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Comparative analysis of type 2b von Willebrand disease mutations:
implications for the mechanism of von Willebrand factor binding to
platelets
KA Cooney and D Ginsburg
Department of Internal Medicine, University of Michigan Medical School, Ann
Arbor, MI 48109-0650 USA.
von Willebrand factor (vWF) is a multimeric glycoprotein that forms an
adhesive link following vascular injury between the vessel wall and its
primary ligand on the platelet surface, glycoprotein Ib (GpIb). Type 2b von
Willebrand disease (vWD) is a qualitative form of vWD resulting from
enhanced binding of vWF to platelets. Molecular characterization of the vWF
gene in patients with type 2b vWD has resulted in identification of a panel
of mutations associated with this disorder, all clustered within the GpIb
binding domain in exon 28 of the vWF gene. We have expressed six of the
most common type 2b vWD mutations in recombinant vWF and show that each
mutation produces a similar increase in vWF binding to platelets in the
absence or presence of ristocetin. Furthermore, expression of more than one
type 2b vWD mutation in the same molecule (cis) or in different molecules
within the same multimer (trans) failed to produce an increase in vWF
platelet binding compared with any of the individually expressed mutations.
Taken together, these data support the hypothesis that the vWF GpIb binding
domain can adopt either a discrete "on" or "off" conformation, with most
type 2b vWD mutations resulting in vWF locked in the on conformation. This
model may have relevance to other adhesive proteins containing type A
domains.
Volume 87,
Issue 6,
pp. 2322-2328,
03/15/1996
Copyright © 1996 by The American Society of Hematology
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