Genetic Variants in the FGB and FGG Genes Mapping in the Beta and Gamma Nodules of the Fibrinogen Molecule in Congenital Quantitative Fibrinogen Disorders Associated with a Thrombotic Phenotype

Abstract

<jats:p>Fibrinogen is a hexameric plasmatic glycoprotein composed of pairs of three chains (Aα, Bβ, and γ), which play an essential role in hemostasis. Conversion of fibrinogen to insoluble polymer fibrin gives structural stability, strength, and adhesive surfaces for growing blood clots. Equally important, the exposure of its non-substrate thrombin-binding sites after fibrin clot formation promotes antithrombotic properties. Fibrinogen and fibrin have a major role in multiple biological processes in addition to hemostasis and thrombosis, i.e., fibrinolysis (during which the fibrin clot is broken down), matrix physiology (by interacting with factor XIII, plasminogen, vitronectin, and fibronectin), wound healing, inflammation, infection, cell interaction, angiogenesis, tumour growth, and metastasis. Congenital fibrinogen deficiencies are rare bleeding disorders, characterized by extensive genetic heterogeneity in all the three genes: FGA, FGB, and FGG (enconding the Aα, Bβ, and γ chain, respectively). Depending on the type and site of mutations, congenital defects of fibrinogen can result in variable clinical manifestations, which range from asymptomatic conditions to the life-threatening bleeds or even thromboembolic events. In this manuscript, we will briefly review the main pathogenic mechanisms and risk factors leading to thrombosis, and we will specifically focus on molecular mechanisms associated with mutations in the C-terminal end of the beta and gamma chains, which are often responsible for cases of congenital afibrinogenemia and hypofibrinogenemia associated with thrombotic manifestations.</jats:p>

Risk Factors for Tigecycline-Associated Hypofibrinogenemia

“… 9 The physiological concentration of fibrinogen in plasma is 1.80–4.20 g/L. 27 And the reference ranges of plasma fibrinogen varies from region to region and among different laboratories. It is the highest concentration of proteins among the plasma coagulation factors.…”

“…Fibrinogen is involved in the coagulation, which plays a central role in the hemostatic and thrombosis process. 27 The half-life of fibrinogen is 3–4 days, and it is an acute-phase reaction protein. Fibrinogen production is regulated by cytokines.…”

Interfacial Modeling of Fibrinogen Adsorption onto LiNbO3 Single Crystal–Single Domain Surfaces

“…The two end nodules (forming the C-terminal portions of the D regions) are similar and are made of the C-terminal ends of β and γ chains, while the center is a slightly smaller nodule (within the E region) that consists of the N-terminal ends of the six polypeptide chains. The central nodule is connected to the distal β-nodules and γ-nodules through two elongated coiled-coil regions [ 11 ].…”

A Novel Amino Acid Substitution, Fibrinogen Bβp.Pro234Leu, Associated with Hypofibrinogenemia Causing Impairment of Fibrinogen Assembly and Secretion

“…Quantitative disorders are afibrinogenemia and hypofibrinogenemia, which correspond to the complete absence of fibrinogen or decreased immunological fibrinogen levels, respectively [ 6 ]. Quantitative disorders due to mutations lead to decreased amounts of fibrinogen by causing defects in the synthesis of the constituent chains or in fibrinogen assembly, stability, or secretion [ 7 ]. Generally, afibrinogenemia is caused by homozygous or compound mutations, and hypofibrinogenemia is induced by heterozygous mutations [ 7 ].…”

“…Quantitative disorders due to mutations lead to decreased amounts of fibrinogen by causing defects in the synthesis of the constituent chains or in fibrinogen assembly, stability, or secretion [ 7 ]. Generally, afibrinogenemia is caused by homozygous or compound mutations, and hypofibrinogenemia is induced by heterozygous mutations [ 7 ]. On the other hand, qualitative disorders comprise dysfibrinogenemia and hypodysfibrinogenemia, which have reduced functional fibrinogen levels or disproportionately decrease the functional and immunological levels, respectively [ 8 ].…”