previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010; 8: 1256-65.Summary. Background: Different rates of inhibitor development after either plasma-derived (pdFVIII) or recombinant (rFVIII) FVIII have been suggested. However, conflicting results are reported in the literature. Objectives: To systematically review the incidence rates of inhibitor development in previously untreated patients (PUPs) with hemophilia A treated with either pdFVIII or rFVIII and to explore the influence of both study and patient characteristics. Methods: Summary incidence rates (95% confidence interval) from all included studies for both pdFVIII and rFVIII results were recalculated and pooled. Sensitivity analysis was used to investigate the effect of study design, severity of disease and inhibitor characteristics. Meta-regression and analysis-of-variance were used to investigate the effect of covariates (testing frequency, follow-up duration and intensity of treatment). Results: Two thousand and ninety-four patients (1167 treated with pdFVIII, 927 with rFVIII; median age, 9.6 months) from 24 studies were investigated and 420 patients were observed to develop inhibitors. Pooled incidence rate was 14.3% (10.4-19.4) for pdFVIII and 27.4% (23.6-31.5) for rFVIII; high responding inhibitor incidence rate was 9.3% (6.2-13.7) for pdFVIII and 17.4% (14.2-21.2) for rFVIII. In the multi-way ANOVA study design, study period, testing frequency and median follow-up explained most of the variability, while the source of concentrate lost statistical significance. It was not possible to analyse the effect of intensity of treatment or trigger events such as surgery, and to completely exclude multiple reports of the same patient or changes of concentrate. Conclusions: These findings underscore the need for randomized controlled trials to address whether or not the risk of inhibitor in PUPs with hemophilia A differs between rFVIII and pdFVIII.

Introduction/background: Development of neutralizing inhibitors against factor VIII (FVIII) is a major complication of haemophilia A treatment. Aim: The ongoing, international, open-label, uncontrolled, observational immune tolerance induction (ObsITI) study evaluates ITI, the standard of care in patients with inhibitors. Patients/methods: Forty-eight prospective patients in this interim analysis received a single plasmaderived, von Willebrand factor-stabilized, FVIII concentrate (pdFVIII/VWF) for ITI. According to recommended Bonn protocol, 'low responders' at ITI start (<5 BU) received 50-100 IU FVIII kg À1 daily, or every other day; 'high responders' (≥5 BU) received 100 IU FVIII kg À1 every 12 h. Results: Forty of 48 patients (83.3%), had at least one risk factor for poor ITI-prognosis at ITI start (i.e. age ≥7 years, >2 years since inhibitor diagnosis, inhibitor titre ≥10 BU at the start of ITI, or prior ITI failure). Nonetheless, 34 patients (70.8%) achieved complete success, 3 (6.3%) partial success, 1 (2.1%) partial response; ITI failed in 10 patients (20.8%), all with poor prognosis factors. All six low responders achieved complete success. ITI outcome was significantly associated with inhibitor titre level at ITI start (P = 0.0068), number of poor prognosis factors for ITI success (P = 0.0187), monthly bleeding rate during ITI (P = 0.0005) and peak inhibitor titre during ITI (P = 0.0007). Twenty-two of 35 high responder patients (62.9%) with ≥1 poor prognosis factor achieved complete success. Conclusion: Treatment with a single pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in haemophilia A patients with inhibitors and poor prognosis for ITI success.

We have generated, by expert consensus, target plasma levels of factor concentrate to be used to tailor treatment for persons with haemophilia.

Patients with hemophilia who develop inhibitors present a particular challenge in therapeutic management. Although such patients are at high risk for severe bleeding episodes, the optimal treatment approach--prophylaxis--is ineffective unless inhibitors are eliminated. Several protocols for immune tolerance induction have been used. Success rates may vary depending both on patient variables and on factors related to the therapeutic regimen, including concentrate purity and von Willebrand factor (VWF) content. Several in vitro studies testing inhibitor plasma samples against various factor VIII (FVIII) concentrates have shown lower FVIII inhibitor titer compared with concentrates with greater VWF content. Recent in vivo observations also support the importance of VWF content, based on evidence of reduced rates of success of immune tolerance induction with use of the high-purity FVIII products that became available in the early 1990s. Current data thus support use of FVIII concentrates containing VWF in immune tolerance induction; other variables may also contribute to the relative success of this treatment. Studies are needed to delineate these variables in order to improve management of this potentially devastating complication of hemophilia treatment.

In order to assess inhibitor development in previously untreated patients (PUPs) with severe (factor VIII [FVIII]<1%) and moderate (FVIII 1 to 5%) hemophilia A, a prospective study was initiated in 1976. During the 23-year study period, 72 hemophiliacs were frequently exposed prophylactically or on demand to plasma-derived (pd) (n = 51) or recombinant FVIII (rFVIII) (n = 21) concentrates (median 270 exposure days [ED]). Inhibitor testing was performed before the first exposure and at regular intervals thereafter. Of the 72 hemophilia A patients, 22 (32%) developed an inhibitor after 15 ED in median (range 4 to 195); 17 (77%) were high responders (>5 Bethesda Units [BU]), and the remaining 5 patients (23%) were low responders (>0.6 to 5 BU). The severely affected patients (n = 46) showed a significantly higher frequency of inhibitor formation (43%) than did the moderate ones (8%). Comparing the severely affected patients receiving pd products exclusively (n = 35) with those treated with recombinant concentrate (n = 11), 37% of the pd group developed a high-titer inhibitor (>5 BU, median 290 ED in noninhibitor patients) and 36% of the recombinant group (median 49 ED in the noninhibitor patients). However, the exposure status of the recombinant noninhibitor patients is rather low and therefore remains a high risk of developing further inhibitors in the future. The mutation type profile revealed no difference between the pd- and the recombinant-treated patients.

Persistent high-titre inhibitors after immune tolerance induction (ITI) increase the risks of haemorrhage and arthropathy, resulting in high morbidity and mortality. Long-term prophylaxis with bypassing agents may avert these risks. This study was performed to assess the effectiveness and safety of early prophylaxis with FEIBA in preventing bleeding and joint damage after failed ITI. Seven paediatric patients proceeded immediately after failed ITI to long-term FEIBA prophylaxis at 60-100 IU kg(-1) dosages and various dosing intervals depending upon bleeding tendency. Bleeding episodes and joint status were assessed. Thrombin generation assays (TGA) were also used to gauge treatment response. FEIBA prophylaxis was commenced at a median age of 6.0 years (range, 1.5-11.8 years) and continued for a median duration of 6.9 years (range, 0.8-17.1 years). The mean annual incidence of joint bleeding was 1.5 episodes per year with a 95% CI of 0.7-3.0 episodes per year. Muscle bleeding incidence was 0.9 episodes per year (CI, 0.6-1.2 episodes per year). No patient experienced major joint damage during prophylaxis. Median Pettersson and orthopaedic joint scores at the last follow-up evaluation were 4 (range, 0-12) and 2 (range, 0-4) respectively. Endogenous thrombin potential (ETP) measured by TGA exceeded 80% of normal after FEIBA infusion in the majority of the patients. Between regular prophylactic infusions, mean trough ETP equalled 2.6 fold of the inhibitor plasma control mean. FEIBA prophylaxis was well-tolerated without serious thrombotic or other complications. The only adverse event involved venous access. Therefore early long-term FEIBA prophylaxis is valuable in controlling bleeding and preserving joint integrity in young patients failing ITI.

AHCDC: Association of Hemophilia Clinic Directors of Canada; AICE: Italian Association of Hemophilia Centres; ATHN: American Thrombosis and Hemostasis Network; EAHAD: European Association for Haemophilia and Allied Disorders; EHC: European Hemophilia Consortium; FIX: Coagulation Factor IX; FVIII: Coagulation Factor VIII; HAL: Haemophilia Activity List; HJHS: Haemophilia Joint Health Score; HTC: Hemophilia Treatment Centre; HTCCNC: Hemophilia Treatment Centre Collaborative Network of China; MASAC: Medical and Scientific Advisory Council; MDT: Multidisciplinary team; NHD: National Haemophilia Database; NHF: National Hemophilia Foundation; PK: Pharmacokinetics; POCUS: Point of care ultrasound; PWH: People with haemophilia; SHIELD: Supporting Hemophilia through International Education, Learning and Development; WFH: World Federation of Hemophilia.

The development of inhibitors in previously untreated patients (PUPs) with haemophilia A is correlated with a variety of endogenous and exogenous risk factors. It is still controversial whether recombinant factor VIII (rFVIII) products pose a higher risk for inhibitor development than plasma-derived (pd) FVIII concentrates, particularly with intact von Willebrand factor (VWF). A systematic review on the epidemiology of inhibitors in haemophilia A investigated the influence of different FVIII products on inhibitor formation. Patients treated with a single pd product had a lower cumulative incidence (0-12.4%) than those treated with a single recombinant concentrate (36.0-38.7%) independent of disease severity, study size, or inhibitor testing frequency. However, this analysis does not take into account the heterogeneity of the study populations. A study investigating the effects of different variables on inhibitor development in PUPs was started 13 years ago by the Paediatric Committee of the German, Austrian and Swiss Society on Thrombosis and Haemostasis Research. This prospectively conducted study revealed a slight difference (P = 0.08) in terms of type of concentrate. In the group of severe haemophiliacs treated with pdFVIII concentrate (n = 57), 12 patients developed an inhibitor (21%), whereas 17 of 47 patients receiving rFVIII (36%) were affected by this complication. This observation was substantiated by retrospective Italian and French analyses. These results, as well as hypothetical considerations, indicate that there is a body of evidence that FVIII products with VWF may be less immunogenic in PUPs. However, in order to provide more evidence a well-designed randomized study is needed.