Blood, 1 August 2001, Vol. 98, No. 3, pp. 661-666
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
The impaired polymerization of fibrinogen Longmont
(B
166Arg
Cys) is not improved by removal of disulfide-linked
dimers from a mixture of dimers and cysteine-linked monomers
Karim C. Lounes,
Jerry B. Lefkowitz,
Agnes H. Henschen-Edman,
Andrew I. Coates,
Roy R. Hantgan, and
Susan T. Lord
From the Department of Pathology and Laboratory
Medicine and the Department of Chemistry, University of North Carolina,
Chapel Hill, NC; Department of Pathology, University of Colorado School
of Medicine, Denver, CO; Department of Molecular Biology and
Biochemistry, University of California, Irvine, CA; and the Department
of Biochemistry, Wake Forest University School of Medicine,
Winston-Salem, NC.
This study identified a new substitution in the B
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 hemorrhage at childbirth and a
subsequent mild bleeding disorder. The neo-Cys residues were always
found to be disulfide-bridged to either an isolated Cys amino acid or to the corresponding Cys residue of another abnormal fibrinogen molecule, forming dimers. Removing the dimeric molecules using gel
filtration did not correct the fibrin polymerization defect. Fibrinogen
Longmont had normal fibrinopeptide A and B release and a functional
polymerization site "a." Thus, the sites "A" and "a" can
interact to form protofibrils, as evidenced by dynamic light-scattering measurements. These protofibrils, however, were unable
to associate in the normal manner of lateral aggregation, leading to
abnormal clot formation, as shown by an impaired increase in turbidity.
Therefore, it is concluded that the substitution of Arg166
Cys-Cys
alters fibrinogen Longmont polymerization by disrupting interactions
that are critical for normal lateral association of protofibrils.
