High levels of anti-factor VIII immunoglobulin G4 and immunoglobulin G total are associated with immune tolerance induction failure in people with congenital hemophilia A and high-responding inhibitors.

Background: Immune tolerance induction (ITI) is the treatment of choice to eradicate neutralizing anti-factor (F)VIII alloantibodies (inhibitors) in people with inherited hemophilia A. However, it is not successful in 10% to 40% of the cases. The biological mechanisms and biomarkers associated with ITI outcome are largely unknown. Objectives: The aim of this study was to investigate the association of plasma cytokines (interferon-γ, tumor necrosis factor, interleukin [IL]-2, IL-4, IL-5, IL-6, IL-10, and IL-17A), chemokines (IL-8/CXCL8, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IP-10/CXCL10), and anti-FVIII immunoglobulin (Ig) G total, IgG1, and IgG4 with ITI outcome. Methods: In this cross-sectional analysis of the Brazilian Immune Tolerance Study, we assessed plasma levels of anti-FVIII IgGs using an enzyme-linked immunosorbent assay with plasma-derived FVIII and recombinant FVIII as target antigens, immobilized in microplates. Results: We assayed 98 plasma samples of moderately severe and severe (FVIII activity, <2%) people with hemophilia A after completion of a first ITI course. Levels of anti-recombinant FVIII IgG total and IgG4 were higher in people with hemophilia A who failed ITI (IgG total optical density [OD], 0.37; IQR, 0.15-0.73; IgG4 OD, 2.19; IQR, 0.80-2.52) than in those who had partial (IgG total OD, 0.03; IQR, 0.00-0.14; IgG4 OD, 0.39; IQR, 0.09-1.11; P < .0001 for both) or complete success (IgG total OD, 0.04; IQR, 0.00-0.07; IgG4 OD, 0.07; IQR, 0.06-0.40; P < .0001 for both). Plasma cytokines, chemokines, and anti-FVIII IgG1 were not associated with ITI outcome. Conclusion: Our results show that high levels of plasma anti-FVIII IgG4 and IgG total are associated with ITI failure.

Quality of life in children and adolescents with blood coagulation disorders and hemoglobinopathies.

The aim of this study was to evaluate the impact of oral conditions and health-related quality of life (HRQoL) on oral health-related quality of life (OHRQoL) in children and adolescents with blood coagulation disorders and hemoglobinopathies (BCDH). The study was cross-sectional and included 61 individuals aged 2 to 18 years with BCDH. Exams for dental caries (dmft/DMFT index), oral hygiene (simplified oral hygiene index - OHI-S), and gingival health (modified gingival index - MGI) were performed. The pediatric quality of life inventory™ (PedsQL™) generic core scale and oral health scale were used to measure HRQoL and OHRQoL. Spearman's correlation coefficient (ρ) and the Mann-Whitney test (α = 0.05) were conducted to assess the relationship between covariates and the PedsQL™ oral health scale. The mean PedsQL™ oral health scale score was 76.66 (SD = 21.36). Worse OHRQoL was correlated with poor oral hygiene (ρ = -0.383; p: 0.004), poor gingival health (ρ = -0.327; p = 0.014), and better HRQoL (ρ = 0.488; p < 0.001). Greater untreated dental caries experience was associated with worse OHRQoL (p = 0.009). Worse oral health status in children and adolescents with BCDH negatively impacts OHRQoL, and OHRQoL and quality of life analyzed from a generic perspective are positively correlated constructs in this population.

Prediction of inhibitor development in previously untreated and minimally treated children with severe and moderately severe hemophilia A using a machine-learning network.

BACKGROUND: Prediction of inhibitor development in patients with hemophilia A (HA) remains a challenge. OBJECTIVES: To construct a predictive model for inhibitor development in HA using a network of clinical variables and biomarkers based on the individual similarity network. METHODS: Previously untreated and minimally treated children with severe/moderately severe HA, participants of the HEMFIL Cohort Study, were followed up until reaching 75 exposure days (EDs) without inhibitor (INH-) or upon inhibitor development (INH+). Clinical data and biological samples were collected before the start of factor (F)VIII replacement (T0). A predictive model (HemfilNET) was built to compare the networks and potential global topological differences between INH- and INH+ at T0, considering the network robustness. For validation, the "leave-one-out" cross-validation technique was employed. Accuracy, precision, recall, and F1-score were used as evaluation metrics for the machine-learning model. RESULTS: We included 95 children with HA (CHA), of whom 31 (33%) developed inhibitors. The algorithm, featuring 37 variables, identified distinct patterns of networks at T0 for INH+ and INH-. The accuracy of the model was 74.2% for CHA INH+ and 98.4% for INH-. By focusing the analysis on CHA with high-risk F8 mutations for inhibitor development, the accuracy in identifying CHA INH+ increased to 82.1%. CONCLUSION: Our machine-learning algorithm demonstrated an overall accuracy of 90.5% for predicting inhibitor development in CHA, which further improved when restricting the analysis to CHA with a high-risk F8 genotype. However, our model requires validation in other cohorts. Yet, missing data for some variables hindered more precise predictions.

Extended half-life recombinant factor VIII treatment of hemophilia A in Brazil: an expert consensus statement

Introduction Treatment of hemophilia A in Brazil is offered to all patients at no cost. However, several unmet medical needs exist. Method In this study, we applied the Delphi method to discuss with seven hemophilia A specialists the challenges that patients and the health system face regarding hemophilia A treatment and opportunities for improvement. Results A consensus was obtained regarding the number of weekly infusions and patient adherence to treatment. The bleeding profile, unfavourable pharmacokinetics (PKs), low adherence and high daily activity were patient profiles that would benefit from using the extended half-life (EHL) recombinant factor VIII (rFVIII). The advantages of treatment with the EHL rFVIII were the lower number of infusions per week, which could increase patient adherence and decrease the risk of bleeds, due to a more constant plasma level, a lower value. Additionally, the EHL rFVIII could improve quality of life, especially in patients with high daily activity, such as adolescents and young adults. The panelists mentioned that EHL rFVIII, if available, could be offered first to the priority group (adolescents between 12 and 19 years old), followed by adults (20 to 64 years old) and elderly people (over 65 years old). Conclusion In summary, the EHL rFVIII offers the optimal prophylaxis by decreasing the dose frequency, increasing the treatment adherence and improving the QoL, without compromising safety and efficacy.

Time between inhibitor detection and start of immune tolerance induction: Association with outcome in the BrazIT study.

BACKGROUND: Immune tolerance induction (ITI) is the treatment of choice for eradication of anti-factor VIII (FVIII) neutralizing alloantibodies (inhibitors) in people with inherited hemophilia A and high-responding inhibitor (PwHA-HRi). The association between ITI outcome and time elapsed between inhibitor detection and start of ITI (∆tinhi-ITI ) is debatable. OBJECTIVE: The aim of this study was to evaluate this association among a large cohort of severe PwHA-HRi. METHODS: Severe (factor VIII activity level <1%) PwHA-HRi on ITI (n = 142) were enrolled in 15 hemophilia treatment centers. PwHA-HRi were treated according to the Brazilian ITI Protocol. ITI outcomes were defined as success (i.e., recovered responsiveness to exogenous FVIII) and failure (i.e., no responsiveness to exogenous FVIII and requirement of bypassing agents to control bleeding). RESULTS: Median ages at inhibitor detection and at ITI start were 3.2 years (interquartile range [IQR], 1.6-8.1) and 6.9 years [IQR, 2.6-20.1), respectively. PwHA-HRi were stratified according to ∆tinhi-ITI quartiles: first (0.0-0.6 year), second (>0.6-1.7 year), third (>1.7-9.2 years), and fourth quartile (>9.2-24.5 years). The overall success rate was 65.5% (93/142), with no difference among first, second, third, and fourth quartiles (62.9%, 69.4%, 58.3%, and 71.4%, respectively) even after adjusting the analyses for potential confounders. CONCLUSION: In conclusion, delayed ITI start is not associated with failure of ITI in PwHA-HRi. Therefore, ITI should be offered for these patients, regardless of the time elapsed between the detection of inhibitor and the ITI start.

Access to dental care for patients with inherited bleeding and hemoglobin disorders.

AIM: To identify the main barriers to dental care access for patients with inherited bleeding (IBD) and hemoglobin disorders (HbD). METHODS: Patients with IBD and HbD were invited to participate in this study between August 2019 and March 2020. Data were collected through a questionnaire consisting of socioeconomic and demographic items and questions about access to dental services and history of dental treatment. Univariate and multiple Poisson regression model was used to determine associations between professional refusal of dental care and other co-variables (p < .05). RESULTS: The participants (29.1%) have already had professional refusal of dental care and participants with IBD (53.2%) did not feel confident with their local dentist due to their bleeding tendency. Most (64.6%) felt apprehensive about visiting the local dentist and high prevalence of refusal to provide dental care was associated with age (prevalence ratio [PR] = 1.021; 95% confidence interval [CI] = 1.010-1.032). Individuals with low bleeding risk were less likely to be denied dental care by a professional compared to those with high bleeding risk (PR = 0.536; 95%CI = 0.291-0.990). CONCLUSION: Professional refusal of dental care was high among patients with IBD, particularly older adults and with an increased risk of bleeding.

Extended half-life recombinant factor VIII treatment of hemophilia A in Brazil: an expert consensus statement.

INTRODUCTION: Treatment of hemophilia A in Brazil is offered to all patients at no cost. However, several unmet medical needs exist. METHOD: In this study, we applied the Delphi method to discuss with seven hemophilia A specialists the challenges that patients and the health system face regarding hemophilia A treatment and opportunities for improvement. RESULTS: A consensus was obtained regarding the number of weekly infusions and patient adherence to treatment. The bleeding profile, unfavourable pharmacokinetics (PKs), low adherence and high daily activity were patient profiles that would benefit from using the extended half-life (EHL) recombinant factor VIII (rFVIII). The advantages of treatment with the EHL rFVIII were the lower number of infusions per week, which could increase patient adherence and decrease the risk of bleeds, due to a more constant plasma level, a lower value. Additionally, the EHL rFVIII could improve quality of life, especially in patients with high daily activity, such as adolescents and young adults. The panelists mentioned that EHL rFVIII, if available, could be offered first to the priority group (adolescents between 12 and 19 years old), followed by adults (20 to 64 years old) and elderly people (over 65 years old). CONCLUSION: In summary, the EHL rFVIII offers the optimal prophylaxis by decreasing the dose frequency, increasing the treatment adherence and improving the QoL, without compromising safety and efficacy.

Effect of the First Factor VIII Infusions on Immunological Biomarkers in Previously Untreated Patients with Hemophilia A from the HEMFIL Study.

Hemophilia A (HA) is an inherited bleeding disorder which requires continuous replacement with factor (F) VIII concentrate. The main complication of HA is the development of neutralizing alloantibodies which inhibit FVIII activity (inhibitors). The objective of this study was to investigate the effect of the first FVIII infusions on immunological biomarkers in previously untreated patients with HA. Plasma samples were collected at enrollment before any FVIII infusion (T0) and at inhibitor development (INB +/T1) or up to 35 exposure days without inhibitors (INB -/T1). Anti-FVIII antibodies (immunoglobulin M, immunoglobulin G [IgG] 1, IgG3, and IgG4), chemokines (CCL2, CCL5, CXCL8, CXCL9, and CXCL10), and cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, interferon-γ, tumor necrosis factor, and IL-17) were assessed. A total of 71 children with severe HA were included, of whom 28 (39.4%) developed inhibitors. Plasma levels of anti-FVIII IgG4, IL-6, and CXCL8 were higher at INB +/T1 when compared with INB -/T1. This group presented a mixed cytokine profile and higher plasma levels of CXCL9 and CXL10 when compared with INB +/T1. We conclude that exposure to FVIII triggers a proinflammatory response mediated by IL-6 and CXCL8 in patients with HA who developed inhibitors. Regardless of inhibitor status, the immune system of all HA patients is stimulated after infusions of FVIII.

Haemophilia Experiences, Results and Opportunities (HERO study) in Brazil: Assessment of the psychosocial effects of haemophilia in patients and caregivers.

INTRODUCTION: The international Haemophilia Experiences, Results and Opportunities (HERO) study assessed the psychosocial aspects of life for people with haemophilia (PWH) and their caregivers in several countries. Brazil was not included in this initiative. AIM AND METHODS: An observational, multicentre, cross-sectional study was performed involving PWH (moderate-to-severe haemophilia) and their caregivers, from November 2014 to July 2015. The primary objective was to quantify the extent of the primary psychosocial factors affecting PWH in their everyday life. Descriptive statistics and comparisons between Brazilian and global respondents are presented. RESULTS: A total of 100 adult male PWH and 100 caregivers (responding on behalf of their oldest affected child aged <18 years) completed the survey. Sixty-eight per cent of the PWH had haemophilia A without inhibitors. Chronic pain and hepatitis C were the most common conditions related to haemophilia. On the EQ-5D assessment, 64% of PWH reported extreme/moderate pain. Treatment for depression or anxiety was reported by 18% of PWH and by 29% of caregivers. There was a lower employment rate for PWH in Brazil, compared to the countries included in the original HERO survey (51% vs 60%); 71% of PWH stated that haemophilia has a negative impact on their work. Over the previous 5 years, 58% of PWH and 68% of caregivers did not have difficulties in obtaining the concentrated factor for treatment. CONCLUSIONS: Our study presents an overview of the psychosocial aspects of life with haemophilia in Brazil, providing a basis for health policy decisions and may further improve comprehensive care for PWH.

Translation, validation and reliability of the functional capacity questionnaire Haemophilia Activities List for haemophilia patients in Brazil.

INTRODUCTION: To date, none of the available assessment instruments to evaluate functional abilities for individuals with haemophilia has been translated and validated in Brazil. AIM: To translate, and test the construct validity, internal consistency and the reliability of the Haemophilia Activities List (HAL) for the Brazilian population with severe and moderate haemophilia (type A or B) and to investigate differences in the self-perception of functional abilities in patients adults with haemophilia classified according to the presence of joint bleeding and the performance of orthopaedic surgeries. METHODS: The translation and transcultural adaptation following the steps: (a) translation; (b) synthesis (consensual version); (c) back-translation; (d) review by the committee of experts; (e) pretest in the target population; and (f) final version of the instrument. Correlations between HAL scores and the scores of the Health Assessment Questionnaire (HAQ) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were determined for construct validation. Reliability was tested using the test and retest method, and internal consistency was calculated by Cronbach's α. RESULTS: The HAL-BR was applied to 52 individuals with haemophilia (34.51 ± 12.87 years). The process of translation and cross-cultural adaptation produced similar versions between the translations A moderate correlation was observed between HAL and the HAQ (r = -0.55) and WOMAC scores (r = -0.58). The reliability was ICC = 0.972, CI (0.917-0.997) ICC = 0.876, CI (0.631-0.978) for inter- and intra-examiners. No difference was found in the total HAL score between the groups with and without bleeding. The group subjected to surgery compared to the group of not subjected to surgery presented in the HAL domains worse function in 'lying down/sitting/kneeling/standing', 'self-care' and 'complex lower extremities activities' as well as in total HAL score. CONCLUSION: The Brazilian version of the HAL was proven to be a valid and reliable evaluation tool for adults with haemophilia in Brazil.

Immune status of patients with haemophilia A before exposure to factor VIII: first results from the HEMFIL study.

Previous cross-sectional studies showed that some patients with haemophilia A (HA) without inhibitor presented a pro-inflammatory profile during factor VIII (FVIII) replacement therapy. Furthermore, an anti-inflammatory/regulatory state was described in HA patients after inhibitor development. However, no study investigated the levels of these biomarkers before exposure to exogenous FVIII. This study investigated the immunological profile of previously untreated patients (PUPs) with HA in comparison with non-haemophiliac boys. A panel of chemokines and cytokines was evaluated in the plasma of 40 PUPs with HA and 47 healthy controls. The presence of microparticles was assessed in the plasma of 32 PUPs with HA and 47 healthy controls. PUPs with HA presented higher levels of CXCL8 (IL8), IL6, IL4, IL10, IL2, IL17A (IL17), and lower levels of CXCL10 (IP-10) and CCL2 (MCP-1) than the age-matched healthy controls (P < 0·05). We also observed higher levels of microparticles derived from endothelium, erythrocytes, platelets, leucocytes, neutrophils, and T lymphocytes in patients in comparison with controls (P < 0·05). Compared with controls, PUPs with HA presented a distinct immunological profile, characterized by a prominent pro-inflammatory status that appears to be regulated by IL4 and IL10.