A role for von Willebrand factor in immune tolerance induction in patients with haemophilia A and inhibitors

In the era of safe factor VIII (FVIII) concentrates for replacement therapy and of the diffusion of primary prophylaxis to prevent arthropathy, the development of antibodies against therapeutically administered FVIII (inhibitors) remains the most serious complication of treatment of haemophilia A1. Circulating inhibitors, occurring in approximately 30% of severe (FVIII:C <1%) previously untreated patients (PUPs), result in partial or complete lack of efficacy of replacement therapy and hamper prophylaxis implementation in children1–2. Inhibitor patients are therefore exposed to higher morbidity, in terms of severity of bleeding and of their long-term sequelae of joint deterioration, and to a worse quality of life, mainly related to the poor orthopaedic status1,3–6. Thus, restoring the safe and effective standard FVIII treatment is crucial after inhibitor diagnosis and especially in children7–8. Immune tolerance induction (ITI) by means of regular and prolonged administration of FVIII concentrates is currently the only strategy proven to achieve such an objective, providing the complete inhibitor eradication (success) or avoiding high anamnestic response and enabling clinical response to FVIII infusions (partial success) in the majority of cases8. In spite of intensive clinical and molecular research, mechanisms affecting inhibitor generation and, on the other hand, the modulation and the eradication of such an adverse immune response, are still poorly elucidated9–10. A series of genetic, non-modifiable, as well environmental, thus potentially modifiable, conditions, have been identified as predictors of inhibitor development and/or response to ITI. The greatest interest is presently devoted to some treatment-related factors, which are more clearly affected by clinical choices, both at first replacement infusions in PUPs or when ITI is started in inhibitor patients, such as FVIII dose, regimen and type of concentrate1,8–9,11. In particular, the hypothesis of the different immunogenicity and/or antigenicity of recombinant and plasma-derived, von Willebrand Factor (VWF) containing, FVIII concentrates, affecting the rate of inhibitor development and of ITI success, is being keenly debated12–13. Clarifying this issue deserves important pathophysiological, clinical and, not least, economic implications. In the following paragraphs clinical and experimental data concerning the potential role of VWF in this setting, with emphasis on ITI, will be discussed.