Fibrinogen αC domain: Its importance in physiopathology

Abstract

Essentials The C‐terminal domain of the fibrinogen α chain (αC domain) is implicated in different severe diseases via clotting abnormalities or amyloid deposits. Certain anomalies of the fibrinogen molecule lead to amyloid deposits in the kidney, inducing renal insufficiency. In contrast, in Alzheimer's disease, fibrinogen is normal, but due to an inflammatory process, fibrinogen crosses into the brain and interacts with Aβ, leading to formation of pathological deposits. Abstract Fibrinogen, involved in coagulation, is a soluble protein composed of two sets of disulfide‐bridged Aα, Bβ, and γ‐chains. In this review, we present the clinical implications of the αC domain of the molecule in Alzheimer's disease, hereditary renal amyloidosis and a number of thrombotic and hemorrhagic disorders. In Alzheimer's disease, amyloid beta peptide (Aβ) is increased and binds to the αC domain of normal fibrinogen, triggering increased fibrin(ogen) deposition in patients’ brain parenchyma. In hereditary renal amyloidosis, fibrinogen is abnormal, with mutations located in the fibrinogen αC domain. The mutant αC domain derived from fibrinogen degradation folds incorrectly so that, in time, aggregates form, leading to amyloid deposits in the kidneys. In these patients, no thrombotic tendency has been observed. Abnormal fibrinogens with either a point mutation in the αC domain or a frameshift mutation resulting in absence of a part of the αC domain are often associated with either thrombotic events or bleeding. Mutation of an amino acid into cysteine (as in fibrinogens Dusart and Caracas V) or a frameshift mutation yielding an unpaired cysteine in the αC domain is often responsible for thrombotic events. Covalent binding of albumin to the unpaired cysteine via a disulphide bridge leads to decreased accessibility to the fibrinolytic enzymes, hence formation of poorly degradable fibrin clots, which explains the high incidence of thrombosis. In contrast, anomalies due to a frameshift mutation in the αC connector of the molecule, provoking deletion of a great part of the αC domain, are associated with bleeding.

Potential Biomarkers of Acute Ischemic Stroke Etiology Revealed by Mass Spectrometry-Based Proteomic Characterization of Formalin-Fixed Paraffin-Embedded Blood Clots

“…Fibrinogen alpha chain is one of the three chains forming the soluble protein fibrinogen and one of the most abundant proteins in LAA clots. Apart from its crucial role in coagulation ( 20 ), several studies highlight that the C-terminal domain of the fibrinogen α chain (αC domain) is implicated in different clotting abnormalities ( 59 ), amyloid deposits in Alzheimer's disease ( 60 ) and familiar renal amyloidosis ( 61 ). For example, there is some evidence that the α-fibrinogen T312A variant might influence clot structure through increased factor XIII cross-linking, leading to the formation of fibrin clots that could predispose to embolization ( 62 , 63 ).…”

Zinc(II) Chelate Binds to Fibrinogen and Its αC Region

“…In addition, possible roles for metal ions in αC functions such as cell adhesion, wound healing and fibrinolysis [21] are of interest. Moreover, mutations in αC that result in clotting disorders and amyloid deposition in some cases, could be investigated further [22].…”

Fibrin(ogen) in human disease: both friend and foe

“…130 Fibrinogen-driven renal hereditary amyloidosis is a rare group of disorders with autosomal-dominant inheritance caused by heterozygosity for mutations in the αCdomain, which result in improper folding and amyloid formation followed by accumulation and deposition in the kidneys. 66 Other elements present in the deposits can further contribute to fibrin(ogen) amyloid formation, namely amyloidosis-enhancing factor 131 and serum amyloid A. 132 The latter binds to purified fibrinogen and induces amyloid formation and spontaneous dense, matted fibrin(ogen) deposits, independently of thrombin.…”

“…Amyloidosis is associated with hypertension, nephrotic syndrome, and renal failure. 66 Several renal amyloidogenic mutations in fibrinogen have been described (Online Supplementary Table S2). Patients with these mutations do not have a bleeding disorder and, when measured, the clotting times of patients with these variants are normal, except those with p.Thr544LeufsTer24 who had a prolonged thrombin time and low fibrinogen level.…”

“…37 Interestingly, four out of seven mutations result in an amino acid change to cysteine, which may bind to albumin, resulting in structurally abnormal clots. 66 Polymorphisms in the fibrinogen genes 67 have also been linked to CVD: for example, Aα p.Thr331Ala, which alters factor XIII-mediated cross-linking, results in fibrin clots prone to undergo embolization. 68 Post-translational modifications of fibrinogen (e.g., oxidation, phosphorylation, glycosylation and sialyation), might also have a role in CVD by affecting clot architecture, the rate and form of fibrin networks or the interaction with platelets and fibrinolysis.…”