The role of VWF for the success of immune tolerance induction

One of the primary and most serious treatment-related complications in haemophilia A is the formation of anti-factor VIM (FVIII) antibodies, which significantly impacts patient care. For these patients, immunomodulatory therapy becomes important to induce immunological tolerance to FVIII. Immune tolerance induction (ITI) is an efficient therapeutic approach to eliminating inhibitors. Several ITI protocols are currently in use, including the Malmö-, Bonn- and van-Creveld-protocol. Successful utilisation of these protocols enables regular FVIII treatment (in the case of surgery and bleeding), prophylactic treatment (to prevent haemophilic arthropathy and life-threatening bleeding), improvement in quality of life and cost savings. Success rates with ITI may vary depending on patient variables and factors related to the therapeutic regimen, including concentrate purity and von Willebrand factor (VWF) content. Both in vitro and in vivo studies support the clinical observation that the VWF content may have an important role in the success rate of ITI. Over the past 25 years extensive experience has been gained in ITI using the VWF/FVIII product Haemate®P/Humate-P®. Overall success rates of around 80% have been observed using the Bonn-protocol with plasma-derived VWF/FVIII, whereas the success rates with high-purity or recombinant FVIII products were much lower at 3 German haemophilia centres. Further research is required to better understand the impact of different variables on ITI including the role of VWF, and this is being investigated in several ongoing studies. Meanwhile, current guidelines recommend the use of VWF-FVIII concentrates for ITI where first-line therapy with high-purity FVIII concentrates has failed.