Fibrinogen deficiency, congenital

Other Names: Congenital fibrinogen deficiency

Congenital fibrinogen deficiency is a rare bleeding disorder, affecting either the quantity (afibrinogenemia, hypofibrinogenemia) or quality (dysfibrinogenemia) of circulating fibrinogen. There is a strong association between fibrinogen activity levels and clinical bleeding severity.

Patients with afibrinogenemia experience frequent, often severe, spontaneous bleeds into the muscles and joints and are at significant risk of intracranial hemorrhage.

Patients with hypofibrinogenemia are usually asymptomatic; however, they are vulnerable to bleeding after trauma.

Dysfibrinogenemia is associated with both spontaneous bleeding and a relatively high risk of thrombosis.

Affected individuals may be susceptible to severe bleeding (hemorrhaging) episodes, particularly during infancy and childhood. Bleeding can occur anywhere in the body, including the skin, nose, oral cavity, gastrointestinal tract, liver, genital and urinary (genitourinary) tract, joints, muscles and central nervous system. Bleeding can also happen in the skull (intracranial hemorrhage) and is a leading cause of death and disability in individuals with congenital afibrinogenemia.

Women are at increased risk for vaginal bleeding and increased blood loss during menstruation (menometrorrhagia) and tend to have recurrent miscarriages. Other manifestations of the disease include risk of spontaneous spleen rupture, formation of painful bone cysts, poor wound healing, and increased risk of formation of unstable clots that can lodge in blood vessels and occlude them (thromboembolic complications).

Cause

Absence of fibrinogen in the blood is a result of mutations in one of three genes, known as the fibrinogen alpha-chain (FGA), beta-chain (FGB), and gamma-chain (FGG) genes Mutations in FGA, FGB and FGG can affect blood levels of fibrinogen in multiple ways. Some mutations impair fibrinogen synthesis by preventing the DNA from being read properly. Other mutations affect the fibrinogen protein itself, either by impairing its synthesis, its secretion, or the fusion of the different subunits of the protein. In all cases, the final result is the same: fibrinogen is absent from the blood. As the conversion of fibrinogen to fibrin is one of the crucial steps of blood coagulation (coagulation cascade), its absence severely impairs clot formation and can lead to episodes of prolonged bleeding.

Inheritance

Autosomal recessive inheritance, a 25% chance

Congenital afibrinogenemia follows an autosomal recessive inheritance pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent.

Signs & Symptoms

The absence of fibrinogen in the circulating blood of individuals with congenital afibrinogenemia makes them unable to effectively coagulate their blood, leading to prolonged bleeding. Bleeding episodes can be spontaneous or due to minor trauma and can happen anywhere in the body, including the skin, nose, oral cavity, gastrointestinal tract, liver, genital and urinary (genitourinary) tract and central nervous system . Symptoms begin to show at birth with umbilical cord bleeding in around 85% of individuals . Bleeding might also be noticed in the stools or vomit of newborns. Intracranial hemorrhage is a leading cause of death and disability in affected individuals. Signs of intracranial hemorrhage include vomiting, dizziness, headache, confusion and seizures. Patients can suffer from long term sequelae such as psychomotor impairment after an episode of bleeding inside the skull Joint bleeding (hemarthrosis) might cause pain and limit movement. Most severe cases of joint bleeding might require total joint replacement (arthroplasty) . Pain and movement limitation can also happen from accumulation of blood (hematoma) in muscles. Some patients also experience bleeding in the bones (interosseous hemorrhage) after minimal trauma. Formation of bone cysts containing blood can happen, particularly in long bones, and cause bone pain. Other symptoms related to congenital afibrinogenemia include an increased risk of spontaneous rupture of the spleen, poor wound healing, and formation of unstable clots that can lodge in blood vessels and occlude them (embolus).

Diagnosis

Diagnosis of congenital afibrinogenemia is made with a combination of blood coagulation tests, tests that measure blood levels of fibrinogen, and genetic testing. These tests include thrombin time (TT), prothrombin time (PTT), activated partial thromboplastin time (aPTT) and reptilase time. Tests to measure levels of fibrinogen, including the Clauss method and ELISA, will not detect any fibrinogen in the circulating blood Genetic testing of the parents and affected individual (proband) is used to detect disease-causing (pathogenic) mutations in the FGA, FGB, and FGY genes

Treatment

Individuals with congenital afibrinogenemia need to be treated with fibrinogen replacement therapy. Fresh frozen plasma and blood product made from plasma (cryoprecipitate) may be injected to replace fibrinogen. The goal of the treatment is to restore and maintain normal fibrinogen levels. In some patients, fibrinogen replacement therapy might provoke the formation of unstable clots that will detach and disseminate throughout the body, potentially occluding blood vessels (thromboembolic complications). These patients should be administered an anticoagulant with their treatment, preferably low-molecular-weight heparin For less severe bleeding episodes, patients can be given amino acids that prevent clot dissolution (antifibrinolytic amino acids), namely epsilon-aminocaproic acid and tranexamic acid. The major advantage of this treatment is that it is non-injectable Other treatment is symptomatic and supportive and include joint replacement surgery (arthroplasty) after joint damage due to excessive bleeding (hemarthrosis) and neurosurgical interventions to control severe bleeding inside the skull (intracranial hemorrhage).

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Human fibrinogen concentrate, pasteurized (Brand name: RiaSTAP®) Treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency (afibrinogenemia and hypofibrinogenemia).

NIH genetic and rare disease info

• NIH info on Fibrinogen deficiency, congenital

Fibrinogen deficiency, congenital is a rare disease.

Fibrinogen deficiency, congenital Resources
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