The Structural Error And Its Relation To The Malfunction In Some Abnormal Fibrinogens

The primary structure elucidation of normal human fibrinogen has recently been completed. Thus, it is now possible to analyse the structure- function relationship in detail. In abnormal fibrinogens the function is altered. It is obvious that information about the corresponding structural errors would be of great importance. Functional abnormality of fibrinogen has been described for more than 70 cases. However, only in a single case, Fibrinogen Detroit, the structural error was identified by Blombäck’s group. Recently, our group has analysed several abnormal fibrinogen by separating the three peptide chains and performing direct sequence analysis of the chains. The first fibrinogen (obtained from R. Marx and W. Schramm) had an Arg→Asn substitution in position 19 of the Aa-chain, i.e. in the same position as in Fibrinogen Detroit, and was characterised by delayed A- peptide release and monomer polymerisation. The second fibrinogen (obtained from C. and J. Soria) had an Arg→Cys exchange in position 16 of the Aα- chain, and was characterised by absence of releasable A-peptide. The third fibrinogen (obtained from V. Hofmann) had the same substitution as the previous, but in the heterozygous state, and was characterised by delayed A-peptide release. It is obvious that when the Arg residue in position 16, i.e. at the thrombin cleavage site, is replaced by a neutral residue thrombin will not cleave. When the Arg residue in position 19 is exchanged the cleavage is slowed down. Several other fibrinogens with delayed A-peptide release showed, however, no primary structure error in this section of the molecule.