Dysfibrinogenemia

Updated: Feb 11, 2019
  • Author: Russell Burgess, MD; Chief Editor: Perumal Thiagarajan, MD  more...
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Overview

Practice Essentials

Fibrinogen disorders are rare conditions that are classified as either qualitative (type II) or quantitative (type I). Dysfibrinogenemia is a term used to describe a qualitative (ie, functional) fibrinogen disorder wherein abnormality in the fibrin molecule results in defective fibrin clot formation. The other qualitative fibrinogen disorder, hypodysfibrinogenemia, is characterized by both defective clot formation and reduced fibrinogen antigen levels.

In quantitative fibrinogen disorders, only the amount of fibrinogen in circulation is affected. Hypofibrinogenemia is characterized by low fibrinogen levels, whereas afibrinogenemia, an autosomal recessive disease, is characterized by the complete deficiency of fibrinogen. [1]

Congenital dysfibrinogenemia can be inherited in an autosomal-dominant, codominant, or autosomal-recessive pattern affecting the fibrinogen alpha, fibrinogen beta, or fibrinogen gamma genes. More than 100 mutations that result in the phenotype of abnormal fibrinogen have been identified; over 90% of those are point missense mutations. [2]

Dysfibrinogenemia may also be acquired. Chronic liver disease is the most common cause; up to 50% of patients with severe liver disease secondary to cirrhosis, hepatoma, or hepatitis exhibit bleeding complications. [3]  Other causes of acquired dysfibrinogenemia include chronic malignancies and 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]

Individuals with fibrinogen disorders may be asymptomatic or may experience bleeding or thrombotic events (or, rarely, in congenital dysfibrinogenemias, both simultaneously). Clinical manifestatoins that do occur are generally mild, but may be life threatening in severity. (See Presentation.)

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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.

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. [5]

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. [6]

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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.

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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.

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Prognosis

Prognosis is good for patients with congenital dysfibrinogenemias. Events of bleeding or thrombosis are usually relatively mild. Acquired dysfibrinogenemia carries a worse prognosis because it is due to a severely damaged liver.

While many patients with congenital dysfibrinogenemias are asymptomatic, those who experience symptoms commonly have only mild bleeding or thrombotic events, although these are extremely rare. Severe hemorrhagic episodes may characterize a few abnormal fibrinogen variants (eg, Imperate, Dettori, Detroit).

Patients with dysfibrinogenemia of liver disease often have a more severe bleeding disorder than patients with an inherited disorder. The condition tends to worsen as the liver disease worsens.

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. [7]

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