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.)
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]
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. 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]
Acquired dysfibrinogenemia is more likely to present as bleeding than as thrombosis. Patients with acquired dysfibrinogenemia often have no history of bleeding or clotting, and family history is not significant for hematological events.[2]
Clinical manifestations of dysfibrinogenemia are heterogeneous, ranging from absence of symptoms to major bleeding or thrombosis, chronic thromboembolic pulmonary hypertension, and renal amyloidosis.[8]
In a review of 101 patients with congenital dysfibrinogenemia by Casini and colleagues, the cumulative incidence rate of major bleeding was determined to be 19.2%, and cumulative incidence rate for thrombotic events was determined to be 30.1%.[7]
Bleeding is usually mild and may not manifest until after a surgical procedure. Patients with severe liver disease may experience extreme bleeding. Bleeding may involve the following:
Thrombotic events that may occur include the following:
Combined bleeding and thrombotic tendencies are extremely rare and associated only with congenital dysfibrinogenemias.
In female patients with congenital afibrinogenemia, recurrent massive intraabdominal bleeding due to rupture of Graafian follicle during ovulation has been described.
Another rare manifestation of dysfibrinogenemia is hereditary renal amyloidosis, in which the amyloid fibril consists of abnormal fibrinogen fragments. These cases are associated with obliterative glomerular lesions. The mutations are clustered around the aminoterminal end of the α chain.
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.
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. Although the coagulation assay, thrombin time (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.[9]
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.
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.[10] Recommended testing for fibrinogen disorders, and expected results, are as follows:
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 functioning appropriately. For this reason, assess both the clottable (functional) fibrinogen, which should be decreased, and the antigenic fibrinogen (detected only by immunoassay), which should be within the reference range. Definitive characterization of the abnormal fibrinogen can be performed in a research laboratory.[11]
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.
Medical treatment is not indicated in the majority of patients. When patients experience clinically significant bleeding, fresh frozen plasma (FFP) or cryoprecipitate may be transfused, depending on the severity of the bleeding.
Venous thromboembolism secondary to congenital dysfibrinogenemia should be treated with low-molecular-weight heparin.[7] 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.[2]
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.[12]
Although many patients with fibrinogen disorders remain asymptomatic or have only mild clinical manifestations, treatment may be indicated for cases of severe bleeding or thromboembolism.
Clinical Context: 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.
Clinical Context: 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).
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.[13]
Clinical Context: Used in patients with thrombotic tendencies who develop deep venous thrombosis, arterial thrombosis, or pulmonary embolism.
Clinical Context: 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.
Clinical Context: 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.
Prevent recurrent or ongoing thromboembolic occlusion of the vertebrobasilar circulation.