Fibrinogen alpha C domain: Its importance in physiopathology

Fibrinogen, involved in coagulation, is a soluble protein composed of two sets of disulfide-bridged A alpha, B beta, and gamma-chains. In this review, we present the clinical implications of the alpha C 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 (A beta) is increased and binds to the alpha C 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 alpha C domain. The mutant alpha C 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 alpha C domain or a frameshift mutation resulting in absence of a part of the alpha C 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 alpha C 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 alpha C connector of the molecule, provoking deletion of a great part of the alpha C domain, are associated with bleeding.