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Thromb Haemost 2002; 88(02): 221-229
DOI: 10.1055/s-0037-1613191
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Schattauer GmbH

Von Willebrand Factor Modulates Factor VIII Immunogenicity: Comparative Study of Different Factor VIII Concentrates in a Haemophilia A Mouse Model

Mathias Behrmann
1   Institute for Biophysical Chemistry and Biochemistry, Johann-Wolfgang-Goethe-University, Frankfurt am Main, Germany
,
John Pasi
2   Division of Haematology, University of Leicester, Leicester, UK
,
Jean-Marie R. Saint-Remy
3   Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
,
Ronald Kotitschke
4   Biotest Pharma GmbH, Dreieich, Germany
,
Michael Kloft
4   Biotest Pharma GmbH, Dreieich, Germany
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 10. August 2001

Accepted after resubmission 30. April 2002

Publikationsdatum:
07. Dezember 2017 (online)

    Lizenzen und Reprints

Summary

The development of an immune response towards factor VIII (FVIII) remains the major complication of haemophilia A replacement therapy. Product-related risk factors have recently been identified on the basis of epidemiological studies, but the mechanism is not understood. To this end, various commercially available FVIII concentrates were administered by the IV route to FVIII-knockout mice and the resulting immune response was characterised. Significantly higher inhibitor titres (Bethesda assay) were observed for one recombinant FVIII and one plasma-derived FVIII product depleted in von Willebrand factor (VWF). Inhibitor titres were reduced upon pre-incubation of FVIII with purified VWF. Epitope specificity of anti-FVIII IgG was characterised using FVIII-fragments produced in E. coli. Concentrates with no or reduced VWF-level elicited antibodies recognising predominantly the acidic a1 and a3 regions. Addition of VWF prior to injection also modified the epitope specificity. FVIII concentrates, therefore, show qualitative and quantitative variations in immunogenicity, which are at least partly modulated by VWF.

Keywords

Haemophilia A - factor VIII - von Willebrand factor - animal model - immunogenicity
 

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