According to the Canadian escalating model, the dose and frequency of administration can be adapted to individual demands. More recent publications describe the prevention of inhibitors attributed to early prophylaxis. These reports have led to the clinical practice GSI-IX cost to start prophylaxis very early. The German model, in particular, recommends low dose and low frequency prophylaxis to be started before the first bleed in order to avoid factor VIII (FVIII)

administration in an acute bleeding situation with an upregulated immune system in the context with so called “danger signals”. This strategy, however, is yet to be proven. In addition, the high costs of prophylaxis, difficult venous access in young children and the knowledge that more than 10% of severe haemophilia patients possess

a milder phenotype have been barriers for the initiation of early prophylaxis. The development of an inhibitor against FVIII/FIX represents the most serious complication in the treatment of a Regorafenib haemophilic patient. An incidence of around 30% in previously untreated patients (PUPs) with severe haemophilia has been described. The development of neutralizing antibodies directed against FVIII, which usually occurs during the initial phase of FVIII exposure (first 50 exposure days [EDs]), is carried out by a complex immune response in which both genetic (FVIII gene mutation, ethnicity, HLA type, immunogenotype) and environmental factors (age of start of treatment, intensity of the treatment and administration mode, type of factor concentrate) are involved. Since the introduction of recombinant FVIII (rFVIII) concentrates, the influence of the type of factor on inhibitor development has been intensely debated. Two possible explanations have been considered in order to explain the rather low inhibitor formation with the use of plasma-derived concentrates (pdFVIII): an immunomodulatory effect by cytokines and the presence of von Willebrand factor. However, systematic reviews and meta-analyses of numerous studies on development of inhibitors in PUPs could not show convincing evidence selleck kinase inhibitor in favour of any of the product

types. The results of randomized, prospective trials are necessary to resolve the debate. The identification of the factors with an impact on inhibitor development, particularly treatment related ones, can offer clues to design prevention strategies. In 2003, a North American and European consensus meeting about haemophilia stipulated that primary prophylaxis should be started before age 2 years, before any clinically evident joint bleeding, and before the onset of joint damage [1]. However, precisely when joint damage begins is unclear, and the following factors complicate the clinical picture: not all patients with haemophilia develop arthropathy [2], only a few joint bleeds may cause damage [3], and the number of clinical haemarthroses correlates only weakly with magnetic resonance imaging (MRI) outcomes [4].