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Blood, 1 June 2002, Vol. 99, No. 11, pp. 3993-3998
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
A novel mechanism of factor VIII protection by von
Willebrand factor from activated protein C-catalyzed inactivation
Keiji Nogami,
Midori Shima,
Katsumi Nishiya,
Kazuya Hosokawa,
Evgueni L. Saenko,
Yoshihiko Sakurai,
Masaru Shibata,
Hiroshi Suzuki,
Ichiro Tanaka, and
Akira Yoshioka
From the Department of Pediatrics, Nara Medical
University, Japan; Fujimori Kogyo, Kawasaki,
Japan; and American Red Cross, Holland Laboratory,
Rockville, MD.
The protective effect of von Willebrand factor (VWF) toward
activated protein C (APC)-catalyzed inactivation of factor VIII (FVIII) has been attributed mainly to inhibition of FVIII binding to
phospholipid. In the present study, we demonstrated that VWF-mediated FVIII protection from APC also results from direct inhibition of FVIII
binding to APC. Inhibition of FVIII binding to anhydro-APC by VWF would
be consistent with partial or complete overlap of the FVIII binding
sites for APC and VWF. We examined, therefore, the inhibitory effects
of 6 synthetic peptides spanning residues 1996 to 2028 around the
previously localized APC binding region (FVIII residues 2009-2018).
Peptide 2009 to 2018 inhibited FVIII binding to anhydro-APC by 83%
(50% inhibition, 55 µM). Similarly, peptide 2013 to 2022 inhibited
FVIII binding to VWF by 84% (50% inhibition, 25 µM). It was also
found that peptides 2009 to 2018 and 2013 to 2022 optimally bound to
anhydro-APC and VWF, respectively. A rabbit antipeptide IgG, raised
against peptide 2009 to 2022, blocked the binding of both anhydro-APC
and VWF to FVIII. This immunoglobulin G inhibited proteolytic cleavage
of FVIII by APC. Our results indicate that the essential regions for
the binding of APC and VWF to FVIII overlap and that the protective
effect of VWF on APC-catalyzed FVIII inactivation includes competitive inhibition of APC binding to FVIII by VWF.
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