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Fibrinogen

Conversion of fibrinogen into fibrin is the last stage of the coagulation sequence. Fibrinogen plays an important role in fibrin clot formation, factor XIIIa mediated fibrin crosslinking, platelet aggregation and fibrinolysis. If fibrinogen is quantitatively or qualitatively abnormal, bleeding or thrombosis may ensue.

Decreased clottable fibrinogen may be due to a quantitative deficiency, called hypofibrinogenemia, or a qualitative abnormality, known as dysfibrinogenemia. Acquired hypofibrinogenemia may occur in severe liver disease, acute DIC, and primary fibrinolysis. Fibrinogen levels below 70 mg/dL inhibit the coagulation cascade. Dysfibrinogenemia may be either hereditary or acquired. Both forms can cause bleeding and the inherited form can also cause venous and arterial thrombosis.

Hereditary afibrinogenemia (absence of fibrinogen, the homozygous state) and hypofibrinogenemia (the heterozygous state, levels about half normal) have been described. Inherited dysfibrinogenemia should be suspected in patients with unexplained bleeding or thrombosis, especially if there is a family history with an autosomal dominant pattern of inheritance. Approximately 55% of patients with inherited dysfibrinogenemia are asymptomatic, 25% have bleeding and 20% have thrombosis. Approximately 14% experience both bleeding and thrombosis. The prevalence of inherited dysfibrinogenemia among patients with a history of venous thrombosis is 0.8%.

Bleeding manifestations are nonspecific and include nose bleeds, easy bruising, heavy menstruation, muscle and joint hemorrhage, postoperative bleeding, bleeding during or after childbirth and delayed wound healing. Thrombotic manifestations are also nonspecific and include deep vein thrombosis, thrombophlebitis, pulmonary embolism and arterial thrombosis.

Approximately 245 mutations in the fibrinogen genes have been reported. These mutations interfere with thrombin-mediated release of fibrinopeptide A and/or B from fibrinogen, which is necessary for fibrin polymerization. Mutations associated with thrombosis appear to cause defective fibrinolysis by interfering with the binding of tissue plasminogen activator or plasmin to fibrin.

Acquired dysfibrinogenemia should be suspected in patients with an unexplained prolongation of the thrombin time. The most common etiology is disease of the liver or biliary tract. Specific diseases include:

  • Cirrhosis
  • Chronic active hepatitis
  • Acute liver failure
  • Acetaminophen overdose
  • Graft versus host disease
  • Obstructive jaundice
  • Paraneoplastic syndrome (hepatoma, renal cell carcinoma)
  • Mithramycin therapy

The thrombin time is the primary screening test for both inherited and acquired dysfibrinogenemia. A laboratory testing algorithm for the diagnosis of dysfibrinogenemia is shown below.

The initial test is the thrombn time. If it is normal, then the next test is the reptilase time. If both tests are normal, the diagnosis is excluded. If either test is prolonged, then the confirmatory test is the fibrinogen activity:antigen ratio. If this test is normal, the diagnosis can be excluded.

A variety of clinical conditions other than dysfibrinogenemia can also prolong the thrombin time including:

  • Amyloidosis
  • Argatroban therapy
  • Bovine thrombin, topical
  • Heparin
  • Hirudin
  • Tissue plasminogen activator (TPA)
  • Urokinase
  • Radioconrast agents – diatrizoate, ioxaglate, ioxitalamate, iopamidol, metrizamide

Because fibrinogen is an acute phase reactant, elevated levels are frequently seen in inflammatory disorders, pregnancy, or after surgery. Many epidemiological studies have reported an association between coronary heart disease (CHD) and various “inflammatory” factors, including plasma levels of fibrinogen, C-reactive protein, albumin, and white blood cell (WBC) count. The risk ratio of an elevated fibrinogen level for coronary heart disease (CHD) is1.8. Higher fibrinogen levels may promote CHD by increasing blood viscosity and enhancing platelet aggregation. Fibrinogen may also mediate part of the effect of smoking on CHD, because its levels are approximately 10% higher in smokers than non-smokers.

Specimen requirement is one light blue top (sodium citrate) tube.

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