24 | 2023; 7:S1 3. Ataga, KI, Kutlar, A, Kanter, J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med. 2017;376(5):429-439. 4. Morrison, M, Palermo, G, Schmitt, C. Lack of ethnic differences in the pharmacokinetics and pharmacodynamics of inclacumab in healthy Japanese and Caucasian subjects. Eur J Clin Pharmacol. 2015;71(11):1365-1374. 5. Kling, D, Stucki, C, Kronenberg, S, et al. Pharmacological control of platelet-leukocyte interactions by the human anti-P-selectin antibody inclacumab – preclinical and clinical studies. Thromb Res. 2013;131(5):401-410. 6. Schmitt, C, Abt, M, Ciorciaro, C. First-in-Man Study With Inclacumab, a Human Monoclonal Antibody Against P-Selectin. J Cardiovasc Pharmacol. 2015;65(6):611-619.

We read with interest the study done by Loomans et al (1); wherein the authors have found that out of 148 deceased mild and moderate hemophilia patients, 62 (42%) expired due to excessive bleeding i.e. due to the disorder itself and out of these 12% died of intracranial (IC) bleed. Thus, the authors rightly conclude that non-severe hemophilia A patients also have an increased risk of death due to IC bleed and thus demonstrating the need for specialized care for these patients. India harbors the second highest number of patients with hemophilia globally, majority belonging to the poverty-stricken section (2). This article is protected by copyright. All rights reserved.

Essentials Research suggests that intensive treatment episodes may increase the risk to develop inhibitors. We performed an international nested case-control study with 298 non-severe hemophilia A patients. Surgery and a high dose of factor VIII concentrate were associated with increased inhibitor risk. Physicians need to review arguments for factor VIII dose and elective surgery extra critically. SUMMARY:Background Inhibitor development is a major complication of treatment with factor VIII concentrates in hemophilia. Findings from studies among severe hemophilia A patients suggest that intensive treatment episodes increase the risk of developing inhibitors. Objectives We set out to assess whether intensive treatment is also associated with an increased risk of inhibitor development among non-severe hemophilia A patients. Patients/Methods We performed a nested case-control study. A total of 75 inhibitor patients (cases) and 223 control patients were selected from 2709 non-severe hemophilia A patients (FVIII:C, 2-40%) of the INSIGHT cohort study. Cases and controls were matched for date of birth and cumulative number of exposure days (EDs) to FVIII concentrates. Conditional logistic regression was used to calculate both unadjusted and adjusted odds ratios (aOR); the latter were adjusted for a priori specified confounders. Results Peak treatment of 5 or 10 consecutive EDs did not increase inhibitor risk (aOR, 1.0; 95% confidence interval (CI), 0.4-2.5; and aOR, 1.8; CI, 0.6-5.5, respectively). Both surgical intervention (aOR, 4.2; CI, 1.7-10.3) and a high mean dose (> 45 IU kg-1 /ED) of FVIII concentrate (aOR, 7.5; CI, 1.6-35.6) were associated with an increased inhibitor risk. Conclusions Our findings suggest that high-dose FVIII treatment and surgery increase the risk of inhibitor development in non-severe hemophilia A. Together with the notion that non-severe hemophilia A patients are at a lifelong risk of inhibitor development, we suggest that in the future physicians will review the arguments for the FVIII dose and elective surgery extra critically.

HaemophiliaVolume 22, Issue 3 p. e241-e244 Letter to the Editor Dissecting intensive treatment as risk factor for inhibitor development in haemophilia C. L. Eckhardt, C. L. Eckhardt Department of Pediatric hematology, Emma Children's hospital, Academic Medical Center, Amsterdam, the NetherlandsSearch for more papers by this authorA. S. van Velzen, A. S. van Velzen Department of Pediatric hematology, Emma Children's hospital, Academic Medical Center, Amsterdam, the NetherlandsSearch for more papers by this authorC. J. Fijnvandraat, C. J. Fijnvandraat Department of Pediatric hematology, Emma Children's hospital, Academic Medical Center, Amsterdam, the NetherlandsSearch for more papers by this authorJ. G. van der Bom, Corresponding Author J. G. van der Bom Jon J. van Rood Center for Clinical Transfusion Research, Sanquin Research and Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands Correspondence: Johanna G. van der Bom, Center for Clinical Transfusion Research, Sanquin Research, Plesmanlaan 1a, 2333 BZ Leiden, the Netherlands. Tel.: +31 71 5268871; fax: +31 71 568 5191; e-mail: J.G.vanderBom@lumc.nlSearch for more papers by this author C. L. Eckhardt, C. L. Eckhardt Department of Pediatric hematology, Emma Children's hospital, Academic Medical Center, Amsterdam, the NetherlandsSearch for more papers by this authorA. S. van Velzen, A. S. van Velzen Department of Pediatric hematology, Emma Children's hospital, Academic Medical Center, Amsterdam, the NetherlandsSearch for more papers by this authorC. J. Fijnvandraat, C. J. Fijnvandraat Department of Pediatric hematology, Emma Children's hospital, Academic Medical Center, Amsterdam, the NetherlandsSearch for more papers by this authorJ. G. van der Bom, Corresponding Author J. G. van der Bom Jon J. van Rood Center for Clinical Transfusion Research, Sanquin Research and Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands Correspondence: Johanna G. van der Bom, Center for Clinical Transfusion Research, Sanquin Research, Plesmanlaan 1a, 2333 BZ Leiden, the Netherlands. Tel.: +31 71 5268871; fax: +31 71 568 5191; e-mail: J.G.vanderBom@lumc.nlSearch for more papers by this author First published: 14 April 2016 https://doi.org/10.1111/hae.12944Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume22, Issue3May 2016Pages e241-e244 RelatedInformation

Essentials Factor VIII levels vary in mild and moderate hemophilia A (MHA) patients with the same mutation. We aimed to estimate the variation and determinants of factor VIII levels among MHA patients. Age and genotype explain 59% of the observed inter‐individual variation in factor VIII levels. Intra‐individual variation accounted for 45% of the variation in the three largest mutation groups.

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, 60-81). 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 (age-adjusted 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 development of factor (F) VIII neutralizing alloantibodies (inhibitors) is a major complication of treatment with FVIII concentrates in hemophilia A and the etiology is still poorly understood. The low‐affinity Fc gamma receptors (FcγR), which are expressed on immune cells, provide an important link between cellular and humoral immunity by interacting with IgG subtypes. Genetic variations of the genes encoding FcγRs (FCGR genes) have been associated with susceptibility to infectious and autoimmune diseases.