Congenital fibrinogen deficiency

Synonyms

2

Overview

Congenital fibrinogen deficiency (Congenital afibrinogenemia) is a rare inherited blood disorder in which the blood does not clot normally due to a lack of, or a malfunction involving the protein fibrinogen. This leads to an excessive bleeding during injuries and the frequent formation of bruises and blood clots. Fibrinogen deficiency is inherited in an autosomal recessive way, so male and female patients are affected with the same probability. The frequency of congenital fibrinogen deficiency is estimated to be 1-2 cases per million people. The disease can already be diagnosed at birth due to excessive bleeding from the umbilical cord. Treatment of congenital fibrinogen deficiency is based on the replacement of fibrinogen to the body with the help of blood plasma or fibrinogen concentrates.

Symptoms

Causes

Afibrinogenemia is caused by a severe lack of fibrinogen (coagulation factor I), a protein in the blood that is essential in the blood clotting (coagulation) process. This defect in fibrinogen synthesis can result from mutations in one or another of the fibrinogen genes alpha (FGA), beta (FGB) or gamma (FGG). Each of these three genes provides instructions for making one part (subunit) of the fibrinogen protein. When an injury occurs, fibrinogen is converted to fibrin, the main protein in blood clots. Fibrin proteins attach to each other, forming a stable network that makes up the blood clot. If there is a mutation in the FGA, FGB or FGG gene, the respective subunit is not made and the fibrinogen protein cannot be assembled. This results in the absence of fibrin, so blood clots cannot form, leading to the excessive bleeding seen in people with afibrinogenemia.

Prevention

There is no known prevention. Couples who are thinking about having children may find genetic counseling helpful.

Afibrinogenemia is inherited in an autosomal recessive manner, meaning that in order to be affected, an individual must have inherited two abnormal genes, one from each parent. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene. Individuals with just one mutated gene are called carriers and have about half of the normal level of fibrinogen in their blood. They typically don't show signs or symptoms of the condition. When 2 carriers of an autosomal recessive condition have children, each child has a:

• 25% (1 in 4) chance to be affected,
• 50% (1 in 2) chance to be an unaffected carrier like each parent,
• 25% (1 in 4) chance to be unaffected and not be a carrier. 

Diagnosis

The age at diagnosis varies. Congenital fibrinogen deficiency is often first diagnosed in the newborn period because of excessive umbilical cord bleeding. If the health care provider suspects a bleeding disorder, laboratory tests can determine the type and extent. In these tests, the blood of the patient is analysed for its capability to form blood clots through different methods, as well as for the presence of fibrinogen.

Tests include:

• Bleeding time: With a small, automatic device a minor cut is done on the patient’s forearm. The cut is of standardised width and depth. A blood pressure cuff is used above the wound, to maintain venous pressure at a special value. The time it takes for bleeding to stop (as thus the time it takes for a platelet plug to form) is measured.  
• Clotting time: In this method, a reagent containing a high concentration of thrombin that triggers clot formation when added to citrated blood plasma is used. The time to clot formation is recorded and is read off of a reference curve for tests performed with known concentrations of fibrinogen.  
• Fibrinogen levels: Various immunoassays are commercially available for the quantitative measurement of fibrinogen assay. These assays only asses fibrinogen concentrations, not fibrinogen function. In fibrinogen deficiency, fibrinogen concentrations are low, usually less than 0.1 g/L, and often undetectable in symptomatic individuals.  
• Partial thromboplastin time (PTT): The partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT or APTT) is a performance indicator measuring the efficacy of both the intrinsic and the common coagulation pathways. In order to activate the intrinsic pathway, phospholipid, an activator (e.g. silica), and calcium are mixed into the plasma sample. The time is measured until a clot (thrombus) forms. The test is termed "partial" due to the absence of tissue factor from the reaction mixture.  
• Prothrombin time (PT): measures the extrinsic pathway of coagulation. They are used to determine the clotting tendency of blood. Tissue factor (also known as factor III) is added, and the time the sample takes to clot is measured optically.  
• Thrombin time: In testing for thrombin time, a reagent containing thrombin is added to citrated plasma and the time to clot formation is measured. The thrombin time is prolonged by fibrin degradation products, low concentrations of fibrinogen and thrombin inhibitors. However, the specificity is poor because a prolonged thrombin time can occur in the presence of inhibiting substances like heparin and direct thrombin inhibitors. Furthermore, results can significantly vary between laboratories as the test is not standardized.  
• Reptilase time: The snake venom reptilase is added to the blood sample in the reptilase time test. It directly activates fibrinogen by cleaving fibrinopeptide A. The advantage over the thrombin time is that this test is not affected by substances like heparin.

All of these tests are abnormal in fibrinogen deficiency.

Genotyping

Genotyping identification of the specific molecular defect may be useful for fibrinogen deficiency. It can be useful in diagnosis confirmation, screening of relatives for carrier status, family counseling, and prenatal diagnosis. A review of all available clinical and genetic data from 50 homozygous fibrinogen deficiency patients demonstrated no clear genotype/phenotype correlations. One possible explanation for this variability is the existence of modifier genes or alleles. Some variants may increase the severity of bleeding whereas others may ameliorate the phenotype. Such modifiers have yet to be identified; however, common variants predisposing to thrombophilia may have a role in decreasing the severity of bleeding.

Imaging Studies

In the investigation of suspected bleeding, appropriate imaging studies (eg, brain CT scanning or MRI) may reveal the presence of suspected central nervous system hemorrhages. 

Prognosis

Excess bleeding is common with this condition. These episodes may be severe, or even fatal. Bleeding in the brain is a leading cause of death in patients with this disorder. Recurrent spontaneous abortions can occur in women with congenital fibrinogen deficiency.

Treatment

There is no known prevention or cure for afibrinogenemia. To treat bleeding episodes or to prepare for surgery to treat other conditions, patients may receive:

• The liquid portion of the blood (plasma)
• Fibrinogen (RaiSTAP)
• A blood product containing concentrated fibrinogen (cryoprecipitate) through a vein (transfusion) 

Prophylactic therapy should also be considered for patients with recurrent bleeding episodes, CNS hemorrhage, or during pregnancy for women with recurrent miscarriage.

Individuals with afibrinogenemia should consider the following as part of their management plan:

• Consultation with a hematologist/hemostasis specialist, particularly for patients who require fibrinogen replacement therapy.
• Genetic counseling and family studies, especially for individuals with extensive family history or those considering pregnancy.
• Follow-up by a comprehensive bleeding disorder care team experienced in diagnosing and managing inherited bleeding disorders.
• Vaccination with the hepatitis B vaccine because transfusion increases the risk of hepatitis. 

Resources

Refer to Research Publications.