Key Points• The inhibitor incidence in nonsevere hemophilia A patients with certain F8 mutations approaches the inhibitor incidence in severe patients.• These findings are highly relevant for clinical practice, as they facilitate identification of high-risk patients based on F8 genotype.Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as KaplanMeier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR,. The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A. (Blood. 2013; 122(11):1954-1962 IntroductionPatients with hemophilia A who are treated with factor VIII concentrates are at risk of developing factor VIII neutralizing alloantibodies (inhibitors).1,2 Inhibitor development is one of the most challenging complications in the treatment of hemophilia A, as it increases the bleeding tendency while it renders treatment with therapeutic factor VIII concentrates ineffective. Although inhibitor development is less frequently observed in patients with nonsevere hemophilia A (baseline factor VIII activity of 2-40 IU/dL), the clinical impact can be profound. In these patients, inhibitors may also interact with their endogenous factor VIII, resulting in a decrease of the factor VIII plasma level below 1 IU/dL 1 and major bleeding complications. 4 Identification of patients at risk of developing inhibitors may help to prevent this serious complication. However, currently there are no tools available to predict individual inhibitor risk in nonsevere hemophilia patients.The type of mutation in the factor VIII gene (F8) is an important risk factor for inhibitor development. [5][6][7] Nonsevere hemophilia A is generally caused by F8 missense mutations.8 Despite information on large numbers of F8 mutations associated with nonsevere hemophilia A that is collected in international databases, 9,10 it is not possible to calculate the inhibitor risk for specific F8 mutations, as data on exposure days to thera...

In haemophilia A patients factor VIII (FVIII) recovery and half-life can vary substantially. There are parameters known to modulate FVIII pharmacokinetics (PK), but they explain only about 34% of the variability. The aim of this study was to identify new parameters that influence FVIII PK and thus to expand the current knowledge. FVIII PK were determined in 42 haemophilia A patients (37 severe, 5 moderate) without inhibitor. Patients' characteristics and laboratory parameters were evaluated for an association with FVIII PK. We analysed plasma levels of low-density lipoprotein receptor-related protein 1 (LRP1) and protein C (PC) activity, which had been hypothesized to influence FVIII activity. Furthermore, four variations in intron 6 of the LRP1 gene, which had been shown to influence LRP1, were investigated. FVIII half-life differed widely from 6.2 to 20.7 h, with a median of 10.0 h. Patients with blood group O had shorter FVIII half-life compared to patients with non-O blood group (median FVIII half-life 9.0 h vs. 10.4 h, P = 0.018). Age was significantly associated with FVIII half-life (r = 0.32, P = 0.035). Besides age, also VWF antigen (r = 0.52, P < 0.001) and blood group (r = -0.37, P = 0.015) was associated with FVIII half-life. No correlation was found with FVIII- or LRP1-genotype, LRP1 or PC concentrations. Our data showed large differences in FVIII PK between individual patients and revealed age, blood group and VWF levels as important determining factors for FVIII half-life. FVIII genotype or levels of LRP1 or PC had no influence on FVIII PK.

Summary. Background: The life expectancy of non-severe hemophilia A (HA) patients equals the life expectancy of the non-hemophilic population. However, data on the effect of inhibitor development on mortality and on hemophilia-related causes of death are scarce. The development of neutralizing factor VIII antibodies in non-severe HA patients may dramatically change their clinical outcome due to severe bleeding complications. Objectives: We assessed the association between the occurrence of inhibitors and mortality in patients with non-severe HA. Methods: In this retrospective cohort study, clinical data and vital status were collected for 2709 non-severe HA patients (107 with inhibitors) who were treated between 1980 and 2011 in 34 European and Australian centers. Mortality rates for patients with and without inhibitors were compared. Results: During 64 200 patient-years of follow-up, 148 patients died (mortality rate, 2.30 per 1000 person-years; 95% confidence interval (CI), 1.96-2.70) at a median age of 64 years (interquartile range [IQR], 49-76). In 62 patients (42%) the cause of death was hemophilia related. Sixteen inhibitor patients died at a median age of 71 years (IQR,. In ten patients the inhibitor was present at time of death; seven of them died of severe bleeding complications. The all-cause mortality rate in inhibitor patients was > 5 times increased compared with that for those without inhibitors (ageadjusted mortality rate ratio, 5.6). Conclusion: Inhibitor development in non-severe hemophilia is associated with increased mortality. High rates of hemophilia-related mortality in this study indicate that non-severe hemophilia is not mild at all and stress the importance of close follow-up for these patients.

The substantial variability in pharmacokinetic parameters in hemophilia patients A poses a challenge for optimal treatment with factor VIII (FVIII) products. We investigated the effect of FVIII-specific immunoglobulin G (IgG) on FVIII half-life in a cohort of 42 adult patients with severe and moderate hemophilia A without inhibitors. Fifteen (35.7%) of 42 patients tested positive for FVIII-binding IgG with titers ‡1:20 in the initial antibody screen, 9 of these 15 patients had FVIII-specific antibodies with titers ‡1:40, mostly low-tomoderate-affinity IgG1 and IgG3, and 1 had high-affinity IgG4 and later developed low-titer FVIII inhibitors. His brother with low-to-moderate-affinity IgG1 and IgG3 also later developed low-titer FVIII inhibitors. The presence of FVIII-specific IgG subclass titer ‡1:40 antibodies was significantly associated with shorter FVIII half-life (median, 7.8 hours [interquartile range, 6.6-9.2 hours]) vs 10.4 hours [interquartile range, 8.9-13.8 hours]); the regression coefficient adjusted for log age and log von Willebrand factor (VWF) antigen was 20.32 (P 5 .004), accounting for 16.9% of the observed variability of FVIII half-life in our cohort. Our data indicate a significant contribution of non-neutralizing FVIII-specific IgG to FVIII half-life reduction in hemophilia A patients. Thus, screening for FVIII-specific IgG could be beneficial in tailoring FVIII prophylactic regimens. (Blood. 2016;128(2):293-296) IntroductionProphylactic treatment of hemophilia A patients with factor VIII (FVIII) products is presently state of the art.1 FVIII pharmacokinetics differ significantly, which poses a challenge for optimal treatment design. It is generally accepted that the von Willebrand factor (VWF) level significantly influences pharmacokinetic (PK) parameters such as FVIII half-life.2-5 Different VWF levels only partially explain the variability in FVIII half-life, which leaves the question of which other parameters are accountable. This study was conducted to evaluate the effect of non-neutralizing, FVIII-specific immunoglobulin G (IgG) antibodies on FVIII half-life. Study designPlasma samples from a cohort of 42 patients with hemophilia A (recently described by Kepa et al 2 ) were screened for FVIII-binding IgG antibodies. Antibodies were analyzed by using fully validated semiquantitative, directbinding enzyme-linked immunosorbent assays (ELISAs) as described in Whelan et al. 6 Details of the validation procedure as well as details of the cutoff determination and the sensitivity of the ELISAs are provided in Whelan et al 6 and Hofbauer et al. 7 Initially, all samples were screened in a 1:20 dilution for FVIII-binding IgG antibodies. Samples that tested positive were characterized for titers of FVIIIbinding IgG subclasses and apparent affinities. The specificity of FVIII-binding antibodies was tested in all samples with antibody titers $1:40 by using an affinity ELISA.7 Antibodies without conclusive apparent affinity were considered unspecific. Antibodies with titers ,1:40 (eg, 1:20)...