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Influence of mutations and size of multimers in type II von Willebrand
disease upon the function of von Willebrand factor
O Christophe, AS Ribba, D Baruch, B Obert, C Rouault, K Niinomi, G Pietu, D Meyer and JP Girma
INSERM U.143, Hopital de Bicetre, Paris, France.
We compared the properties of plasma von Willebrand factor (vWF) from
normal individuals and from two patients with type IIA (Glu875Lys) and type
IIB (duplication of Met 540) von Willebrand disease (vWD) with the
corresponding fully multimerized recombinant proteins. We included
cryosupernatant from normal human plasma and type IIA plasma (Cys509Arg).
Functions of vWF were analyzed by binding assays to platelets in the
presence of ristocetin or botrocetin. Parameters of binding (number of
binding sites per vWF subunit, and dissociation constant Kd) were
quantitatively estimated from the binding isotherms of 125I-botrocetin or
glycocalicin to vWF, independently of the size of the multimers. We found
that ristocetin- or botrocetin-induced binding to platelets was correlated
in all cases with the size of vWF multimers. In the absence of inducer,
only type IIB rvWF Met-Met540 spontaneously bound to platelets. No
significant difference of binding of purified botrocetin to vWF was found
between normal and patients' plasma, or between wild-type rvWF (rvWF-WT)
and rvWF-Lys875. In contrast, affinity of botrocetin for type IIB rvWF
Met-Met540 was decreased. Botrocetin-induced binding of glycocalicin to vWF
from all plasma and cryosupernatant was similar. Compared with rvWF-WT,
binding of glycocalicin to rvWF-Lys875 was normal. In contrast, the
affinity for type IIB rvWF Met-Met540 was 10-fold greater. Thus, our data
suggest that, in the patients tested, the abnormal IIA phenotype results
from the lack of large-sized multimers and is independent of the point
mutations. In contrast, the type IIB mutation is directly involved by
providing a conformation to the vWF subunits that allows the high molecular
weight multimers to spontaneously interact with platelet glycoprotein Ib.
Volume 83,
Issue 12,
pp. 3553-3561,
06/15/1994
Copyright © 1994 by The American Society of Hematology
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This article has been cited by other articles:
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A.-S. Ribba, L. Hilbert, J.-M. Lavergne, E. Fressinaud, C. Boyer-Neumann, C. Ternisien, I. Juhan-Vague, J. Goudemand, J.-P. Girma, C. Mazurier, et al.
The arginine-552-cysteine (R1315C) mutation within the A1 loop of von Willebrand factor induces an abnormal folding with a loss of function resulting in type 2A-like phenotype of von Willebrand disease: study of 10 patients and mutated recombinant von Willebrand factor
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N. Ajzenberg, A.-S. Ribba, G. Rastegar-Lari, D. Meyer, and D. Baruch
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June 15, 2000;
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3796 - 3803.
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C. Perrault, N. Ajzenberg, P. Legendre, G. Rastegar-Lari, D. Meyer, J. A. Lopez, and D. Baruch
Modulation by Heparin of the Interaction of the A1 Domain of von Willebrand Factor With Glycoprotein Ib
Blood,
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B. Obert, A. Houllier, D. Meyer, and J.-P. Girma
Conformational Changes in the A3 Domain of von Willebrand Factor Modulate the Interaction of the A1 Domain With Platelet Glycoprotein Ib
Blood,
March 15, 1999;
93(6):
1959 - 1968.
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