Involvement of low-density lipoprotein receptor-related protein (LRP) in the clearance of factor VIII in von Willebrand factor-deficient mice

Factor VIII is tightly noncovalently linked to von Willebrand factor (vWF) in plasma with a stoichiometry of 1:50, and vWF deficiency results in secon dary factor VIII deficiency, with accelerated clearance of factor VIII from the circulation, We used a murine model of severe von Willebrand disease ( vWF knockout mice) to study the effect of a recombinant vWF/pro-vWF prepara tion (rpvWF) on factor VIII survival and to investigate whether low-density lipoprotein receptor-related protein (LRP) might be involved in the in viv o clearance of factor VIII in the absence of vWF, vWf deficient mice receiv ed 70 U/kg rpvWF in the first series of experiments, and in a second series , 80 mg/kg receptor-associated protein (RAP) as a recombinant fusion protei n to block the action of LRP. Factor VIII levels were measured at time 0, o r 1 or 3 hours after administration of rpvWF or RAP. RAP induced a sustaine d rise in factor VIII levels comparable to that induced by rpvWF, In a thir d series, the preadministration of RAP resulted in a slower disappearance o f factor VIII antigen (measured by an enzyme-linked immunosorbent assay spe cific for human factor VIII) after infusion of recombinant factor VIII, The se findings suggest that the accelerated clearance of factor VIII seen in t he absence of vWF may be a result of the involvement of LRP in factor VIII metabolism. (C) 2000 by The American Society of Hematology.