Catabolism of the coagulation factor VIII - Can we prolong lifetime of f VIII in circulation?

The coagulation factor VIII is required for normal haemostasis, because deficiency or genetic defects in this molecule cause a life-threatening coagulation disorder known as hemophilia A. While the role of fVIII in the intrinsic pathway of blood coagulation has been extensively studied, the mechanisms responsible for fVIII turnover in circulation have not been characterized until recently. This review? focuses on the finding that fVIII catabolism in vitro and in vivo is mediated by low-density lipoprotein receptor-related protein (LRP), representing a hepatic clearance receptor. FVIII interaction with LRP involves two distinct sites localized within the C2 and A2 domains of fVIII. We discuss the contribution of the A2 site (residues 484-509) and the C2 site in fVIII catabolism in the presence and absence of vWf. We present the evidence that LRP-mediated fVIII catabolism is facilitated by cell-surface heparan sulfate proteoglycans (HSPGs), which bind to the A2 residues 558-565 of fVIII. Because both LRP- and HSPGs-binding sites within the A2 domain are potentially exposed in the circulating fVIII/vWf complex, we discuss the possibility of prolongation of the fVIII lifetime in circulation by disrupting these sites employing site-directed mutagenesis. In its turn, generation of a novel recombinant fVIII may be prospective for more efficient hemophilia A therapy. (C) 2001, Elsevier Science Inc.