Practice Essentials
Dysfibrinogenemia is a rare coagulation disorder resulting from an abnormal or decreaased level of fibrinogen, which is a 340 kDa glycoprotein produced in the liver, necessary to form blood clots and control bleeding. Dysfibrinogenemia has two forms: congenital and acquired. The rare congenital form is asymptomatic in approximately 40% of cases, with the remainder of affected individuals experiencing bleeding (50%) or bleeding and thrombotic (clotting) episodes (10%).
Congenital dysfibrinogenemia can be inherited as an autosomal-dominant, codominant, or autosomal-recessive disorder affecting the fibrinogen alpha, fibrinogen beta, or fibrinogen gamma genes (FGA, FGB, or FGG, respectively). More than 100 mutations that result in the phenotype of abnormal fibrinogen have been identified; over 90% of those are point missense mutations. [1] There are two types of congenital dysfibrinogenemia: Type I, in which there is absence (afibrinogenemmia) or low levels of circulating fibrinogen (hypofibrinogenemia); and type II, in which fibrinogen levels are normal or low but the fibrinogen has low functional activity (dysfibrinogenemia). [2]
The more common acquired form of dysfibrinogenemia is typically caused by liver diseases such as cirrhosis, hepatitis, or tumors. [3] Other causes of acquired dysfibrinogenemia include autoimmune diseases. A case of acquired dysfibrinogenemia caused by an autoantibody that inhibited fibrin polymerization in a patient previously diagnosed with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, strokelike episodes) has also been reported. [4]
When present, clinical manifestations of dysfibrinogenemia are generally mild. In some cases, however, they may be life-threatening. (See Presentation.)
While the majority of patients with dysfibrinogenemia require no treatment, those who experience clinically significant bleeding can benefit from fresh frozen plasma (FFP) or cryoprecipitate, depending on the severity of the bleeding. Anticoagulation is indicated for venous thromboembolism secondary to congenital dysfibrinogenemia. Fibrinogen replacement therapy may prevent pregnancy complications. (See Treatment.)
Pathophysiology
In the clotting cascade, the various blood coagulation factors function in concert to produce a balance between fibrin clot formation and its subsequent degradation. When any factor in the cascade is absent, decreased, or abnormal, the delicate balance is disrupted, possibly leading to bleeding or thrombotic disorders. The clinical manifestations range from no symptoms to life-threatening events, depending on which coagulation factor is affected and the degree to which it is affected.
In normal fibrin clot formation, a fibrin monomer forms after thrombin cleaves fibrinopeptide A and B from the alpha and beta chains of the fibrinogen molecule. The fibrin monomer, which is insoluble, aggregates spontaneously into fibrin polymer. Factor XIIIa then catalyzes the cross-linkage between different fibrin chains, forming a stabilized fibrin polymer or clot. Eventually, plasmin lyses the fibrin clot.
Fibrogen is encoded by the FGA, FGB and FGG genes. Causative mutations can occur in any of the three genes, but FGB mutations are the least common. [5, 6]
Acquired dysfibrinogenemia occurs most often in patients with severe liver disease. The impairment of fibrinogen, which is synthesized in the liver, is due to a structural defect caused by an increased carbohydrate content that interferes with the polymerization of the fibrin, depending on the degree of abnormality of the fibrinogen molecule. Rarely, dysfibrinogenemia may also be associated with malignancies, most commonly primary or secondary liver tumors, but acquired dysfibrinogenemia has also been reported in patients with renal cell carcinoma.
One of the rarer disorders of coagulation is congenital dysfibrinogenemia, a qualitative abnormality of the fibrin molecule. Multiple variations of these dysfibrinogenemias have been elucidated. Each is named for the city where it was first discovered. With only rare exceptions, the congenital dysfibrinogenemias are inherited in an autosomal dominant or codominant fashion. Depending on the fibrinogen abnormality, defects may occur in one or more of the steps in fibrin clot formation, although the most common defect involves polymerization of the fibrin monomer. [7]
Bleeding may ensue when a fibrin clot forms that cannot be effectively stabilized. Bleeding in patients with congenital dysfibrinogenemia tends to be relatively mild or even absent; it is only a laboratory curiosity and is not life threatening. In contrast to the bleeding experienced by approximately half of the patients with congenital dysfibrinogenemia, one subset of patients (diagnosed with fibrinogen Oslo I) has an abnormal fibrinogen that is associated with thromboembolic complications that are often relatively mild. The abnormal fibrinogen in these patients forms a fibrin clot that is resistant to fibrinolysis by plasmin. [8]
Etiology
Congenital dysfibrinogenemias are most often inherited in an autosomal dominant or codominant fashion. Several variants are inherited autosomal recessively.
Acquired dysfibrinogenemias occur in severe liver disease. The fibrinogen molecule produced by the impaired liver is not functional or able to form a stable fibrin clot.
Epidemiology
Congenital dysfibrinogenemia has been reported in only 200-300 families. Transmission is autosomal dominant or codominant, except in a few cases that appear to be transmitted recessively. Acquired abnormalities of fibrinogen may complicate liver disease: approximately 50% of patients with severe liver disease exhibit bleeding secondary to abnormal fibrinogen molecules.
Dysfibinogenemia has no known predilection for race or sex.
Prognosis
Prognosis is good for patients with congenital dysfibrinogenemias because bleeding or thrombotic events are rare and usually mild, though severe hemorrhagic episodes may characterize a few abnormal fibrinogen variants (eg, Imperate, Dettori, Detroit). On the other hand, patients with acquired dysfibrinogenemia often have a worse prognosis because it is associated with severe liver disease and experieince more severe bleeding episodes than patients with the inherited type. The condition tends to worsen as the liver disease worsens.
During pregnancy, dysfibrinogenemia increases the risk for significant hemorrhage, thrombosis, and/or fetal loss. [9]
A multicenter study of 101 patients with congenital dysfibrinogenemia found that, over a mean 8.8 year follow-up period after diagnosis, the incidence of major bleeding and of thrombotic events was 2.5 and 18.7 per 1000 patient-years, respectively. By age 50 years, those cumulative incidences were estimated at 19.2% and 30.1%. In addition, of 111 pregnancies identified, the incidence of spontaneous abortions and postpartum hemorrhage were 19.8% and 21.4%, respectively. Abnormal bleeding was a complication in nine of 137 surgical procedures analyzed. [10]
