Factor VIII inhibitors: von Willebrand factor makes a difference in vitro and in vivo.
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.


CONCLUSIONS
Our results demonstrate that VWF exerts a protective effect, reducing inhibitor inactivation of FVIII, both in vitro and in vivo.
Department of Pediatrics, Medical College of Wisconsin Blood Research Institute, BloodCenter of Wisconsin Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI, USA.
Q
Q
Shi
E L
EL
Kuether
J A
JA
Schroeder
C L
CL
Perry
S A
SA
Fahs
J
J
Cox Gill
R R
RR
Montgomery
D000818:Animals; D000906:Antibodies / Q000737:chemistry; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001667:Binding, Competitive; D001792:Blood Platelets / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D006467:Hemophilia A / Q000188:drug therapy; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D014841:von Willebrand Factor / Q000737:chemistry* / Q000235:genetics
D000906:Antibodies; D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D005169:Factor VIII