The Malmö protocol combines high-dose FVIII and immunosuppressive therapies and has shown success in 10/16 (62.5%) of patients. The Van Creveld protocol, which uses low-dose FVIII (25–50 IU kg−1 every second day) in patients with an inhibitor titre <10 Bethesda units (BU)

at the start of therapy, has demonstrated success in 21/24 (87.5%) patients. In routine clinical practice, treatment often involves variations of these three main ITI protocols. To date, there is no clear understanding of how ITI works although several hypothetical mechanisms have been proposed. These include the development of anti-idiotypic antibodies [5, 6], depletion of memory www.selleckchem.com/products/atezolizumab.html B cells [7], or generation of FVIII-specific regulatory T cells [8, 9]. Based on ITI protocols currently in use, it is known that the FVIII/IX complex

is the only essential component. At present, there are no biomarkers that can be utilized to assist in understanding the mechanistic process of ITI. Thus, current knowledge stems mainly AZD1152-HQPA from clinical observations and analyses of retrospective data. Data generated during the 1990s from a global perspective indicated that ITI is significantly influenced by the maximum historical titre (higher titres are associated with poorer outcomes), the pretitre at the start of ITI, the time between diagnosis and treatment (the shorter the better), treatment age (the younger the better) and FVIII dose [10]. The protocol for the subsequent

prospective International ITI study (in good-risk patients) considered these historical observations, and recruited children (aged selleck <8 years at the time of randomization; peak historical titre ≥5 and ≤200 BU mL−1; starting titre ≤10 BU mL−1 before randomization) as soon as possible after inhibitor detection [11]. Since the mid-1970s, 91 patients with inhibitors have been treated at the Bonn Centre according to the Bonn protocol which uses plasma-derived (pd) FVIII/von Willebrand factor (VWF) for ITI in patients at any age. Of these, 68 and 23 patients were classified as high and low responders respectively. All patients were treated by the same physician using a standardized protocol. The overall success rate of ITI was 78%, with a failure rate of 15% and with some treatments either ongoing (3%) or withdrawn (4%). Considering only high responders with available data, the success rate was 71% (42/59 patients). Interestingly, patient age at the start of therapy or time from diagnosis to the start of ITI did not influence the success rate in high responders, reflecting the fact that many patients were adults. By multivariate analysis, maximum inhibitor titre was the only independent variable that significantly affected the high-responder success rate.