A GAMMA-GLY-268 TO GLU SUBSTITUTION IS RESPONSIBLE FOR IMPAIRED FIBRIN ASSEMBLY IN A HOMOZYGOUS DYSFIBRINOGEN KURASHIKI-I

A new type of gamma Gly-268 (<G(G)under bar A>) to Glu (<G(A)under bar A>) substitution has been identified in a homozygous dysfibrinogen by analyses of the affected polypeptide and its encoding gene derived fr om a 58 year-old man manifesting no major bleeding or thrombosis. The functional abnormality was characterized by impaired fibrin assembly m ost likely due to failure to construct properly aligned double-strande d fibrin protofibrils. This presumption was deduced from the following findings: (1) Factor XIIIa-catalyzed cross-linking of the fibrin gamm a-chains progressed in a normal fashion, indicating that the contact b etween the central E domain of one fibrin monomer and the D domain of another took place normally; (2) Nevertheless, factor XIIIa-catalyzed cross-linking of the fibrinogen gamma-chains was obviously delayed, su ggesting that longitudinal association of D domains of different fibri n monomers, ie, D:D association was perturbed; (3) Plasminogen activat ion catalyzed by tissue-type plasminogen activator was not as efficien tly facilitated by polymerizing fibrin monomer derived from the patien t as by the normal counterpart. Therefore, gamma Gly-268 would not be involved in the 'a' site residing in the D domain, which functions as a complementary binding site with the thrombin-activated 'A' site in t he central E domain, but would be rather involved in the D:D self asso ciation sites recently proposed for human fibrinogen. Thus, the gamma Glu-268 substitution newly identified in this homozygous dysfibrinogen seems to impair proper alignment of adjacent D domains of neighboring fibrin molecules in the double-stranded fibrin protofibril, resulting in delayed fibrin gel formation. (C) 1996 by The American Society of Hematology.