Congenital dysfibrinogenemia is a term used to describe a relatively rare condition wherein an inherited abnormality in the fibrin molecule results in defective fibrin clot formation. The complications associated with abnormal clot formation range from asymptomatic to life threatening. Fortunately, 40% of patients with congenital dysfibrinogenemia are asymptomatic; however, 50% of patients have a bleeding disorder and the remaining 10% have a thrombotic disorder or combined thrombotic and bleeding tendencies. Acquired dysfibrinogenemias, often called dysfibrinogenemia of liver disease, are the most common causes. Up to 50% of patients with severe liver disease secondary to cirrhosis, hepatoma, or hepatitis exhibit bleeding complications.
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. 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 the fibrinogen, which is manufactured in the liver, is due to a structural defect caused by an increased carbohydrate content impairing 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 are 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.
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.
Only 200-300 families are reported to have congenital dysfibrinogenemia. Hereditary transmission is autosomal dominant or codominant except in a few cases that appear to be transmitted recessively. Approximately 50% of patients with severe liver disease exhibit bleeding secondary to abnormal fibrinogen molecules.
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.
Prevalence is not increased in any race.
Prevalence is not increased in either sex.
Bleeding occurs in approximately 50% of patients with an inherited disorder. Usually the bleeding is mild and may not manifest until after a surgical procedure. Patients with severe liver disease may experience extreme bleeding. Bleeding may occur due to the following:
Postoperative wound dehiscence
Defective wound healing
Severe hemorrhage (rare)
Mild soft tissue hemorrhage
Thrombotic events attributable to dysfibrinogenemia occur in less than 10% of patients with hereditary dysfibrinogenemias. Thrombotic events that may occur include the following:
Venous thrombosis (usually mild)
Arterial thrombosis (rare)
Combined bleeding and thrombotic tendencies are extremely rare and associated only with congenital dysfibrinogenemias.
Although many patients with inherited dysfibrinogenemia remain asymptomatic, signs that arise tend to be associated with poor wound healing, surgical wound dehiscence, and postsurgical bleeding out of proportion to that expected.
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.