Lastly, experience with the use of pdVWF/FVIII concentrate is also available from a prospective, naturalistic study

conducted in haemophilia centres in Italy (n = 9) and Spain (3) [20]. Between 1999 and 2005, 17 patients received ITI therapy with pdVWF/FVIII concentrate (Fanhdi®; Grifols S.A., Barcelona, Spain). All patients had poor risk features for successful treatment: all were aged 7 years or older at the start of therapy, including 10 adults; only one patient had an inhibitor for less than 2 years; two patients had peak inhibitor titres of >200 BU. At the start of treatment, four patients had inhibitor titres of >10 BU, and four patients had failed previous ITI therapy. Nine patients were initiated on a low-dose regimen [50 IU kg−1 (three times a week)] and eight on a high-dose regimen (100 or 200 IU kg−1 day−1). Patients received ITI for anywhere from 4 to 33 months. In terms of Rapamycin nmr patient outcomes, 9 of 17 patients (53%) achieved complete success after a median of 24 months (Table 3), including two of the four patients who

had failed previous ITI therapy. Seven patients achieved a partial success (Table 3), with sustained low inhibitor titres (median 1.5 BU, range 1.1–2.8) but with abnormal FVIII recovery and/or half-life, while the remaining patient withdrew from treatment after 12 months when the inhibitor titre was still 70 BU. Based on the evidence available to date, it is not possible to state with confidence that pdVWF/FVIII is the product of choice when initiating patients on ITI therapy. Of the few published studies, all have their limitations: patient numbers were selleck inhibitor small, none of the studies was randomized, and all used different ITI therapy protocols. Although the 53% complete response rate reported by Gringeri and colleagues appears promising [20], this is counteracted to some extent by the 32% complete response rate reported by Kurth et al. [19]. Despite this uncertainty, recommendations published by European [21] and International [22] consensus heptaminol panels state that ‘FVIII concentrates containing VWF should be considered for patients who fail ITI using high purity

FVIII’. Some reasons have been postulated as to why pdVWF/FVIII concentrates may enhance ITI therapy compared with recombinant products. In brief, one of these postulates centres around a potential protective effect of the presence of VWF. The VWF binds to different epitopes in the A3 and C2 domains of FVIII which may offer it protection against degradation by proteinases. Similarly, most inhibitors are also directed at epitopes on the A3 and C2 domains along with the A2 domain. As such, the presence of VWF on the FVIII molecule leads to (i) masking of epitope sites by VWF thereby preventing inhibitors (neutralizing antibodies) from binding to the FVIII molecule and (ii) increased stability (i.e. reduced clearance) of the FVIII molecule.