The impaired polymerization of fibrinogen Longmont (B beta 166Arg -> Cys) is not improved by removal of disulfide-linked dimers from a mixture of dimers and cysteine-linked monomers

This study identified a new substitution in the B beta chain of an abnormal fibrinogen, denoted Longmont, where the residue Arg166 was changed to Cys. The variant was discovered in a young woman with an episode of severe hemo rrhage at childbirth and a subsequent mild bleeding disorder. The neo-Cys r esidues were always found to be disulfide-bridged to either an isolated Cys amino acid or to the corresponding Cys residue of another abnormal fibrino gen molecule, forming dimers. Removing the dimeric molecules using gel filt ration did not correct the fibrin polymerization defect. Fibrinogen Longmon t had normal fibrinopeptide A and B release and a functional polymerization site "a." Thus, the sites "A" and "a" can interact to form protofibrils, a s evidenced by dynamic light-scattering measurements. These protofibrils, h owever, were unable to associate in the normal manner of lateral aggregatio n, leading to abnormal clot formation, as shown by an impaired increase in turbidity. Therefore, it is concluded that the substitution of Arg166 --> C ys-Cys alters fibrinogen Long-mont polymerization by disrupting interaction s that are critical for normal lateral association of protofibrils.