Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + AFIBRINOGENEMIA AND HYPOFIBRINOGENEMIA Download Section PDF Listen +++ ++ 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 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. +++ 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. The bleeding time is prolonged and platelet aggregation is abnormal; both can be corrected by infusion of plasma or fibrinogen. +++ Treatment, Course, and Prognosis ++ 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 post-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. 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. + DYSFIBRINOGENEMIA Download Section PDF Listen +++ ++ 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 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 or to a familial thrombophilia. Hereditary renal amyloidosis is an autosomal dominant trait in which there is progressive extracellular deposition of “amyloid” protein in the kidneys, due in some instances, to deposition of fragments of a structurally abnormal fibrinogen. More than 100 distinct mutations have been identified in patients with dysfibrinogenemia and hypodysfibrinogenemia. The described mutants are very often named after the city of origin of the family or the city of the laboratory characterizing the mutation. +++ Clinical Features ++ Most patients are asymptomatic (identified as a result of routine coagulation screening). About 25% have abnormal bleeding, and 20% have thrombophilia. Some patients have both thrombophilia and bleeding. Bleeding is usually not severe (eg, epistaxis, menorrhagia, mild to moderate postoperative hemorrhage). Spontaneous abortion may occur, and excessive bleeding or thromboembolism may be seen postpartum. Defective wound healing occurs with several variants. Thrombosis is usually venous but may be arterial. Renal amyloidosis occurs in some families. +++ Laboratory Features ++ Coagulation tests requiring the formation of a fibrin clot are usually prolonged (eg, prothrombin time, activated partial thromboplastin time, thrombin time). Some variants may be detected only by abnormalities of the thrombin and/or reptilase times. It is essential to compare fibrinogen concentrations determined by different methods: functional, immunologic, and chemical. The diagnosis is based on an abnormally low functional fibrinogen level, with a normal level by immunologic or chemical methods. In hypodysfibrinogenemia, reduced levels are found by all three methods. Here the diagnosis must be made from abnormal thrombin and reptilase times. Impaired platelet aggregation and clot retraction have been reported in some families. In one family, enhanced platelet aggregation has been described. +++ Treatment ++ Patients with bleeding or undergoing surgery may require replacement therapy with cryoprecipitate or fibrinogen concentrate as outlined for afibrinogenemia. Thromboembolism is treated with anticoagulants following standard protocols. Administration of cryoprecipitate or fibrinogen concentrate prior to surgery may be beneficial both to increase the level of normal fibrinogen and to dilute the prothrombotic fibrinogen. In patients with life-threatening thromboembolic disease undergoing surgery, plasma exchange has been effective. ++ For a more detailed discussion, see Marguerite Neerman-Arbez and Phillipe de Moerloose: Hereditary Fibrinogen Abnormalities, Chap. 125 in Williams Hematology, 9th ed.
For a more detailed discussion, see Marguerite Neerman-Arbez and Phillipe de Moerloose: Hereditary Fibrinogen Abnormalities, Chap. 125 in Williams Hematology, 9th ed.