Factor VIII inhibitors: von Willebrand factor makes a difference in vitro and in vivo
Article first published online: 30 OCT 2012
© 2012 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 10, Issue 11, pages 2328–2337, November 2012
How to Cite
SHI, Q., KUETHER, E. L., SCHROEDER, J. A., PERRY, C. L., FAHS, S. A., COX GILL, J. and MONTGOMERY, R. R. (2012), Factor VIII inhibitors: von Willebrand factor makes a difference in vitro and in vivo. Journal of Thrombosis and Haemostasis, 10: 2328–2337. doi: 10.1111/j.1538-7836.2012.04902.x
- Issue published online: 30 OCT 2012
- Article first published online: 30 OCT 2012
- Accepted manuscript online: 21 AUG 2012 10:35AM EST
- Received 10 July 2012, accepted 14 August 2012
- inhibitory antibody;
Summary. Background: The important association between von Willebrand factor (VWF) and factor VIII (FVIII) has been investigated for decades, but the effect of VWF on the reactivity of FVIII inhibitory antibodies, referred to as inhibitors, is still controversial.
Objective: To investigate the interaction among VWF, FVIII and FVIII inhibitory antibodies.
Methods: Three sources of inhibitors were used for in vitro studies, including the plasma from immunized VWFnullFVIIInull mice, purified plasma IgG from human inhibitor patients, or human monoclonal antibody from inhibitor patients’ B-cell clones. Inhibitors were incubated with recombinant human FVIII (rhFVIII) either with or without VWF. The remaining FVIII activity was determined by chromogenic assay and inhibitor titers were determined. For in vivo studies, inhibitors and rhFVIII were infused into FVIIInull or VWFnullFVIIInull mice followed by a tail clip survival test.
Results: VWF has a dose-dependent protective effect on FVIII, limiting inhibitor inactivation of FVIII in both mouse and human samples. A preformed complex of VWF with FVIII provides more effective protection from inhibitors than competitive binding of antibodies and VWF to FVIII. The protective effect of VWF against FVIII inactivation by inhibitors was further confirmed in vivo by infusing inhibitors and FVIII into FVIIInull or VWFnullFVIIInull mice followed by a tail clip survival test.
Conclusion: Our results demonstrate that VWF exerts a protective effect, reducing inhibitor inactivation of FVIII, both in vitro and in vivo.