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A gamma Gly-268 to Glu substitution is responsible for impaired fibrin
assembly in a homozygous dysfibrinogen Kurashiki I
K Niwa, M Takebe, T Sugo, Y Kawata, J Mimuro, S Asakura, Y Sakata, J Mizushima, A Maeda, H Endo and M Matsuda
Division of Hemostasis and Thrombosis Research, Institute of Hematology,
Jichi Medical School, Tochigi, Japan.
A new type of gamma Gly-268 (GGA) to Glu (GAA) substitution has been
identified in a homozygous dysfibrinogen by analyses of the affected
polypeptide and its encoding gene derived from a 58 year-old man
manifesting no major bleeding or thrombosis. The functional abnormality was
characterized by impaired fibrin assembly most likely due to failure to
construct properly aligned double-stranded fibrin protofibrils. This
presumption was deduced from the following findings: (1) Factor
XIIIa-catalyzed cross-linking of the fibrin gamma-chains progressed in a
normal fashion, indicating that the contact between 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, suggesting that longitudinal
association of D domains of different fibrin monomers, ie, D:D association
was perturbed; (3) Plasminogen activation catalyzed by tissue-type
plasminogen activator was not as efficiently facilitated by polymerizing
fibrin monomer derived from the patient 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 the central E domain, but would be rather
involved in the D:D self association 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.
Volume 87,
Issue 11,
pp. 4686-4694,
06/01/1996
Copyright © 1996 by The American Society of Hematology
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