Alterations of fibrinogen structure in human disease

Products of normal and pathologic metabolism can react with proteins to cause covalent modification. When such modifications affect fibrinogen they can potentially alter fibrinogen function. Those that have been best studied are oxidation, nitration, homocysteinylation and glycation. It appears that the clottability of fibrinogen is maintained unless the degree of modification is extensive. However, modest degrees of fibrinogen modification can alter the rate of assembly of fibrin monomers into a fibrin clot and the fiber structure and packing. In addition, some types of modification affect lysine residues that are critical to binding, activation and activity of fibrinolytic enzymes. Any of these alterations could potentially affect the susceptibility of fibrin clots to fibrinolysis, and have been shown to do so in vitro. In the case of homocysteinylation and glycation, good evidence exists that fibrinogen modification affects clot stability in vivo. However, direct evidence is still lacking that these modifications contribute to the increased atherothrombotic risk associated with hyperhomocysteinemia and diabetes.