.