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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1703-1708
Involvement of low-density lipoprotein receptor-related protein
(LRP) in the clearance of factor VIII in von Willebrand
factor-deficient mice
Hans Peter Schwarz,
Peter J. Lenting,
Bernd Binder,
Judith Mihaly,
Cecile Denis,
Friedrich Dorner, and
Peter L. Turecek
From Baxter Hyland Immuno and University of Vienna, Vienna, Austria;
Center for Blood Research, Harvard University, Boston, MA; and
Department of Plasma Protein Technology, CLB, Amsterdam, The
Netherlands.
Factor VIII is tightly noncovalently linked to von Willebrand factor
(vWF) in plasma with a stoichiometry of 1:50, and vWF deficiency
results in secondary 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 preparation (rpvWF) on factor VIII survival and
to investigate whether low-density lipoprotein receptor-related protein
(LRP) might be involved in the in vivo clearance of factor VIII in the
absence of vWF. vWF-deficient mice received 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 protein to
block the action of LRP. Factor VIII levels were measured at time 0, or
1 or 3 hours after administration of rpvWF or RAP. RAP induced a
sustained rise in factor VIII levels comparable to that induced by
rpvWF. In a third series, the preadministration of RAP resulted in a
slower disappearance of factor VIII antigen (measured by an
enzyme-linked immunosorbent assay specific for human factor VIII) after
infusion of recombinant factor VIII. These findings suggest that the
accelerated clearance of factor VIII seen in the absence of vWF may be
a result of the involvement of LRP in factor VIII metabolism.
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