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.