Recombinant von Willebrand factor: potential therapeutic use.

Abstract

Human von Willebrand factor (vWF) produced by recombinant technology offers a new perspective in treatment of von Willebrand disease (vWD). Several limitations connected with plasma-derived vWF concentrates, such as proteolytic degradation during the manufacture process, variation in multimer composition, lack of high molecular weight multimers, and donor dependence, can be overcome by rec-vWF. Recombinant vWF (rec-vWF) is produced by continuous fermentation of transformed mammalian cells. Biotechnological processes have been developed to isolated rec-vWF fractions with low, medium, and high degrees of multimerization. Structural analysis of rec-vWF demonstrated that it undergoes post-translational modifications comparable with plasma-derived vWF, such as multimerization, pro-peptide processing, and glycosylation. Functional analysis showed that rec-vWF exhibited activities comparable with plasma-derived vWF, such as platelet binding, platelet aggregation, collagen binding, and coagulation factor VIII (FVIII) binding. Collagen binding and platelet aggregation activity increased with the increasing multimer size of rec-vWF. Infusion of rec-vWF in antibody-induced vWF-deficient mice resulted in a significant decrease in bleeding. Infusion of rec-vWF in vWF-deficient dogs and pigs with severe vWD caused an increase in the endodenous FVIII level. Stabilization of FVIII in vivo was mediated both by high and low molecular weight rec-vWF molecules. Apparently, rec-vWF resisted proteolytic degradation in the circulation and no satellite bands were formed. Functional analysis in vitro and in vivo demonstrated the therapeutic potentials of rec-vWF, correction of vWF level, and stabilization of FVIII in plasma.