A novel mechanism of factor VIII protection by von Willebrand factor from activated protein C-catalyzed inactivation

48Citations
Citations of this article
33Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

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. © 2002 by The American Society of Hematology.

Cite

CITATION STYLE

APA

Nogami, K., Shima, M., Nishiya, K., Hosokawa, K., Saenko, E. L., Sakurai, Y., … Yoshioka, A. (2002). A novel mechanism of factor VIII protection by von Willebrand factor from activated protein C-catalyzed inactivation. Blood, 99(11), 3993–3998. https://doi.org/10.1182/blood.V99.11.3993

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free