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 f VIII in the intrinsic pathway of blood coagulation has been extensively studied, the mechanisms responsible for f VIII turnover in circulation have not been characterized until recently. This review focuses on the finding that f VIII 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 f VIII. We discuss the contribution of the A2 site (residues 484-509) and the C2 site in f VIII catabolism in the presence and absence of vWf. We present the evidence that LRP-mediated f VIII catabolism is facilitated by cell-surface heparan sulfate proteoglycans (HSPGs), which bind to the A2 residues 558-565 of f VIII. Because both LRP- and HSPGs-binding sites within the A2 domain are potentially exposed in the circulating f VIII/vWf complex, we discuss the possibility of prolongation of the f VIII lifetime in circulation by disrupting these sites employing site-directed mutagenesis. In its turn, generation of a novel recombinant f VIII may be prospective for more efficient hemophilia A therapy.
Ananyeva
N M
NM
Holland Laboratory, American Red Cross, Rockville, Maryland 20855, USA.
Kouiavskaia
D V
DV
Shima
M
M
Saenko
E L
EL
D005169:Factor VIII / Q000378:metabolism* / Q000502:physiology; D006467:Hemophilia A / Q000097:blood* / Q000235:genetics; D006497:Heparan Sulfate / Q000494:pharmacology; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism* / Q000502:physiology; D014841:von Willebrand Factor / Q000502:physiology
D005169:Factor VIII; D006497:Heparan Sulfate; D026502:LDL-Receptor Related Proteins; D014841:von Willebrand Factor