Factor VIII inhibitors: von Willebrand factor makes a difference in vitro and in vivo. J Thromb Haemost 2012 Nov;10(11):2328-37
Date
08/23/2012Pubmed ID
22908929Pubmed Central ID
PMC3670966DOI
10.1111/j.1538-7836.2012.04902.xScopus ID
2-s2.0-84868144084 (requires institutional sign-in at Scopus site) 21 CitationsAbstract
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.
Author List
Shi Q, Kuether EL, Schroeder JA, Perry CL, Fahs SA, Cox Gill J, Montgomery RRAuthors
Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of WisconsinQizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAntibodies
Antibodies, Monoclonal
Binding, Competitive
Blood Platelets
Dose-Response Relationship, Drug
Factor VIII
Hemophilia A
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Protein Binding
Recombinant Proteins
von Willebrand Factor
