Chapter 81: Hereditary Disorders of Fibrinogen

AFIBRINOGENEMIA AND HYPOFIBRINOGENEMIA

• Quantitative disorders of fibrinogen may be afibrinogenemia or hypofibrinogenemia, depending on the severity.

• Normal fibrinogen levels range from 150 to 350 mg/dL. In afibrinogenemia, the fibrinogen concentration is less than 20 mg/dL. In hypofibrinogenemia, the level is less than normal.

• Approximately 100 distinct mutations have been identified in patients with afibrinogenemia (in homozygosity or in compound heterozygosity) or in hypofibrinogenemia. Causative mutations can be divided into two main classes: null mutations with no protein production at all and mutations producing abnormal protein chains that are retained inside the cell.

Clinical Features

• Congenital afibrinogenemia is a rare disorder of hepatic biosynthesis of fibrinogen, inherited as an autosomal recessive trait, with low levels of fibrinogen typically found in both parents.

• Bleeding varies from minimal to severe. Umbilical cord bleeding may occur after birth. Later, bleeding may be from mucosal surfaces, into muscles, or into joints.

• Spontaneous abortions are frequent.

• Death is most often a result of intracranial hemorrhage.

• Hereditary hypofibrinogenemia appears to be caused by abnormal intracellular hepatic storage of fibrinogen.

Laboratory Features

• All laboratory tests depending on formation of a clot are abnormal in afibrinogenemia or hypofibrinogenemia but can be corrected by mixing with normal plasma or fibrinogen solutions.

• The diagnosis is established by demonstrating a reduced fibrinogen concentration by immunologic testing.

• Platelet aggregation is abnormal and can be corrected by infusion of plasma or fibrinogen.

Treatment, Course, and Prognosis

• Replacement therapy with fibrinogen concentrate or cryoprecipitate (if available) may be required.

• Fibrinogen concentrate should be given to increase the plasma concentrations by at least 150 mg/dL. One gram of fibrinogen concentrate raises the plasma fibrinogen level by 20 mg/dL in adults.

• Cryoprecipitate typically contains 300 mg of fibrinogen per unit. Approximately 50% to 70% of the administered fibrinogen circulates after transfusion, and the biologic half-life of fibrinogen is 3 to 5 days. The recommended initial dose is 1 unit of cryoprecipitate (300 mg of fibrinogen) per 5 kg of body weight to reach hemostatic levels of fibrinogen.

• Patients should receive one-third of the initial loading dose daily as long as is necessary to sustain the fibrinogen level.

• Cryoprecipitate or fibrinogen concentrate may be given during pregnancy to prevent spontaneous abortion or premature birth.

• Thrombosis can occur after administration of fibrinogen, and antifibrinogen antibodies may develop.

DYSFIBRINOGENEMIA

• Inherited dysfibrinogenemia is the production of structurally abnormal fibrinogen molecules with altered functional properties. At least 300 families with this fibrinogenemia have been described thus far.

• Hypodysfibrinogenemia refers to patients with low levels of circulating abnormal fibrinogen.

Etiology and Pathogenesis

• Dysfibrinogenemia is inherited as an autosomal dominant trait. Most patients are heterozygous but some are homozygous.

• Fibrinogen abnormalities usually affect one or more phases of fibrin formation:

  — Impaired fibrinopeptide release

  — Defective ...