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Blood, 1 December 2000, Vol. 96, No. 12, pp. 3779-3785
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
End-linked homodimers in fibrinogen Osaka VI with a
B -chain extension lead to fragile clot structure
Teruko Sugo,
Chizuko Nakamikawa,
Nobuhiko Yoshida,
Kazuki Niwa,
Masazumi Sameshima,
Jun Mimuro,
John W. Weisel,
Akira Nagita, and
Michio Matsuda
From the Center for Molecular Medicine, Jichi Medical
School, Tochigi, Japan; Toshiba Hospital, Tokyo, Japan; Department of
Cell Biology, The Tokyo Metropolitan Institute of Medical Science,
Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan;
Department of Cell and Developmental Biology, University of
Pennsylvania, School of Medicine, Philadelphia, PA; and Department of
Pediatrics, Kawasaki Medical School, Kurashiki, Japan.
The authors have identified a 12-residue carboxyl-terminal
extension of Lys-Ser-Pro-Met-Arg-Arg-Phe-Leu-Leu-Phe-Cys-Met in a dysfibrinogen derived from a woman heterozygotic for this abnormality and associated with severe bleeding. This extension is due to a T-to-A
mutation that creates AAG encoding Lys at the stop (TAG) codon, thus
translating 36 base pairs in the noncoding region of the B gene. The
extra Cys residues appear to be involved in 1 or 2 disulfide bonds
between 2 adjacent abnormal fibrinogen molecules, forming a fibrinogen
homodimer as indicated by sodium dodecyl sulfate-polyacrylamide gel
electrophoresis. Indeed, about half of the fibrinogen molecules exist
as end-linked dimers oriented in parallel or with an angle, as observed
by transmission electron microscopy. These end-linked dimers may well
alter the conformations of D and DD regions on fibrin assembly, leading
to increased fiber branching at their sites in the growing
protofibrils. By scanning electron microscopy, the Osaka VI fibrin
network appears to have a lacelike structure composed of highly
branched, thinner fibers than the normal fibrin architecture. Such
fibrin networks may be easily damaged to form large pores when fluids
are allowed to pass through the gels. The fragility of Osaka VI fibrin
clots, further confirmed by permeation and compaction studies, may
account for the massive bleeding observed in this patient.
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