Congenital Disorders of Fibrinogen

Congenital fibrinogen disorders include a spectrum of defects that fall into two categories: quantitative (type I) and qualitative (type II) fibrinogen disorders. Quantitative (type I) disorders include the absence of fibrinogen (afibrinogenemia) or low fibrinogen activity and antigen levels typically <150 mg/dL (hypofibrinogenemia). Qualitative (type II) disorders entail low fibrinogen activity but discordant normal antigen (dysfibrinogenemia) or reduced antigen (hypodysfibrinogenemia). The incidence of afibrinogenemia is estimated at 1 in 1 million; however, it is higher in areas where consanguinity is common. Hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia are thought to occur more frequently; however, estimating the incidence of these subtypes is challenging, as most patients are asymptomatic. Patients with these disorders can present with a spectrum of clinical manifestations including no symptoms, bleeding, thrombosis, or both hemorrhagic and thrombotic complications.

Pathophysiology

Fibrinogen is a 340-kDa hexamer synthesized by hepatocytes that consists of two sets of three homologous polypeptide chains: Aα, Bβ, and γ ( Fig. 115.1 ). These chains are joined at their respective amino terminus by five disulfide bridges forming a central E region (E domain). The E domain also contains fibrinopeptide A (FPA) and fibrinopeptide B (FPB) on the α and β chains, respectively, and is flanked by two D regions (D domains) on either side. Fibrinogen circulates in the plasma at 150–350 mg/dL and has a half-life of 3–4 days. Platelet alpha granules also contain an internalized pool of fibrinogen.

Role in Coagulation

Fibrinogen plays a critical role in both primary and secondary hemostasis. Fibrinogen released from platelet alpha granules serves as a bridge for the platelet glycoprotein IIb/IIIa receptor on the platelet surface during platelet aggregation. After the formation of a platelet plug, the coagulation cascade is activated and thrombin is generated. Thrombin subsequently cleaves fibrinogen to fibrin inducing release of FPA and FPB from the central E domain to form a fibrin clot. The fibrin units are assembled into an organized polymeric structure and cross-linked by factor XIIIa to further stabilize the fibrin clot. Antithrombin is an important regulator of coagulation; it inhibits thrombin formation and sequesters circulating thrombin within fibrin. Fibrinogen also interacts with plasminogen, tissue plasminogen activator, and α2-antiplasmin to help regulate fibrin deposition and fibrinolysis.

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