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• W3088134498 abstract "In modern hemophilia care, the most significant treatment-related complication is the development of neutralizing antibodies (inhibitors) to the deficient clotting factor. The majority of inhibitor studies have focused on severe hemophilia A where established recommendations for inhibitor eradication are available.1 In persons with non-severe hemophilia A (NSHA), inhibitor development can have a profound clinical impact, with bleeding complications similar to those seen in severe hemophilia A or acquired hemophilia.2 Despite the lifelong risk of inhibitor development in persons with NSHA, data on inhibitor treatment strategies are scarce.3 In persons with NSHA with inhibitors, low-titer inhibitors (<5 Bethesda units [BU]) can sometimes be transient and spontaneously disappear with time. For high-titer inhibitors (≥5 BU) or persistent low-titer inhibitors that lead to bleeding, options for inhibitor eradication include immune tolerance induction (ITI), immunosuppressive (IS) agents, or observation with avoidance of re-exposure to factor VIII (FVIII) concentrates. The reported success rates of these approaches are conflicting and are based on case reports or case series, which are highly heterogeneous and subject to publication bias.4, 5 In 2014, we conducted a survey of practice-patterns for inhibitor eradication in adult persons with NSHA with inhibitors at United States (US) hemophilia treatment centers (HTCs) using case-based scenarios. This survey found that there were substantial variation in treatment approaches adopted by experienced hematologists.6 However, this survey had a low response rate, with only 28 respondents reporting treating at least one adult NSHA with inhibitors in the past 5 years, thus limiting its generalizability.6 To overcome this limitation, we set out to describe the treatment approaches used for inhibitor eradication in persons with NSHA with inhibitors in the US using the ATHNdataset. This is a national registry where >40 000 persons with bleeding disorders opt-in to contribute their demographic and clinical information for research. The ATHNdataset started enrolling persons with congenital bleeding disorders on 1 January 2010. As all data were de-identified, the definition of a human subject was not met. This study was considered Non-Human Subject Research by the University of Utah Institutional Review Board. The ATHNdataset was queried on 31 December 2018, to extract information on demographics (age, race, ethnicity and hemophilia diagnosis), inhibitor status, eradication treatment (ITI, IS therapy, or none), and use of FVIII bypassing agents. Persons with NSHA were defined as persons with mild hemophilia A (FVIII activity [FVIII:C] >5%-50%) or moderate hemophilia A (FVIII:C −1%-5%). For this analysis, only participants with a clinically relevant FVIII inhibitor were classified to be inhibitor positive. A clinically relevant FVIII inhibitor was defined as ≥2 inhibitor titers of ≥1.0 BU (criterion 1) or ≥2 inhibitor titers of ≥0.6 BU that met one of the following two criteria: (a) a decrease in FVIII:C to at least 50% of baseline activity (criterion two) or (b) spontaneous bleeding symptoms coincident with inhibitor detection (criterion three). Data on eradication treatment and the use of FVIII bypassing agents were obtained from medication records in the ATHNdataset. Detailed information on the specific treatment type (ie, dose and frequency of ITI, type and dose of IS therapy, type and dose of FVIII bypassing agents, interval from inhibitor detection to treatment) and outcomes of eradication treatment (if prescribed) were not consistently reported in the ATHNdataset, thus were not included in this study. Descriptive statistical analyses were used to characterize the therapeutic approaches employed. Continuous variables were reported as medians and inter-quartile ranges (IQR). Categorical variables were expressed as frequencies and percentage values. All statistical analyses were performed using Stata MP v15.1 (College Station, TX, USA). From 1 January 2010 to 31 December 2018, the ATHNdataset included 6624 persons with NSHA, of which 77.3% (n = 5122) had documented exposure to FVIII concentrates, 8.4% (n = 555) had no documented exposure, and information was unknown for the remaining 14.3% (n = 947). From this source population, 171 participants (2.6%) met the definition of having a clinically relevant inhibitor; 94 (55.0%) were identified through criterion one, 27 (15.8%) through criterion two, and 50 (29.2%) through criterion three. Of the 171 participants, 76 inhibitors occurred between 1 January 2010 and 31 December 2018, whereas the remaining 95 were historical inhibitors that occurred prior to 1 January 2010. Almost half of the inhibitor cohort had mild hemophilia (n = 80, 47%). The median age for inhibitor development was 13 years (IQR, 6-36 years). Overall characteristics of the 171 NSHA participants with inhibitors and by treatment groups are shown in Table 1. Of the 171 NSHA participants with inhibitors, 30 (17.5%) received eradication treatment; 23 (76.7%) with ITI, six (20%) with IS agents, and one (3.3%) with both ITI and IS treatment. Of the 30 participants who received eradication treatment, two-thirds (n = 20, 67%) had moderate hemophilia, and 17 (56.7%) received FVIII bypassing agents. The remaining 141 (82.5%) NSHA participants with inhibitors did not receive any eradication treatment, of whom 27 (19.1%) received FVIII bypassing agents. Except for one participant, all individuals identified through criterion two and three were not treated with inhibitor eradication therapies. There was a higher proportion of participants with moderate hemophilia who received eradication treatment compared to those with mild hemophilia (20 of 91, 22.0% vs 10 of 80, 12.5%). The median age at inhibitor development for participants who received eradication treatment was 8 years (IQR, 2-36 years) whereas the median age was 14 years (IQR, 7-37 years) for those who did not. Participants who received eradication treatment were more likely to receive FVIII bypassing agents as compared to those who did not receive eradication treatment (57% vs 19%). Participants who received ITI alone were younger (median age 4 years, IQR, 2-18 years) than those that received exclusively IS agents (median age 47 years, IQR, 29-52 years). We found that the majority of NSHA participants with inhibitors (82.5%) did not receive any eradication treatment. Similarly, the INSIGHT study, an international cohort of 2709 persons with NSHA, reported that 72% (n = 73) of their 101 NSHA participants with inhibitors did not receive any eradication treatment, despite 90% (n = 64) requiring the use of FVIII bypassing agents.5 Overall, these data demonstrate that not all persons with NSHA with inhibitors receive eradication treatment. The INSIGHT study reported that without eradication treatment, 70% of inhibitors cleared spontaneously, although an anamnestic response occurred in 40% of those rechallenged with FVIII concentrates.5 Regardless of whether inhibitors are cleared spontaneously or via eradication treatment, it is essential to determine that no anamnestic response occurs when rechallenged with FVIII concentrates as this can affect future hemostasis management during trauma or while undergoing surgical interventions. Our study reported the use of ITI and IS treatment for inhibitor eradication in a cohort of NSHA with inhibitors in the period between 2010 and 2018. In 2018, emicizumab was approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in persons with hemophilia A with inhibitors based on the results of the HAVEN 1 clinical trial. Although the trial was conducted in persons with severe hemophilia A, the benefits of emicizumab are likely applicable to persons with NSHA presenting with a severe bleeding phenotype at the time of inhibitor development. It remains to be seen whether emicizumab will result in a change in the strategies for inhibitor management and eradication in the NSHA population. Our study has several limitations. We used the ATHNdataset where data entry is entered voluntarily by local HTCs and subject to missing data. Incomplete medication records in the ATHNdataset could have led to underreporting of eradication treatments used. In addition, hemophilia diagnosis, inhibitor status, and titers are determined locally with no central laboratory confirmation. Also, the ATHNdataset is limited to persons receiving care at HTCs. As persons with inhibitors are more likely to be referred to HTCs for management, this could potentially bias our inhibitor cohort resulting in overestimation. Lastly, data on eradication treatment outcomes are not consistently reported in the ATHNdataset which limits our ability to formulate any recommendations. This highlights a critical need for reliable evidence to guide treatment decisions for persons with NSHA with inhibitors. Given the rarity, it is unlikely that an adequate sample size could be accrued to perform a randomized clinical trial investigating the efficacy of inhibitor treatments. Instead, this need could feasibly be addressed by using the ATHNdataset which already has the infrastructure to collect the data required for a prospective observational study. By standardizing assessments of participant characteristics, exposures, and treatment outcomes, as well as improved data collection and data entry, a study of this nature would likely provide results that are more reliable and evidence-based. In conclusion, our study found that the majority of NSHA participants with inhibitors did not receive eradication treatment. Of those that received eradication treatment, ITI was the preferred treatment option. The authors acknowledge the 135+ ATHN-affiliated Hemophilia Treatment Centers and their patients for contributing to the ATHNdataset. Ming Y Lim, MB BChir, received a 2015 HTRS/ATHN DREAM Award from the Hemostasis and Thrombosis Research Society (HTRS) and the American Thrombosis and Hemostasis Network (ATHN), which was supported by an independent medical educational grant from Shire. M.R. has acted as a paid consultant to Bioverativ/Sanofi, CSL Behring, Genentech, Kedrion, NovoNordisk, Pfizer, Shire/Takeda, and uniQure. In addition, his organization has received research support from Bioverativ/Sanofi, BioMarin, Genentech, NovoNordisk, Shire/Takeda, Spark Therapeutics, and uniQure. He is on the Board of Directors of Foundation for Women and Girls with Blood Disorders and Partners in Bleeding Disorders, and is employed by the American Thrombosis and Hemostasis Network. C.L.K. received honoraria for participation in advisory boards with Spark Therapeutics, Pfizer, and Genentech and research support from Novo Nordisk. N.S.K. has received research funding from Takeda, Grifols, and Pfizer. In addition, he is on a steering committee for clinical trials for uniQure and grants review committee for NovoNordisk. M.Y.L. and D.C. report no conflict of interest. Contributions: Ming Y. Lim designed the study, analyzed the data, and wrote the manuscript. Dunlei Cheng analyzed the data and wrote the manuscript. Michael Recht reviewed and edited the manuscript. Christine L. Kempton and Nigel S. Key supervised the study, reviewed and edited the manuscript; all authors approved the final version of the manuscript. All the authors agree to be accountable for all aspects of the work, thereby ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. For original data, please contact [email protected]" @default.
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• W3088134498 title "Management of inhibitors in persons with non‐severe hemophilia <scp>A</scp> in the <scp>United States</scp>" @default.
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