Dysfibrinogenemia

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]

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.

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 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]

In congenital dysfibrinogenemia, bleeding is usually mild and may not manifest until after surgical procedures or major traumatic events. Rarely, however, patients can experience combined hemorrhagic and thrombotic tendencies. In female patients with congenital afibrinogenemia, recurrent massive intra-abdominal bleeding due to rupture of Graafian follicle during ovulation has been reported.[11] In a review of 101 patients with congenital dysfibrinogenemia, the incidence of major bleeding and thrombotic events was 19.2% and 30.1%, respectively.[10]

Patients with acquired dysfibrinogenemia often have no history of bleeding or clotting, and family history is not significant for hematologic events.[1] When present, clinical manifestations of acquired dysfibrinogenemia are heterogeneous and include major bleeding or thrombosis, chronic thromboembolic pulmonary hypertension, and renal amyloidosis.[12]

Bleeding may involve any of the following:

• Menorrhagia
• Postoperative bleeding
• Epistaxis
• Postoperative wound dehiscence
• Defective wound healing
• Gingival bleeding
• Severe hemorrhage (rare)
• Mild soft-tissue hemorrhage

Thrombotic events that may occur include the following:

• Venous thrombosis (usually mild)
• Arterial thrombosis (rare)
• Thromboembolism
• Spontaneous miscarriage

In the absence of bleeding or thrombosis. the physical examination provides no clues suggesting congenital or acquired dysfibrinogenemia.  

The diagnosis is usually based on discrepancies between fibrinogen activity and antigen levels, but could require more specialized techniques for the assessment of fibrinogen function due to some limitations in routine assays.[13] Recommended testing for fibrinogen disorders, and expected results, are as follows:

• Prothrombin time (PT) – Prolonged

• Activated partial thromboplastin time (aPTT) – Prolonged

• Thrombin time (TT) is the most sensitive screening test for dysfibrinogenemias. Expect TT to be prolonged in patients with bleeding tendencies. Shortened TT may occur in patients prone to thrombosis (fibrinogen Oslo I).

• Reptilase time – Prolonged

Genotype analysis, especially of the FGA gene, should be performed in asymptomatic patients with afibrinogenemia or hypofibrinogenemia[2]

Fibrinogen is measured in plasma using the Clauss method, based on the comparison of thrombin clotting times of dilutions of plasma against a plasma standard. The fibrinogen level may be low, within the reference range, or high. However, a level within the reference range or a high level does not imply that the fibrinogen molecule is fully functioning. For this reason, assess both the clottable (functional) fibrinogen, which should be decreased, and the antigenic fibrinogen (detected by immunoassay), which should be within the reference range. Definitive characterization of the abnormal fibrinogen can be performed in a research laboratory.[14]

Euglobulin clot lysis time may aid in the diagnosis. It is a crude measure of fibrinolytic potential. Elevated values occur when the abnormal fibrinogen results in markedly decreased fibrinolysis.

Although the TT reflects the conversion of fibrinogen to fibrin and is useful for diagnosing coagulation disorders involving abnormal fibrinogen, it does not distinguish between qualitative and quantitative defects. Examination of the amplitude of coagulation curves generated during TT tests may provide additional information to help distinguish between fibrinogen disorders following a low fibrinogen measurement by the Clauss method.[15]

In liver-associated acquired dysfibrinogenemia, fibrinogen levels are usually normal, as opposed to congenital dysfibrinogenemia, in which fibrinogen levels are low normal to deficient. In addition, genetic testing of patients with acquired dysfibrinogenemia will not reveal any mutations associated with the congenital variant.

Treatment is not indicated in the majority of patients. When clinically significant bleeding occurs, replacement therapy is indicated. Fresh frozen plasma (FFP) or cryoprecipitate should be administered, depending on bleeding severity and product availability. 

Fibrinogen replacement therapy may prevent pregnancy complications.[9]

Venous thromboembolism secondary to congenital dysfibrinogenemia should be treated with low-molecular-weight heparin.[10] Patients with recurrent thrombotic events may require long-term anticoagulation with warfarin or subcutaneous heparin. Long-term treatment recommendations have not been established and data are lacking to support superiority of any one treatment modality.[1]

Educate patients with congenital dysfibrinogenemias that it is an inherited condition and other family members may also be affected.

The obstetric complications of dysfibrinogenemia include first-trimester pregnancy loss, along with hemorrhage, placental abruption, and thrombosis. Administration of prophylactic cryoprecipitate may prevent recurrent miscarriages. Miesbach et al described the use of fibrinogen concentrates to avoid pregnancy loss in women with dysfibrinogenemia. The investigators performed a retrospective study of 4 women from the same family, each of whom had dysfibrinogenemia and a history of recurrent pregnancy loss. The patients received fibrinogen concentrates from the start of pregnancy until delivery, with 3 of the 4 women achieving delivery.[16]

Class Summary

These are used to replace the clotting factors needed when moderate-to-severe bleeding occurs. This most often occurs in acquired dysfibrinogenemias caused by a severely damaged liver that is unable to make clotting factors.[17]

Cryoprecipitate

The precipitate that forms when fresh frozen plasma (FFP) is thawed contains factor VIII, fibrinogen, vWF, and fibronectin. Primarily used to treat bleeding in patients with fibrinogen deficiencies or abnormalities.

Fresh frozen plasma

Plasma is the fluid compartment of blood containing the soluble clotting factors. Indications for using FFP include bleeding in patients with congenital coagulation defects and multiple coagulation factor deficiencies (severe liver disease).

Class Summary

Prevent recurrent or ongoing thromboembolic occlusion of the vertebrobasilar circulation.

Heparin

Used in patients with thrombotic tendencies who develop deep venous thrombosis, arterial thrombosis, or pulmonary embolism.

Warfarin (Coumadin)

Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Tailor dose to maintain an INR in the range of 2-3.

Enoxaparin (Lovenox)

Chronic subcutaneous therapy may be required in patients with recurrent thrombotic episodes.

Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa.

Average duration of treatment is 7-14 d.