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Hereditary fibrinogen abnormalities comprise two classes of plasma fibrinogen defects: (1) type I, afibrinogenemia or hypofibrinogenemia, in which there are low or absent plasma fibrinogen antigen levels (quantitative fibrinogen deficiencies), and (2) type II, dysfibrinogenemia or hypodysfibrinogenemia, in which there are normal or reduced antigen levels associated with disproportionately low functional activity (qualitative fibrinogen deficiencies). In afibrinogenemia, most mutations of the three encoding genes of fibrinogen chains are null mutations. In some cases, missense or truncating nonsense mutations allow synthesis of the corresponding fibrinogen chain, but intracellular fibrinogen assembly and/or secretion are impaired. In certain hypofibrinogenemic cases, the mutant fibrinogen molecules are produced and retained in the rough endoplasmic reticulum of hepatocytes in the form of inclusion bodies, causing endoplasmic reticulum storage disease. Afibrinogenemia is associated with mild to severe bleeding, whereas hypofibrinogenemia is most often asymptomatic. Thromboembolism also occurs either spontaneously or in association with infusions of fibrinogen-rich fractions. Because fibrin is an antithrombin (termed antithrombin I), the absence of fibrin in afibrinogenemia can render affected patients vulnerable to thrombosis. Women suffer from recurrent pregnancy loss. Hereditary dysfibrinogenemias are characterized by biosynthesis of a structurally abnormal fibrinogen molecule that exhibits reduced functional properties. Dysfibrinogenemia is commonly associated with bleeding, thrombophilia, and both thrombosis and bleeding, but in many patients it is asymptomatic. Hypodysfibrinogenemia is a subcategory of this disorder. Certain mutations involving the C-terminus of the fibrinogen α chain are associated with amyloidosis, in which an abnormal fragment from the fibrinogen αC domain is deposited in the kidneys. The cause for thrombophilia in type II fibrinogen abnormalities often is uncertain but may involve defective calcium binding, impaired tissue-type plasminogen activator-mediated fibrinolysis, resistance to fibrinolysis, defective fibrin polymerization, or reduced thrombin binding to fibrin.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: FFP, fresh-frozen plasma; FGA, fibrinogen Aα-chain gene; FGB, fibrinogen Bβ-chain gene; FGG, fibrinogen γ-chain gene; FpA, fibrinopeptide A; FpB, fibrinopeptide B; LMWH, low-molecular-weight heparin; TAFI, thrombin-activatable fibrinolysis inhibitor; t-PA, tissue-type plasminogen activator.

Several detailed and thoroughly annotated reviews of identified mutations causing inherited fibrinogen disorders have been published1–5 and a registry for hereditary fibrinogen abnormalities6 can be accessed at http://www.geht.org/databaseang/fibrinogen/. Fibrinogen plays a major role in hemostasis as the precursor molecule for the insoluble fibrin clot (Fig. 126–1), but in addition participates in numerous other biologic processes such as inflammation, wound healing, and angiogenesis. Fibrinogen binds plasminogen, α2-antiplasmin, fibronectin, and factor XIII, among other proteins. It also binds to platelets and supports platelet aggregation. After fibrinogen is converted to fibrin by thrombin, it provides nonsubstrate binding sites for thrombin and therefore, fibrinogen is sometimes termed antithrombin I.7 Fibrinogen also binds to vascular endothelial and other cells, plasma or tissue matrix components such as fibronectin and glycosaminoglycans, and peptide growth factors. Fibrin provides a template for assembly and activation of the fibrinolytic system components and is the major substrate for ...

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