Hereditary afibrinogenemia: from genetics to treatments

Hereditary afibrinogenemia is a rare coagulation deficiency characterized by the complete absence of fibrinogen. Most mutations are null mutations affecting the synthesis, the intracellular assembly, or the fibrinogen secretion. Bleeding is the main symptom, often already in the neonatal period with bleeding from the umbilical cord. The bleeding phenotype is severe characterized by frequent muscle hematomas, hemarthroses or cerebral bleeds. Paradoxically, patients with afibrinogenemia also suffer from thrombotic events. Both arterial and venous territories are involved, suggesting a common physiopathology. Other symptoms, such as bone cysts, delayed wound healing or spontaneous spleen ruptures are observed and affect the health-related quality of life. Several fibrinogen concentrates are available, with similar pharmacokinetic properties, efficacy and security profiles. In case of bleeding, fibrinogen supplementation is driven by the severity and the source of bleeding, targeting a fibrinogen level of 1-1.5 g/L. The management of a thrombotic event is challenging as it requires the introduction of a fibrinogen prophylaxis together with the antithrombotic therapy. Pregnancy and delivery are high-risk clinical situations. A multidisciplinary approach and an increasing fibrinogen supplementation throughout the pregnancy is mandatory.