Kubisz et al. Journal of Medical Case Reports 2012, 6:350 http://www.jmedicalcasereports.com/content/6/1/350 initial choice of FVIII concentrate was made according to the availability of FVIII products at the start of the treat- ment. The FVIII inhibitor in a high titer occurred after 2 years of treatment and 20 exposure days (initial inhibitor titer (IT): 5.4BU/mL; Day −453, 453 days before the start of ITI). In order to prevent further immunization, FVIII was omitted from the treatment and on-demand recombinant activated factor VII (rFVIIa; NovoSeven®, NovoNordisk®, Bagsværd, Denmark) was used instead for maintaining hemostasis. The activated prothrombin complex concen- trate factor VIII inhibitor bypass activity (FEIBA [factor eight inhibitor bypass activity]; Baxter International Inc., Deerfield, IL, USA) was not preferred due to the known risk of anamnestic response and prolongation of time period necessary for IT decrease. Within 14 months IT spontaneously decreased to 0.8BU/mL and thus, at the age of 3 years and 20 days, the first ITI could be started. The previously described ITI regimen – a combination of high doses of FVIII as in the original Bonn protocol (100IU/kg intravenous (IV) twice a day; the same FVIII concentrate as in the previous treatment) and pulsed IVIG (1g/kg IV on Days 0, 1, 7, 15 and 21; Kiovig, Baxter AG, Wien, Austria) – was used [5]. Invasive procedures as well as bleedings were managed with on-demand rFVIIa (90μg/kg IV as a bolus, repeated every 2 hours until the cessation of bleeding). The stable IV access was secured via the central venous access device (CVAD; PORT-A-CATH®, Smiths Medical, St. Paul, MN, USA) placed in the subclavian vein. IT imme- diately before the start of ITI (Day −3, 3 days before the start of ITI) was 0.8BU/mL; its highest level was 10.0BU/mL. During ITI, the highest IT was observed in the first month (72.0BU/mL), whereas from the second month only low IT was found with a transient increase during infections. After 12 months IT decreased to 0.1BU/mL and the FVIII pharmacokinetics normalized (recovery time 30 minutes after FVIII: 84.4%; plasma half-life: 6.5 hours; IV response to FVIII: 1.69IU/kg; normal FVIII clearance; testing performed on Day 383 of ITI). Thus, ITI was considered success- ful and terminated on Day 387 of ITI (Figure 1). No adverse events directly associated with the administered agents were observed during ITI. Only one serious hemorrhage (intramuscular in the left thigh; Day 21 of ITI) occurred; its cessation was achieved solely with bypass therapy. However, ITI was complicated with severe bacterial infections associated with CVAD (three episodes of catheter-related sepsis; Days 25, 188, and 216 of ITI). The prophylactic re-treatment with the same plasma- derived FVIII (Fanhdi® 1000IU IV thrice a week without gradual tapering) was initiated after ITI termination. During a 10-month follow-up, no clinical or laboratory signs of FVIII inhibitor and no severe bleeding appeared. Page 2 of 4 Discussion Although current knowledge of ITI is based predomin- antly on results of uncontrolled retrospective studies, case reports and patient registries (International Im- mune Tolerance Registry, German Registry, North American Immune Tolerance Registry) with limited directed comparison of different regimens, it is com- monly accepted that the outcome of ITI is worse in patients with IT more than 10BU/mL at ITI initiation, historical IT more than 200BU/mL and peak IT on ITI more than 250BU/mL [3,7]. Other negative factors – age over 20 years at beginning of ITI, persistence of in- hibitor for more than 5 years, use of FVIII concentrates without vWF, presence of mutations within F8 gene, African origin, and inflammatory challenges dur- ing ITI – were suggested by particular analyses [7-13]. However, the available clinical data on those para- meters are not consistent and sufficient for their gen- eral acceptance. The recently finished International Immune Tolerance Study, involving 115 good-risk patients with severe congenital hemophilia A and high- titer inhibitor on ITI, verified the inverse correlation of historical IT and peak IT on ITI with the treatment success, but failed to show a significant effect of infec- tions on its outcome [14]. The positive effect of IVIG addition to ITI has been reported since the introduction of the Malmö protocol [3,15]. The rapid, although time-limited, improvement in FVIII pharmacokinetics and decrease in IT, accompanied by lower bleeding tendency, was attributed to IVIG [15]. However, these reports are anecdotal and limited almost exclusively to case reports. Therefore, a recent inter- national consensus recommendation does not approve the standard use of IVIG or other immunomodulating agents in first-line ITI [13]. In the presented case, the patient had a good prognos- tic profile, with the low initial, historical, and anamnestic IT and with only one known negative factor (intron 22 inversion). The treatment was well tolerated with rela- tively rare bleedings. CVAD-related sepsis was regarded as the most serious complication. The infections, al- though recurrent and associated with the transient ele- vation of IT, did not result in a marked prolongation of ITI. The normalization of FVIII pharmacokinetics was seen after 13 months, so the ITI duration was compar- able with the mean durations reported in the analyses of patient registries [3,7]. The use of IVIG could, similarly to the observations of other authors, contribute to the relatively low frequency of severe hemorrhages and the normal ITI duration despite repeated inflammatory chal- lenges [4,12]. The bleeding episodes in hemophilia patients with high-titer inhibitor, both prior to and during ITI, are managed with bypass agents: rFVIIa and activated