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Factor VIII and von Willebrand Factor (VWF)

Factor VIII and von Willebrand Factor (VWF). VWF and Inhibitor Antibodies. Main Clinical Difference Between FVIII Concentrates. Immune tolerance is the key area where there are clinical differences between factor VIII concentrates, in: Inhibitor reactivity variation between concentrates

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Factor VIII and von Willebrand Factor (VWF)

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  1. Factor VIII and von Willebrand Factor (VWF) VWF and Inhibitor Antibodies

  2. Main Clinical Difference Between FVIII Concentrates • Immune tolerance is the key area where there are clinical differences between factor VIII concentrates, in: • Inhibitor reactivity variation between concentrates • Inhibitor development in PUPs • Immune tolerance induction

  3. Inhibitors acc. to Preparation Type Pd: Plasma-derived

  4. Inhibitors acc. to Preparation Type Pd: Plasma-derived

  5. Inhibitor Reactivity • In vitro and in vivo evidence now suggests that VWF may affect the reactivity of FVIII inhibitors with FVIII • Berntop et al (1996): Concentrates rich in VWF neutralise inhibitors and yield higher FVIII:C recovery than concentrates containing no, or only traces of, VWF • Amano et al (1995): Inhibitory titres are higher in concentrates with low or absent VWF • Suzuki et al (1996): C2 inhibitors are less inhibitory to FVIII complexed with VWF • Sukhu et al (2000): Statistically significant lower inhibitory titres titres found with VWF-rich concentrates (both intermediate and high purity) vs. monoclonal and recombinant concentrates • Gensana et al (2001): Inhibitor neutralising capacity is significantly higher for FVIII/VWF than for monoclonal FVIII • Kallas et al (2001): Lower neutralisation of FVIII in the presence of VWF • Mancuso et al (2000): Lower inhibitor neutralising capacity with FVIII/VWF than with monoclonal or recombinant FVIII

  6. Structure of Factor VIII and Binding of VWF VWF binds the N-terminal part of the A3 domain and the C-terminal part of the C2 domain

  7. Factor VIII Functional Binding Sites Targeted by Inhibitory Antibodies Heavy chain Light chain IIa, Xa IIa, Xa IIa, Xa A1 A2 B A3 C1 C2 AR1 AR2 AR3 FX FIXa VWF FIXa VWF VWF VWF PL PL Adopted in part from Saenko et al. Haemophilia 2002

  8. The presence of VWF appears to influence the way anti-factor VIII antibodies can react with the factor VIII molecule, preventing antibody binding and/or protecting parts of factor VIII which are important for coagulation interaction Inhibitor Activity Modulated by VWF A1 A2 B A3 C1 C2 AR1 AR2 AR3 VWF PL

  9. Inhibitor Activity Modulated by VWF in Concentrates • Clinical consequences for VWF-containing concentrates • Prevent / reduce inhibitor development in PUPs • FVIII-VWF concentrates may protect against inhibitor development and be the treatment of choice for PUP’s and minimally exposed patients • Immune Tolerance Induction in PTPs • FVIII-VWF concentrates by avoiding antibody reaction may be the first choice in treatment for bleeding and ITI

  10. Inhibitor Activity Modulated by VWF in Concentrates • Clinical evidence appears to support biochemical observations • In PUPs • In PTPs

  11. GTH* PUP Study Results Moderate 161 Haemophilia A PUPs Inhibitor incidence in severe haemophilia A 92 58 24,5 % pdFVIII 29 39,5 % recFVIII 24 4 1 Mild Severe Inhibitor Inhibitors Inhibitors *GTH: Gesellschaft für Thrombose und Hämostase (Society for Thrombosis and Haemostasis) Auerswald, G. GTH Congress 2003

  12. Inhibitor Incidence in PUPs These studies show there is a trend towards less inhibitors in PUPs who received a plasma-derived FVIII concentrate containing VWF

  13. ITI: A Treatment Option in Inhibitor Patients • After treating acute bleeding, the priority is to • Eradicate inhibitor with ITI (Immune Tolerance Induction) with • Bonn protocol • Mälmo protocol

  14. Immune Tolerance Induction – ITI • Choice of product • Inhibitor reactivity and FVIII concentrate • VWF modulation of antibody recognition by VWF-containing concentrates implies potential effectivity in ITI

  15. ITI in Frankfurt

  16. ITI in Bonn and Frankfurt

  17. ITI – Clinical Summary • ITI results at the Bonn and Frankfurt centres have been less successful since the introduction of very high-purity FVIII concentrates depleted in VWF in 1990* • This is not supported by results from the North American IT Registry (DiMichele and Kroner, 1999) • However, only the Bonn and Frankfurt data are based on a reasonably large patient population, identical treatment protocol and success criteria throughout the studied period * Brackmann HH. 1999, 2001; Kreuz W et al. 2001; Kreuz W. 2002

  18. ITIConclusions • Inhibitorsreact differently with different types of factor concentrates • Several studies, mainly in vitro, indicate a modulating role of VWF against inhibitors directed against the C2 region of FVIII • Inhibitor testing against a panel of concentrates may facilitate selection of a least neutralized concentrate thereby improving haemostatic effect and cost/efficacy in ITI

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