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Factor VIII inhibitors: von Willebrand factor makes a difference in vitro and in vivo
Author(s) -
SHI Q.,
KUETHER E. L.,
SCHROEDER J. A.,
PERRY C. L.,
FAHS S. A.,
COX GILL J.,
MONTGOMERY R. R.
Publication year - 2012
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2012.04902.x
Subject(s) - von willebrand factor , in vivo , in vitro , chemistry , medicine , biology , biochemistry , platelet , genetics
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 VWF null FVIII null 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 FVIII null or VWF null FVIII null 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 FVIII null or VWF null FVIII null 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 .