Besides genetic factors, treatment related factors have been studied in relation to inhibitor development. Intensity of treatment was found to influence the risk of inhibitor formation [4,25]. Inflammation associated with major bleeds and/or surgery may provide so-called ‘danger’ signals that account for the effect of treatment intensity on inhibitor development [26]. By contrast,

exposure to FVIII in the absence of immunostimulatory signals during prophylaxis correlates with a reduced risk of inhibitor selleck chemicals formation [4]. Based on these findings, we propose a model in which patients have an individual threshold for developing inhibitors (Fig. 1). Large deletions and nonsense mutation in the FVIII gene result in a relatively low threshold whereas missense mutations increase the threshold for inhibitor formation. Similarly, polymorphic sites within IL-10 and TNFα decrease the threshold for inhibitor formation whereas the presence of the CTLA4-318T allele increases the threshold for inhibitor formation. The previous FVIII exposure also increases GS-1101 the threshold for inhibitor formation (Fig. 1). In this model, intensity of treatment subsequently determines whether sufficient immune activation occurs to overcome the threshold for inhibitor formation (displayed on

the x-axis of Fig. 1). Administration of FVIII in the absence of inflammation

and/or surgery most likely causes only modest immune stimulation which does not suffice to initiate inhibitor development whereas intense treatment associated with surgery is expected to result in increased immune stimulation which eventually results in the development of FVIII inhibitors. Treatment of haemophilia A patients with inhibitors is two-tiered, aiming at both controlling bleeding episodes and restoring tolerance to FVIII. FVIII-bypassing agents like activated prothrombin complex concentrates and recombinant activated factor VII (FVII) are most widely used [27]. Remarkably, tolerance to FVIII can be induced by frequent MCE公司 exposure to medium or high doses of FVIII, so-called immune tolerance induction (ITI) [28–30]. Despite its high overall success, the mechanisms underlying ITI have been poorly defined. Abrogation of an established immune response and induction of long-lasting tolerance in a primed system requires elimination or silencing of effector and memory B and T cells. Studies in a murine model for haemophilia A have shown that high dosages of FVIII prevent the restimulation of FVIII-specific memory B cells [31]. Based on these data, it has been proposed that elimination of FVIII-specific memory B cells might be an early event during ITI in haemophilia A patients with pre-existing inhibitors.