ABSTRACT
Von Willebrand factor (vWF) is a multimeric glycoprotein (GP) that attracts platelets
to the site of vascular injury, mediates platelet-platelet interaction, and stabilizes
factor VIII (FVIII) in the circulation. Quantitative and qualitative defects of vWF
result in von Willebrand disease (vWD), manifested by modest to severe bleeding episodes.
Substitution therapy, with plasma-derived FVIII/vWF complex concentrates, is used
for patients suffering the more severe forms of vWD. Efficacy of these preparations
is often unsatisfactory because inadvertent proteolytic degradation during the manufacturing
process causes them to lack the hemostatically most active high-molecular-weight multimers.
In contrast, recombinant vWF (r-vWF), which is constitutively expressed at high yields
in Chinese hamster ovary (CHO) cells and secreted into the conditioned medium under
perfusion fermentation in ``protein-free'' medium, has high-molecular-weight multimers
of extraordinary structural integrity. Functional analysis has shown that r-vWF promotes
ristocetin cofactor-mediated platelet aggregation, collagen interaction and FVIII
binding, and platelet-collagen adhesion under shear stress. Infusing vWF-deficient
animals with r-vWF corrected vWF concentration and reduced blood loss, subsequently
stabilizing endogenous FVIII associated with the reduction of bleeding time. Compared
with plasma-derived vWF preparations, r-vWF was found to have a prolonged half-life,
further enhancing the potential value of r-vWF as a therapeutic agent for treating
patients suffering from vWD.
KEYWORD
von Willebrand factor - recombinant expression - multimers - biological activity -
animal model
