A rare inherited coagulation disorder characterised by reduced or absent fibrinogen (coagulation factor I) or by the production of dysfunctional fibrinogen, leading to a variable clinical phenotype ranging from no symptoms to severe, life-threatening haemorrhage and/or thrombosis. Congenital fibrinogen disorders include afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia and hypodysfibrinogenemia.

Epidemiology

Congenital fibrinogen disorders are rare, with an estimated prevalence of approximately 1–9 per million individuals for the overall disorder group. Afibrinogenemia is particularly rare, with estimates ranging from 1 to 30 per million individuals. Hypofibrinogenemia and dysfibrinogenemia are thought to be more common, although their exact prevalence is unknown. Both sexes are equally affected. Afibrinogenemia typically presents during the neonatal period or early childhood, whereas hypofibrinogenemia and dysfibrinogenemia may be identified at any age, including incidentally. Higher rates of afibrinogenemia have been reported in populations with increased rates of consanguinity.

Clinical description

The clinical phenotype is highly variable and depends on the type of fibrinogen disorder, the degree of functional deficiency and individual factors. Afibrinogenemia, characterised by the complete absence of circulating fibrinogen, generally carries the greatest risk of bleeding, although clinical severity varies. Hypofibrinogenemia is often associated with milder symptoms, while dysfibrinogenemia may cause bleeding, thrombosis or no apparent clinical manifestations.

Common bleeding manifestations include:

– Umbilical cord bleeding in neonates
– Epistaxis
– Gingival bleeding
– Easy bruising
– Abnormal uterine bleeding, including menorrhagia
– Prolonged bleeding following trauma, dental procedures or surgery

Severe manifestations, particularly in individuals with afibrinogenemia, may include:

– Gastrointestinal bleeding
– Intracranial haemorrhage
– Haemarthroses and deep muscle bleeding
– Excessive bleeding following surgery or significant trauma
– Recurrent pregnancy loss

Congenital fibrinogen disorders may also be associated with thrombotic complications, particularly in certain forms of dysfibrinogenemia, but also in afibrinogenemia. Bleeding and thrombosis may occur in the same individual. In addition, fibrinogen replacement therapy may contribute to an increased thrombotic risk in certain individuals. However, some individuals with hypofibrinogenemia or dysfibrinogenemia remain asymptomatic throughout their lives.

Etiology

Congenital Factor I deficiency is caused by pathogenic variants in the FGA, FGB or FGG genes, which encode the three polypeptide chains of fibrinogen.

Fibrinogen is a soluble plasma glycoprotein essential for blood clot formation. During coagulation, thrombin converts fibrinogen into fibrin, which polymerises to form the structural framework of a blood clot. Fibrinogen also contributes to platelet aggregation.

Congenital fibrinogen disorders are classified according to the quantity and function of circulating fibrinogen:

– Afibrinogenemia: complete or virtually complete absence of circulating fibrinogen.
– Hypofibrinogenemia: reduced circulating fibrinogen concentration, generally accompanied by reduced functional activity.
– Dysfibrinogenemia: impaired fibrinogen function despite a relatively normal antigenic concentration.
– Hypodysfibrinogenemia: reduced circulating fibrinogen concentration accompanied by impaired fibrinogen function.

In most cases, congenital hypofibrinogenemia results from reduced fibrinogen production or secretion. A rare form, hereditary hypofibrinogenemia with hepatic storage (HHHS), is caused by specific variants in FGG that lead to the intracellular accumulation of fibrinogen in hepatocytes. This condition is associated with hypofibrinogenemia and liver disease of variable severity, which may progress to fibrosis or cirrhosis.

Reduced fibrinogen quantity or impaired function can compromise fibrin clot formation and stability, resulting in a variable bleeding tendency. However, congenital fibrinogen disorders may also be associated with thrombotic complications, and bleeding and thrombosis can occur in the same individual. Thrombotic risk may be influenced by the underlying fibrinogen abnormality, individual risk factors and clinical circumstances, including fibrinogen replacement therapy. Although replacement therapy is essential for the prevention or treatment of bleeding in selected patients, thrombotic complications have also been reported in this context.

Management depends on the type and severity of the fibrinogen disorder, the patient’s bleeding history, fibrinogen activity, thrombotic risk and clinical circumstances. Treatment should be individualised and coordinated by a specialist in bleeding disorders.

Treatment options include:

– Fibrinogen concentrate (preferred replacement therapy): used for the treatment and prevention of bleeding when fibrinogen replacement is indicated. It is generally preferred because it provides a specific, concentrated source of fibrinogen without requiring the larger plasma volumes associated with other blood products.
– Cryoprecipitate (alternative treatment): may be considered when fibrinogen concentrate is unavailable or cannot be administered promptly. It is generally not the first-choice replacement product when specific fibrinogen concentrate is available.
– Fresh frozen plasma (alternative in selected circumstances): may be considered when specific fibrinogen concentrate and suitable cryoprecipitate are unavailable, or in emergency situations requiring broader coagulation factor replacement. It is generally less suitable for isolated fibrinogen deficiency because of its relatively low fibrinogen concentration and the larger volumes required.
– Antifibrinolytic agents, such as tranexamic acid, may be useful for selected mucosal bleeding episodes or as an adjunct to replacement therapy, provided there are no relevant contraindications.
– Individualised prophylaxis: may be considered for patients with afibrinogenemia and a history of life-threatening bleeding, recurrent significant bleeding or specific high-risk clinical circumstances. Routine prophylaxis is not necessary for every patient.
– Pregnancy management: requires specialist multidisciplinary care because of the risks of bleeding, pregnancy loss and thrombosis. Fibrinogen replacement may be required according to the individual’s clinical history and circumstances.

Replacement therapy should be guided by the clinical situation and appropriate laboratory monitoring. In patients with dysfibrinogenemia, the potential effects of fibrinogen replacement on both bleeding and thrombotic risk should be carefully considered, as the administration of normal fibrinogen may dilute the dysfunctional fibrinogen and potentially mitigate its prothrombotic effects. Treatment should be individualised according to the underlying fibrinogen abnormality, bleeding and thrombotic history, and the clinical context.

Treatment decisions should be made by the treating specialist, taking into account product availability, local protocols and the individual patient’s bleeding and thrombotic risks.

Prognosis

The prognosis varies according to the type and severity of the fibrinogen disorder. Individuals with mild hypofibrinogenemia or asymptomatic dysfibrinogenemia may have few or no clinical complications. Afibrinogenemia carries a greater risk of severe bleeding, including intracranial haemorrhage, particularly in early life.

With early diagnosis, appropriate fibrinogen replacement and specialist follow-up, many affected individuals can achieve a good long-term outcome. However, pregnancy-related complications and thrombotic events remain important considerations. Lifelong awareness of bleeding and thrombotic risks is essential, with treatment tailored to the individual clinical phenotype.
 

Last update: October 2026