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Semin Thromb Hemost 2001; 27(4): 395-404
DOI: 10.1055/s-2001-16892
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Recombinant von Willebrand Factor: Preclinical Development

Barbara Plaimauer1 , Uwe Schlokat1 , Peter L. Turecek2 , Artur Mitterer1 , Wolfgang Mundt1 , Wilfried Auer2 , Ludwig Pichler2 , Herbert Gritsch,2 Friedrich Dorner1 , Hans-Peter Schwarz2
  • 1Biomedical Research Center, Baxter AG, Hyland-Immuno Division, Orth/Donau, Austria
  • 2Baxter AG, Hyland-Immuno Division, Vienna, Austria
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Publication History

Publication Date:
31 August 2001 (online)

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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

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