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Blood, 1 July 2002, Vol. 100, No. 1, pp. 153-158
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Circulating and binding characteristics of wild-type factor IX
and certain Gla domain mutants in vivo
Tong Gui,
Hui-Feng Lin,
Da-Yun Jin,
Maureane Hoffman,
David L. Straight,
Harold R. Roberts, and
Darrel W. Stafford
From the Departments of Biology, Medicine, and
Pathology, University of North Carolina at Chapel Hill, and the
Departments of Pathology and Laboratory Medicine, Durham Veterans
Administration and Duke University Medical Centers, NC.
Residue K5 in factor IX  -carboxyglutamic acid (Gla)
domain participates in binding endothelial cells/collagen IV. We
injected recombinant factor IX containing mutations at residue 5 (K5A, K5R) into factor IX-deficient mice and compared their behavior with
that of wild-type factor IX. The plasma concentration of factor IX that
binds to endothelial cells/collagen IV (recombinant wild type and K5R)
was consistently lower than that of the one that does not bind (K5A).
Mice treated with wild type or K5R had 79% of the injected factor IX
in the liver after 2 minutes, whereas 17% remained in circulation. In
mice injected with K5A, 59% of the injected factor IX was found in
liver and 31% was found in plasma. When we blocked the liver
circulation before factor IX injection, 74% of K5A and 64% of K5R
remained in the blood. When we treated the mouse with EDTA after
injecting exogenous factor IX, the blood levels of factor IX that bind
to endothelial cells/collagen IV increased, presumably because of
release from endothelial cell/collagen IV binding sites. In contrast,
the levels of the mutants that do not bind were unaffected by EDTA. In
immunohistochemical studies, factor IX appears on the endothelial
surfaces of mouse arteries after factor IX injection and of human
arteries from surgical specimens. Thus, we have demonstrated that
factor IX binds in vivo to endothelial cell-collagen IV surfaces. Our
results suggest that factor IX Gla-domain mediated binding to
endothelial cells/collagen IV plays a role in controlling factor IX
concentration in the blood.
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