Fibrinogen Mitaka II: a hereditary dysfibrinogen with defective thrombin
binding caused by an A alpha Glu-11 to Gly substitution
K Niwa, A Yaginuma, M Nakanishi, Y Wada, T Sugo, S Asakura, N Watanabe and M Matsuda
Division of Hemostasis and Thrombosis Research, Jichi Medical School,
Tochigi, Japan.
A new type of A alpha Glu-11 to Gly substitution has been identified in a
congenitally abnormal fibrinogen, fibrinogen Mitaka II, derived from a
14-year-old female suffering from easy bruising since childhood. Plasma of
the patient and fibrinogen purified therefrom were found to clot slowly by
thrombin but in a normal fashion by ancrod, a thrombin- like snake venom
enzyme. The ancrod-clotted fibrin gels were normally solid and turbid,
whereas the thrombin-clotted gels were initially fragile and transparent
but became gradually normalized during further incubation. On reverse-phase
high-performance liquid chromatography, there was an additional peptide
group eluted distinctly later than the corresponding normal fibrinopeptide
A in the clot-liquor of the patient's samples. Sequence analysis of these
aberrant peptides and isolated A alpha chains of the patient's fibrinogen
showed that Glu at position 11 of the abnormal A alpha chain had been
replaced by Gly. Studies using 125I-labeled thrombin showed that the
binding with thrombin was evidently reduced for her fibrinogen and the
aberrant fibrinopeptide A as compared with that for the normal controls,
indicating that A alpha Glu-11 may be critical for the fibrinogen- thrombin
interaction. Indeed, A alpha Glu-11 of fibrinogen has recently been
proposed to stabilize the local conformation, including the beta- turn, and
to form a salt bridge between its side-chain carboxyl group and the
guanidino group of Arg-173 of thrombin based on crystallographic analyses
using analogs of fibrinopeptide A complexed with thrombin (Stubb et al, Eur
J Biochem 206:187, 1992 and Martin et al, J Biol Chem 267:7911, 1992).
Volume 82,
Issue 12,
pp. 3658-3663,
12/15/1993
Copyright © 1993 by The American Society of Hematology
