All patients with haemophilia A/B and persistent inhibitors should therefore be offered immune tolerance induction (ITI) EMD 1214063 research buy to eliminate the inhibitor and to restore normal clinical responsiveness

to FVIII [5]. Immune tolerance induction (ITI) should be started soon after inhibitor development, but should be delayed until the titre has fallen below 10 BU mL−1. Inhibitor titre <10 at the start of ITI was the most powerful predictor of successful ITI in both the NAITI and IITI studies [6,7] and the inhibitor takes a median of 5 months to fall to this level from the time of diagnosis [8]. The NAITI showed that response to ITI did not fall off until 5 years after inhibitor diagnosis [6]. Inhibitors that fail to fall to Crizotinib order this level over 12–24 months respond poorly to ITI. Regimens in which the start has been delayed until the inhibitor titre has fallen to <10 BU mL−1 have been notably successful [9–11]. A central venous access device (CVAD) is usually inserted to facilitate ITI [8]. Some centres attempt ITI without the use of a CVAD, since infection has been

reported to adversely affect the outcome of ITI. Recent results from the IITI study suggest that infection has no effect on either the proportion achieving tolerance or the time taken to become tolerant, at least in good-risk patients [8]. Implantable CVADS are significantly less likely to become infected than external lines such as Hickman or Broviac catheters [8,12,13]. Immune tolerance is usually initiated using the product used by the patient at the time of inhibitor development. Uncontrolled data have suggested low-purity pdFVIII may induce tolerance more effectively than rFVIII [14–17]. However, the reported success-rates for ITI do not appear to be influenced by the product-type used [18–20]. A randomized comparison of high-dose pdFVIII vs. rFVIII for ITI in poor-risk patients

is in progress [17]. The choice of optimal ITI regimen remains problematic. The IITI and NAITI suggest that poor-risk patients (Peak titre >200 BU, Starting titre >10 BU) are best tolerized using a high-dose regimen (100–200 IU kg−1 Cyclin-dependent kinase 3 FVIII) [6,7]. These registries and the ITI study suggest that high-dose and low-dose (50 IU kg−1 3 X weekly) regimens are equally effective in inducing tolerance [6–8,21,22]. There is no evidence that 200 IU kg−1 day−1 are superior to 100 IU kg−1 day−1. Low-dose ITI takes longer to achieve a negative Bethesda titre, however [6,8], and is associated with significantly greater intercurrent bleeding in early ITI, before the Bethesda titre becomes negative, when 85% of intercurrent bleeding on ITI takes place [8]. Many clinicians may consider that all patients requiring ITI should be started with high-dose to minimize intercurrent bleeding. Once the Bethesda titre has become negative, it may be argued that the dosing could be tailed down in stages to a low-dose regimen.