Hereditary fibrinogen abnormalities make up 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. In some cases, missense or late-truncating nonsense mutations allow synthesis of the corresponding fibrinogen chain, but intracellular fibrinogen assembly and/or secretion is 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 often asymptomatic. Thromboembolism may also occur and affected women may 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, thrombosis, or 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 α C 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, or reduced thrombin binding to fibrin. Replacement therapy with fibrinogen concentrates has proven to be useful for management of fibrinogen disorders but should be adapted to each patient, based on the personal and family history.
Acronyms and Abbreviations
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; PCR: polymerase chain reaction; TAFI, thrombin-activatable fibrinolysis inhibitor; t-PA, tissue-type plasminogen activator.
Several detailed and thoroughly annotated reviews of mutations causing inherited fibrinogen disorders have been published1,2,3 and the previous version of this chapter published in the eighth edition4 contained tables compiling causative mutations identified before 2009. In addition, a registry for hereditary fibrinogen abnormalities5 can be accessed at http://www.geht.org/databaseang/fibrinogen/ that lists variants reported in publications, conference abstracts, and submitted online, with original references. This chapter discusses the major molecular mechanisms leading to disease, as well as the laboratory and clinical aspects of fibrinogen disorders and their treatment, without listing all fibrinogen gene anomalies.
Fibrinogen plays a major role in hemostasis as the precursor molecule for the insoluble fibrin clot (Fig. 125–1). In addition fibrinogen participates in numerous other biologic processes, such as inflammation, wound healing, and angiogenesis. Fibrinogen binds plasminogen, α-antiplasmin, fibronectin, and factor XIII, among other proteins. It also binds to ...