Regulation of Factor VIII Life-Cycle by Receptors from LDL Receptor Superfamily

Abstract

The present review discusses the current concept of receptor-mediated clearance of coagulation factor VIII (FVIII) from the circulation in vivo, which is one of the mechanisms regulating FVIII level in plasma. Several lines of experimental evidence suggest that two receptors from the LDL receptor family, low-density lipoprotein receptor-related protein (LRP) and LDL receptor, cooperate in this process. Administration of receptor-associated protein, a classical antagonist of these receptors, leads to prolongation of FVIII half-life in mice.The elevation of FVIII level and prolongation of its mean residence time, recorded in conditional LRP-deficient mice, directly confirm the physiological role of LRP in mediating clearance of FVIII. Mice with combined LRP and low-density lipoprotein receptor (LDLR) deficiency show a further increase of FVIII level and more impressive, ~5-fold, prolongation of FVIII residence time in the circulation. Receptor-mediated clearance of FVIII is facilitated by heparan sulfate proteoglycans of extracellular matrix, which provide the initial binding of FVIII to the cell surface.We discuss the mapping of the major high-affinity LRP-binding sites to the regions 484-509 and 1811-1818 of A2 and A3 domains of FVIII, respectively; LDLR-binding sites are yet to be identified. Mutagenesis of these sites may result in disruption/reduction of FVIII/receptor interaction and consequently lead to clinically-significant prolongation of FVIII lifetime in the circulation.We demonstrate the feasibility of this approach by the results of Ala-scanning mutagenesis of the A2 LRP-binding site. Generation of a novel recombinant FVIII with prolonged lifetime would meet the demands, improve the efficacy and reduce the cost of FVIII replacement therapy of Hemophilia A.