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AFIBRINOGENEMIA AND HYPOFIBRINOGENEMIA

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  • 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.

  • Mutations resulting in afibrinogenemia or hypofibrinogenemia are presented in Chap. 126, Table 126–1, p. 2055 in Williams Hematology, 8th ed.

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Clinical Features

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  • 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 at 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.

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Laboratory Features

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  • 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.

  • The bleeding time is prolonged and platelet aggregation is abnormal; both can be corrected by infusion of plasma or fibrinogen.

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Therapy, Course, and Prognosis

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

  • Cryoprecipitate typically contains 300 mg of fibrinogen per unit. Approximately 50 to 70 percent of the administered fibrinogen circulates posttransfusion, 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.

  • 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.

  • 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.

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DYSFIBRINOGENEMIA

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  • 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.

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Etiology and Pathogenesis

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  • 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 fibrin polymerization.

    — Defective cross-linking by factor XIIIa.

  • Biochemical abnormalities do not correlate with clinical expression. For example, the same amino acid substitution can lead to either a familial bleeding tendency ...

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