Severe Hemophilia A Research Articles

Real-World Experience of People with Hemophilia A Receiving Turoctocog Alfa Pegol (N8-GP): Results from a Patient Experience Survey.

Turoctocog alfa pegol (N8-GP) is an extended half-life recombinant factor VIII molecule used for the treatment of hemophilia A (HA). The purpose of this study was to investigate real-world experiences of patients with HA treated with N8-GP. A 25-minute online survey was completed by adults (≥18 years) and caregivers of adolescents (12-16 years) with HA receiving N8-GP across six countries (Germany, Italy, Portugal, Spain, UK and US). Patients were recruited using a multichannel approach through recruitment panels, referrals from healthcare professionals and patient associations. The survey comprised a questionnaire with metrics including satisfaction and preferences for N8-GP, quality of life (QoL) and long-term impact. A total of 62 participants (98% male [n=61], mean age 29 years) comprising 46 patients and 16 caregivers completed the survey. Patients (60% non-severe [n=37] and 40% severe [25]) were on N8-GP for a mean period of 1.4 years. Patients expressed satisfaction (95%vs 42%, p<0.001) and preference (91% vs 9%, p<0.001) for N8-GP vs their previous treatments. Most patients with severe HA (87%, p=0.038) and patients on prophylaxis (84%, p<0.001) stated lower frequency of injections as their main reason for satisfaction, while improved QoL drove satisfaction for non-severe patients (81%, p=0.053). Overall, patients perceived that QoL score improved (74.8 vs 65.9, p=0.01) with N8-GP treatment compared with previous treatments. Flexibility to store at room temperature was one of the key convenience factors driving satisfaction. Patients believed that N8-GP can offer a long-term impact in areas such as ability to perform day-to-day activities (68%), independence to live like a person without hemophilia (63%), ability to travel (60%) with a feeling of optimism and hopefulness (82%). Lower frequency of injections, storage flexibility and improved QoL drove satisfaction and preference for N8-GP over previous treatments among patients with HA.

Association between health anxiety dimensions and preventive behaviors during the COVID-19 pandemic among Japanese healthcare workers

ObjectiveHealth anxiety (HA), defined as excessive worry about having a serious medical condition, may affect preventive behaviors during the coronavirus disease 2019 (COVID-19) pandemic. We examined the distinct role of two dimensions of HA—perceived likelihood (probability dimension) and awfulness of illness (awfulness dimension)—in self-protection, as reflected in preventive behaviors during the pandemic. MethodsParticipants comprised 657 healthcare workers. Data were collected between February 24 and 26, 2021. The Short Health Anxiety Inventory determined the HA dimensions. Adherence to the government's recommendations for COVID-19 preventive behaviors was self-rated. An independent association between each HA dimension and participants' adherence to the recommendations was examined using multivariable regression. ResultsWithin the analyzed sample of 560 subjects, severe HA was observed in 9.1 %. The more the participants felt awful, the less frequently they engaged in the recommended preventive behaviors (adjusted odds ratio = 0.993, 95 % confidence interval: 0.989, 0.998, p = 0.003) regardless of their profession, working position, psychological distress, sleep disturbance, and current physical diseases. However, the probability dimension was not associated with their preventive behaviors. ConclusionThe awfulness dimension of HA could be a more sensitive marker of preventive behaviors than the probability dimension. Paying particular attention to the awfulness dimension may help optimize self-protection strategies during the COVID-19 pandemic. A two-dimensional understanding of HA may be useful for the maintenance of the healthcare system and public health as well as healthcare workers’ own health.

Minimum factor VIII levels to prevent joint bleeding in mild hemophilia A

AbstractThe severity of the bleeding phenotype in patients with hemophilia A (HA) broadly correlates with the degree of coagulation factor VIII (FVIII) deficiency in plasma. However, the FVIII level necessary to achieve the goal of zero joint bleeds remains unclear. This study aimed to identify the minimum FVIII level necessary to prevent joint bleeds in patients with HA. In this retrospective study, patients with congenital mild HA treated on demand, aged ≥16 years, with no history of FVIII inhibitors, followed at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, were enrolled. We investigated 270 male patients with a median age of 45 years (16-88) and median lifelong FVIII of 21 IU/dL. One hundred patients (37%) had a lifelong history of at least 1 joint bleed. The mean annualized joint bleeding rate (AJBR) and spontaneous AJBR were 0.016 (standard deviation [SD], 0.032) and 0.001 (SD, 0.010), respectively. After adjusting for age, for each IU/dL increase in FVIII, there was a 6% reduction in AJBR and an 11% reduction in spontaneous AJBR. The minimum FVIII levels needed to prevent lifelong any joint bleeds and spontaneous joint bleeds resulted to be 19.2 IU/dL and 17.7 IU/dL, respectively. In this large cohort of persons with mild HA, we identified the minimum FVIII levels needed to prevent total and spontaneous joint bleeds (19.2 IU/dL and 17.7 IU/dL, respectively). These findings could suggest important implications for the accurate design of prophylactic therapies for persons with moderate and severe HA, including gene therapy.

Large Intron Inversions in Romanian Patients with Hemophilia A-First Report.

Background and Objectives: Despite the vast heterogeneity in the genetic defects causing hemophilia A (HA), large intron inversions represent a major cause of disease, accounting for almost half of the cases of severe HA worldwide. We investigated the intron 22 and intron 1 inversion status in a cohort of Romanian unrelated patients with severe HA. Moreover, we evaluated the role of these inversions as relative risk factors in inhibitor occurrence. Materials and Methods: Inverse shifting-a polymerase chain reaction method was used to detect the presence of intron 22 and intron 1 inversions in 156 Romanian patients with HA. Results: Intron inversion 22 was found in 41.7% of the patients, while intron 1 inversion was detected in 3.2% of the patients. Overall, large intron inversions represented the molecular defect in 44.9% of the studied patients. Our findings are in accord with previously published reports from Eastern Europe countries and with other international studies. The risk of inhibitor development was higher in patients with inversion 1 compared to the patients with HA without any inversion detected. Conclusions: The current study demonstrates the major causative role of large intron inversions in severe HA in Romanian patients. Moreover, our study confirms the contribution of intron 1 inversion in inhibitor development.

A next generation FVIII mimetic bispecific antibody, Mim8, the impact on non-factor VIII related haemostasis assays.

Mim8 is a next generation bispecific antibody developed for the treatment of haemophilia A (HA). Mim8 has an increased potency compared to first generation molecules. The impact on Mim8 on non-FVIII measuring haemostasis assays was assessed in plasma containing Mim8. Congenital severe HA plasma was spiked with increasing concentrations of Mim8 (0-20μg/mL). 28 routine and specialist haemostasis assays were used to measure activities. These included tests for prothrombin time (PT), fibrinogen, thrombin, D-dimer, anti-Xa, heparin induced thrombocytopenia (HIT), clotting factors II-XII, factor XIII, von Willebrand factor (VWF), thrombophilia and DRVVT. Less than 10 % difference was calculated between plasma without Mim8 and plasma spiked to 15μg/mL Mim8 in all assays except thrombin time (-10.5%), APTT-based factor IX, XI and XII, Werfen VWF:RCo (10.6%) and Siemens LA1 (-26.4%) and LA2 (-16.9%). At the expected therapeutic steady state levels of Mim8 (5-8μg/mL), less than 10% difference was calculated for thrombin time and Werfen VWF:RCo. APTT-based assays of FIX, XI and XII are significantly elevated in the presence of Mim8 and should not be performed. A chromogenic FIX assay could be used to accurately measure FIX activity in the presence of Mim8. There was some interference in the DRVVT method we used so local assessment of other DRVVT methods is advised. Differences in all other tests would not be predicted to affect patient management.

Health-related quality of life following valoctocogene roxaparvovec gene therapy for severe hemophilia A in the phase 3 trial GENEr8-1

BackgroundSevere hemophilia A (HA) negatively impacts health-related quality of life (HRQOL). ObjectivesWe aimed to analyze HRQOL in adult men with severe HA without inhibitors after valoctocogene roxaparvovec gene transfer in the phase 3 trial GENEr8-1. MethodsParticipant-reported outcomes were the hemophilia-specific quality of life questionnaire for adults (Haemo-QOL-A), the EQ-5D-5L instrument, the Hemophilia Activities List (HAL), and the Work Productivity and Activity Impairment Questionnaire: Hemophilia Specific (WPAI+CIQ:HS). Participants completed the questionnaires at baseline and through 104 weeks postinfusion with 6 × 1013 vg/kg of valoctocogene roxaparvovec. Scores were analyzed per participant characteristics and outcomes. ResultsFor 132 HIV-negative participants, mean change from baseline in Haemo-QOL-A Total Score met the anchor-based clinically important difference (CID: 5.5) by week 12; the mean (SD) increase was 7.0 (12.6) at week 104. At week 104, improvement in Consequences of Bleeding, Treatment Concern, Worry, and Role Functioning domain scores exceeded the CID (6). EQ-5D-5L Utility Index scores improved above the CID at week 52, but not at week 104. EQ-5D-5L visual analog scale and HAL scores increased from baseline to week 104. Participants reported less activity and work impairment at week 104 than baseline. Participants with problem joints had lower mean baseline Haemo-QOL-A Total and domain scores than those without them, but improved over 104 weeks, except for 11 participants with ≥3 problem joints. Participants with 0 bleeds during the baseline prophylaxis period reported Haemo-QOL-A score improvements above the CID, including in the Consequences of Bleeding domain. ConclusionValoctocogene roxaparvovec provided clinically meaningful HRQOL improvement for men with severe HA.

Immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients with severe hemophilia A: interim results from a phase 3, prospective, multicenter, open-label study

ABSTRACT Aim To determine the immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients (PUPs) with severe hemophilia A (HA). Methods This prospective, phase 3 study (NCT02615691) was conducted in PUPs, or patients with ≤2 exposure days (EDs) prior to screening, aged <6 years with severe HA. The primary endpoint was incidence of factor VIII (FVIII) inhibitor development. This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing FVIII inhibitors or had developed a confirmed inhibitor at any time. Results Of the enrolled patients, 59/80 (73.8%) received ≥1 dose of rurioctocog alfa pegol; 54 received prophylaxis, and 35 on-demand treatment. Incidence of inhibitor development was 0.19 (10/52). Total annualized bleeding rate (95% CIs) was 3.2 (2.0–5.0) for patients receiving prophylaxis and 3.2 (1.6–6.3) for on-demand treatment. Hemostatic efficacy of most bleedings was rated as ‘excellent’ or ‘good’ after 24 hours (122/131 [93.1%]) and at resolution (161/170 [94.7%]). Five patients received ≥1 dose of rurioctocog alfa pegol for immune tolerance induction (ITI) and 1 patient was defined as having ITI success. Thirteen patients experienced 14 treatment-related adverse events, including 10 cases of FVIII inhibitor development. Conclusion This is the first prospective study of rurioctocog alfa pegol for the treatment of PUPs with severe HA. Trial Registration This trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02615691).

Anti-FVIII antibodies in Black and White hemophilia A subjects: do F8 haplotypes play a role?

The most common complication in hemophilia A (HA) treatment, affecting 25% to 30% of patients with severe HA, is the development of alloimmune inhibitors that foreclose the ability of infused factor VIII (FVIII) to participate in coagulation. Inhibitors confer significant pathology on affected individuals and present major complexities in their management. Inhibitors are more common in African American patients, and it has been hypothesized that this is a consequence of haplotype (H)-treatment product mismatch. F8 haplotypes H1 to H5 are defined by nonsynonymous single-nucleotide polymorphisms encoding sequence variations at FVIII residues 1241, 2238, and 484. Haplotypes H2 to H5 are more prevalent in individuals with Black African ancestry, whereas 80% to 90% of the White population has the H1 haplotype. This study used an established multiplex fluorescence immunoassay to determine anti-FVIII antibody titers in plasma from 394 individuals with HA (188 Black, 206 White), measuring their binding to recombinant full-length H1 and H2 and B-domain-deleted (BDD) H1/H2, H3/H5, and H4 FVIII proteins. Inhibitor titers were determined using a chromogenic assay and linear B-cell epitopes characterized using peptide microarrays. FVIII-reactive antibodies were readily detected in most individuals with HA, with higher titers in those with a current inhibitor, as expected. Neither total nor inhibitory antibody titers correlated with F8 haplotype mismatches, andpeptides with D1241E and M2238V polymorphisms did not comprise linear B-cell epitopes. Interestingly, compared with the full-length FVIII products, the BDD-FVIII proteins were markedly more reactive with plasma antibodies. The stronger immunoreactivity of BDD-FVIII suggests that B-domain removal might expose novel B-cell epitopes, perhaps through conformational rearrangements of FVIII domains.

Treatment regimens, patient reported outcomes and health-related quality of life in children with moderate and severe hemophilia A in China: using real-world data

BackgroundProphylaxis therapy for children with moderate and severe hemophilia A (HA) is the optimal treatment regimen. The real-world treatment regimens, patient-reported outcomes, and health-related quality of life (HRQoL) in children with moderate and severe HA in China are less known.ObjectiveThis study aimed to describe real-world treatment regimens and evaluate the association of treatment regimens with comprehensive patient-reported outcomes including bleeds, chronic pain, target joints, disability, and HRQoL in children under 18 years old with HA in China.MethodsReal-world data of a nationwide online cross-sectional survey in 2021 and patients’ coagulation factor utilization data from self-management records from 2020 to 2021 were merged. 373 eligible children were included and categorized by treatment regimens according to the Chinese guideline: on-demand, short-term prophylaxis, and long-term prophylaxis treatment.ResultsCurrently, in China, 4.8% of children with HA are receiving full-dose long-term prophylaxis treatment. Prophylaxis treatment was a significant positive predictor of better patient-reported outcomes and HRQoL. For children with prophylaxis treatment, there were significantly fewer annual bleeds (p < 0.001), lower frequency of chronic pain(p < 0.001), and higher health utility scores(p < 0.01) and EQ-VAS scores(p < 0.05) than children with on-demand treatment.ConclusionAccessible long-term prophylaxis treatment should be promoted for children with moderate and severe HA in China and regular monitoring of their outcomes and HRQoL should be carried out.

Transcatheter aortic valve replacement with the self-expanding ACURATE Neo2 in patients with horizontal aorta: Insights from the ITAL-neo registry

BackgroundHorizontal aorta (HA), defined by an aortic angulation (AA) ≥48°, is associated with worse outcomes particularly after self-expanding (SE) trans-catheter heart valve (THV) implantation. Although the SE ACURATE Neo THV demonstrated favorable procedural success rates in patients with HA, it remains associated with a non-negligible rate of moderate or greater paravalvular leak (PVL). ObjectivesAim of the study was to assess the performance of ACURATE Neo2 in the setting of HA. MethodsWe performed a multicenter cohort analysis on patients with severe aortic valve stenosis and HA undergoing transcatheter aortic valve replacement (TAVR) with the Neo or Neo2 THV enrolled in the ITAL-neo registry. The primary endpoint was a composite of early safety and clinical efficacy at 30 days according to the Valve Academic Research Consortium-3 (VARC-3). Secondary endpoints included the occurrence of moderate or severe PVL and 90-day clinical outcomes. ResultsAmong 900 patients included in the ITAL-neo registry, 407 exhibited HA; of these, 300 received a Neo THV and 107 a Neo2 THV. HA, irrespective of the THV implanted, emerged as an independent risk factor for developing ≥ moderate PVL. Technical and device success at 30-day follow-up was comparable between groups. However, Neo2 was associated with a significantly lower rate of ≥moderate PVL vs. Neo: (5% vs. 15%; p < 0.001), which was confirmed also at 90-day follow-up. Additionally, no correlation was found between ≥moderate PVL and AA in the Neo2 group, while PVL degree increased proportionally to the AA in the Neo cohort. ConclusionIn patients with HA, the new generation Acurate Neo2 THV was associated with a comparable device success rate and a significantly lower rate of ≥moderate PVL, when compared with its predecessor.

Altered frequency of FOXP3+ regulatory T cells is associated with development of inhibitors in patients with severe hemophilia A.

The development of anti-factor VIII (FVIII) antibodies or "inhibitors" is a major complication following FVIII replacement therapy in patients with severe hemophilia A (HA), rendering the treatment inefficient. Data on the role of regulatory T cells (Tregs) in inhibitor formation in these patients are rare. Herein, we aimed to investigate whether a difference in the FOXP3+ Tregs is linked to the formation of the inhibitors in severe HA patients. In this cross-sectional study, 32 patients with severe HA (8 patients with inhibitors and 24 without inhibitors) and 24 healthy controls were enrolled. The frequency of FOXP3+ Tregs was determined using multicolor flow cytometry method. Our results showed that the median level of CD4+ CD25+ FOXP3+ Tregs did not significantly differ between HA patients and healthy controls and between HA patients with and without inhibitors (P > 0.05). However, patients with inhibitors had significantly lower amounts of CD4+ CD25- FOXP3+ Tregs compared to those without inhibitors as well as healthy controls (*P = 0.012 and *P = 0.004, respectively). The frequency of CD4+ CD25+ T cells was significantly higher in HA patients who developed inhibitors compared to the inhibitor-negative ones whereas they were lower in inhibitor-negative patients compared to the healthy controls (*P = 0.013 and *P = *0.029, respectively). The percentages of CD4+ CD25+ T cells were positively correlated with the levels of inhibitors in HA patients (r = 0.45, *P = 0.021). Our data demonstrated for the first time that the CD4+ CD25- FOXP3+ Tregs might be implicated in the prevention of inhibitor formation in severe HA patients.

Four Decades of Carrier Detection and Prenatal Diagnosis in Hemophilia A: Historical Overview, State of the Art and Future Directions.

Hemophilia A (HA), a rare recessive X-linked bleeding disorder, is caused by either deficiency or dysfunction of coagulation factor VIII (FVIII) resulting from deleterious mutations in the F8 gene encoding FVIII. Over the last 4 decades, the methods aimed at determining the HA carrier status in female relatives of HA patients have evolved from phenotypic studies based on coagulation tests providing merely probabilistic results, via genetic linkage studies based on polymorphic markers providing more accurate results, to next generation sequencing studies enabling highly precise identification of the causative F8 mutation. In parallel, the options for prenatal diagnosis of HA have progressed from examination of FVIII levels in fetal blood samples at weeks 20-22 of pregnancy to genetic analysis of fetal DNA extracted from chorionic villus tissue at weeks 11-14 of pregnancy. In some countries, in vitro fertilization (IVF) combined with preimplantation genetic diagnosis (PGD) has gradually become the procedure of choice for HA carriers who wish to prevent further transmission of HA without the need to undergo termination of pregnancies diagnosed with affected fetuses. In rare cases, genetic analysis of a HA carrier might be complicated by skewed X chromosome inactivation (XCI) of her non-hemophilic X chromosome, thus leading to the phenotypic manifestation of moderate to severe HA. Such skewed XCI may be associated with deleterious mutations in X-linked genes located on the non-hemophilic X chromosome, which should be considered in the process of genetic counseling and PGD planning for the symptomatic HA carrier. Therefore, whole exome sequencing, combined with X-chromosome targeted bioinformatic analysis, is highly recommended for symptomatic HA carriers diagnosed with skewed XCI in order to identify additional deleterious mutations potentially involved in XCI skewing. Identification of such mutations, which may profoundly impact the reproductive choices of HA carriers with skewed XCI, is extremely important.

Imlifidase, a new option to optimize the management of patients with hemophilia A on emicizumab

BackgroundEmicizumab is a bispecific, chimeric, humanized immunoglobulin G (IgG)4 that mimics the procoagulant activity of factor (F) VIII (FVIII). Its long half-life and subcutaneous route of administration have been life-changing in treating patients with hemophilia A (HA) with or without FVIII inhibitors. However, emicizumab only partially mimics FVIII activity; it prevents but does not treat acute bleeds. Emergency management is particularly complicated in patients with FVIII inhibitors receiving emicizumab prophylaxis in whom exogenous FVIII is inefficient. We have shown recently that Imlifidase (IdeS), a bacterial IgG-degrading enzyme, efficiently eliminates human anti-FVIII IgG in a mouse model of severe HA with inhibitors and opens a therapeutic window for the administration of exogenous FVIII. ObjectivesTo investigate the impact of IdeS treatment in inhibitor-positive HA mice injected with emicizumab. MethodsIdeS was injected to HA mice reconstituted with human neutralizing anti-FVIII IgG and treated with emicizumab. ResultsIdeS hydrolyzed emicizumab in vitro and in vivo, albeit, at slower rates than another recombinant human monoclonal IgG4. While F(ab’)2 fragments were rapidly cleared from the circulation, thus leading to a rapid loss of emicizumab procoagulant activity, low amounts of single-cleaved intermediate IgG persisted for several days. Moreover, the IdeS-mediated elimination of the neutralizing anti-FVIII IgG and restoration of the hemostatic efficacy of exogenous FVIII were not impaired by the presence of emicizumab and polyclonal human IgG in inhibitor-positive HA mice. ConclusionOur results suggest that IdeS could be administered to inhibitor-positive patients with HA receiving emicizumab prophylaxis to improve and ease the management of breakthrough bleeds or programmed major surgeries.

Sensitive Measurement of Clinically Relevant Factor VIII Levels in Thrombin Generation Assays Requires Presence of Factor XIa.

Hemophilia A (HA) is characterized by decreased or absent factor VIII (FVIII) activity. Current FVIII assays are based on clotting time and thus only provide information about the initiation of coagulation. In contrast, thrombin generation assays (TGAs) can be used to measure the full coagulation spectrum of initiation, propagation, and termination that provide information on the whole course of thrombin generation and inhibition. However, the commercially available TG kits lack sensitivity for measurements of hemophilia plasma within lower FVIII ranges, which is essential for explaining differences in bleeding phenotypes in hemophiliacs at clinically low levels of FVIII. Optimization of the TGA for measurements of low FVIII levels in severe HA patients. TGA measurements were performed in severe HA pooled plasma (n = 10). Investigations of several preanalytical and analytical variables of the assay were performed in a stepwise process and adjusted based on sensitivity toward intrinsic coagulation activation. TGA initiated by tissue factor (TF) alone at varying concentrations was unable to significantly differentiate between FVIII levels below 20%. In contrast, TGA activation with low concentrations of TF in presence of FXIa appeared to be highly sensitive for FVIII changes both in high and low ranges. In addition, a representative TGA curve at trough levels could only be produced using the dual TF/FXIa TGA. We propose a critical optimization for the setup of the TGA for measurements in severe HA plasma. The dual TF/FXIa TGA shows increased sensitivity, especially in lower FVIII ranges, which allows for better individual characterization at baseline, prediction of interventions, and follow-up.

Impact of timing of prophylaxis commencement, F8 genotype and age on factor consumption and health-related quality of life in patients with severe haemophilia A.

The timing of prophylaxis and F8 genotype can impact treatment outcomes in adults with severe haemophilia A (HA). To investigate how F8 genotype, timing, and type of prophylaxis influence arthropathy, bleeding rates, factor consumption and health-related quality of life (HRQoL). Thirty-eight patients with severe HA were enrolled. Bleeding events were recorded retrospectively during median 12.5 months. F8 gene variants were classified as null or non-null. Joint health and HRQoL were assessed with HJHS and EQ-5D-5L, respectively. The median age at prophylaxis start was 1.25 years in the primary prophylaxis group (N=15, median age 26 years) and 31.5 years in the secondary group (N=22, 45 years), respectively. There were significant differences in the medians of HJHS (4 vs. 20, p<.001), EQ-5D-5L index (0.9647 vs. 0.904, p=.022), EQ VAS (87 vs. 75, p=.01) and FVIII consumption (3883 vs. 2737 IU/kg/year, p=.02), between the primary and secondary groups, respectively. Median annualized bleeding rate (ABR) was 0 for both groups. Twenty-five null and thirteen non-null F8 gene variants were identified. In the secondary prophylaxis group, lower median FVIII consumption (1926 vs. 3370 IU/kg/year) was shown for non-null compared to null variants, respectively,with similar ABR and HJHS. Delayed prophylaxis start with intermediate dose intensity prevents bleeds but at a cost of more arthropathy and reduced HRQoL, compared to higher intensity primary prophylaxis. Non-null F8 genotype may allow lower factor consumption with similar HJHS and bleeding rates, compared to null genotype.

The spleen is the major site for the development and expansion of inhibitor producing-cells in hemophilia A mice upon FVIII infusion developing high-titer inhibitor

BackgroundHemophilia A (HA) is a hereditary bleeding disorder caused by defects in endogenous factor (F)VIII. Approximately 30 % of patients with severe HA treated with FVIII develop neutralizing antibodies (inhibitors) against FVIII, which render the therapy ineffective. The managements of HA patients with high-titter inhibitors are especially challenging. Therefore, it is important to understand the mechanism(s) of high-titer inhibitor development and dynamics of FVIII-specific plasma cells (FVIII-PCs). AimsTo identify the dynamics of FVIII-PCs and the lymphoid organs in which FVIII-PCs are localized during high-titer inhibitor formation. Methods and resultsWhen FVIII-KO mice were intravenously injected with recombinant (r)FVIII in combination with lipopolysaccharide (LPS), a marked enhancement of anti-FVIII antibody induction was observed with increasing FVIII-PCs, especially in the spleen. When splenectomized or congenitally asplenic FVIII-KO mice were treated with LPS + rFVIII, the serum inhibitor levels decreased by approximately 80 %. Furthermore, when splenocytes or bone marrow (BM) cells from inhibitor+ FVIII-KO mice treated with LPS + rFVIII were grafted into immune-deficient mice, anti-FVIII IgG was detected only in the serum of splenocyte-administered mice and FVIII-PCs were detected in the spleen but not in the BM. In addition, when splenocytes from inhibitor+ FVIII-KO mice were grafted into splenectomized immuno-deficient mice, inhibitor levels were significantly reduced in the serum. ConclusionThe spleen is the major site responsible for the expansion and retention of FVIII-PCs in the presence of high-titer inhibitors.

Impact of ABO blood group antigens on residual factor VIII levels and risk of inhibitor development in hemophilia A

The clinical phenotype of hemophilia A (HA) does not always correlate with severity. Similarly, the presence of inhibitors does not necessarily increase the risk of bleeding. This paradox between clinical and laboratory findings may be partially attributed to non-modifiable factors, such as blood group, which is known to influence FVIII levels in healthy individuals. Our aim was to assess the effect of ABO blood group antigens on FVIII levels across the severity spectrum of HA and risk of inhibitor development. Data of consecutive patients with HA who visited the coagulation unit of a northern Indian tertiary care hospital between 2010‒2021 were reviewed. Patients with missing blood group data, transfusion histories, or baseline FVIII levels were excluded. Mild, moderate, and severe HA was present in 41 (6.9%), 72 (12.2%), and 479 (80.9%) patients, respectively. There were no differences in the FVIII levels among the various blood groups across the HA severity spectrum. Inhibitors were administered to 35 patients (5.9%). In the multivariate analysis, blood group A was an independent risk factor for the development of inhibitors (adjusted odds ratio 2.70, P=0.04) after adjusting for age at onset of bleeding, FVIII transfusion, age at first FVIII transfusion, and severity of HA. Unlike what is observed in healthy individuals, blood group did not influence residual FVIII levels across the severity spectrum of HA. Patients in group A had a higher risk of developing inhibitors.

The humanistic and economic burden of problem joints for children and adults with moderate or severe haemophilia A: Analysis of the CHESS population studies.

Adequate prophylactic treatment and physical activity improve joint health and clinical outcomes for people with haemophilia A (HA). However, non-clinical joint-related burden of moderate (MHA) and severe (SHA) HA has not been well characterised. To quantify the joint health-related humanistic and economic burden of MHA and SHA in Europe. A retrospective analysis of the cross-sectional CHESS population studies using a patient-centric measure of joint health (problem joints, PJs: chronic joint pain and/or limited range of movement due to compromised joint integrity with or without persistent bleeding) was conducted. Descriptive statistics summarised health-related quality of life (HRQoL), work productivity/activity impairment and costs by number of PJs (0, 1 or ≥2) and HA severity. A total of 1171 patients were included from CHESS-II (n = 468) and CHESS-PAEDs (n = 703). In both studies, 41 and 59% of patients had MHA and SHA, respectively. Prevalence of ≥2 PJs was similar with MHA and SHA (CHESS-II: 23 and 26%; CHESS-PAEDs: 4 and 3%, respectively). HRQoL was worse with an increasing number of PJs (CHESS-II: .81 vs. .66 with 0 and ≥2 PJs, respectively, for MHA; .79 vs. .51 for SHA; CHESS-PAEDs: .64 vs. .26 and .72 vs. .14). Total costs increased with increasing PJs regardless of severity in CHESS-II (€2923 vs. €22,536 with 0 and ≥2 PJs, respectively, for MHA; €11,022 vs. €27,098 for SHA) and CHESS-PAEDs (€6222 vs. €11,043 for MHA; €4457 vs. €14,039 for SHA). Presence of PJs was associated with a substantial humanistic and economic burden on patients with MHA or SHA across the lifespan.

Association between interleukin-2 (rs2069762) gene polymorphism and FVIII inhibitor development in Indonesian patients with severe hemophilia A

BACKGROUND Factor VIII (FVIII) inhibitors in hemophilia A (HA) patients render FVIII replacement therapy ineffective. Although its development cause is unclear, it has been classified into therapeutic and genetic-related etiologies. Single nucleotide polymorphisms (SNPs) in several cytokine genes, including interleukin (IL)-2, could increase the risk of FVIII inhibitor development. This study aimed to evaluate the association between IL-2 (rs2069762) gene SNP and FVIII inhibitor development in Indonesian patients with severe HA.&#x0D; METHODS The IL-2 (rs2069762) gene SNP was examined in 119 HA patients. The presence of FVIII inhibitors was quantified using an enzyme-linked immunosorbent assay, with a titer of &lt;0.28 ng/ml considered negative. Patients were divided into two groups: 59 with FVIII inhibitors (positive group) and 60 without inhibitors (negative group). The genotype of the subjects was determined using peripheral blood mononuclear cells and tetra-primer amplification refractory mutation system-polymerase chain reaction.&#x0D; RESULTS There was no association between IL-2 (rs2069762) gene polymorphism and FVIII inhibitor development on genotypes (p = 0.138) and allele frequencies (p = 0.780).&#x0D; CONCLUSIONS IL-2 (rs2069762) gene polymorphism is not a risk factor in the development of FVIII inhibitors in Indonesian patients with severe HA. Thus, further polymorphism studies in other cytokine genes are required to gain a comprehensive understanding of the FVIII inhibitor development.

Low-dose immune tolerance induction therapy in severe hemophilia a children in China: Starting earlier resulted in better inhibitor eradication outcomes

BackgroundShorter interval-time from inhibitor detection to starting immune tolerance induction (ITI) might predict better ITI outcomes for severe Hemophilia A (SHA) patients with high-risk-inhibitors. However, the prediction-impact of interval-time for these patients on low-dose ITI strategy remained unclear. ObjectivesTo explore the relationship between interval-time and low-dose ITI outcomes in Chinese SHA children with high-risk-inhibitors. MethodsThis was a single-center, retrospective study on SHA children with high-risk-inhibitors (each with immediate pre-ITI inhibitor titer>10 Bethesda Units/mL) undergoing low-dose ITI strategy for ≥24 months. ITI outcomes and their predictive factors were evaluated at the 24th month treatment for each patient. The predictive ability of interval-time on ITI success was determined using receiver operating characteristic (ROC) curve. ResultsAmong 47 patients investigated, 34 (72.3 %) achieved success. Independent predictor for ITI-outcome on multivariate analysis included the interval-time (p = 0.007) and peak inhibitor-titer (p = 0.011). Shorter interval-time predicted ITI success [cut-off value = 22.3 months, area under ROC-curve (AUC) = 0.701] and early-ITI success within 12 month (cut-off value = 9.4 months AUC = 0.704). Linear regression analysis suggested each month interval-time delay delayed success by 0.1552 month. Unlike the interval-time, peak inhibitor-titer had no success-predictive value in high-peak inhibitor-titer patients on ITI with immunosuppressants. ConclusionsInterval-time represented a strong predictive value for outcomes in our low-dose ITI strategy for SHA patients with high-risk-inhibitors. Shorter interval-time was associated with higher success rate and earlier success achievement. The respective interval-time cut-off values were 22.3 months for ITI success and 9.4 months for early-success.