Minor surgical procedures during immune tolerance induction in people with hemophilia A and inhibitors: results from the Brazilian Immune Tolerance (BrazIT) study cohort.

INTRODUCTION: Surgeries are implicated in the development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) in hemophilia A individuals with immune tolerance induction (ITI) treatment being the recommended therapy to eradicate these inhibitors. We evaluated the association of surgical procedures performed during ITI and treatment outcome. METHODS: Patients were treated according to the Brazilian ITI Protocol with outcomes being defined as successful (i.e., recovered responsiveness to exogenous FVIII) and failed (i.e., unresponsiveness to exogenous FVIII thus requiring bypassing agents for bleeding control). Surgical procedures during induction therapy were managed following international recommendations. RESULTS: Treatment success rate was 68.7 % in 163 patients; 33 (20.2 %) were submitted to 43 (96 %) minor and two major surgeries. Personal, hemophilia, inhibitor, and treatment characteristics were similar between patients submitted to surgical procedures or not while on ITI; the success rates were 72.7 % and 67.7 % (p-value = 0.577), respectively. CONCLUSION: No association was found between having a minor surgical procedure and ITI treatment outcome.

Incidence of venous thromboembolism and adequacy of thromboprophylaxis in 2380 acutely-ill hospitalized patients: Results from the PROFMiG cohort study.

INTRODUCTION: Hospital-acquired venous thromboembolism (VTE) is a major cause of preventable deaths. Incidence of VTE and adequacy of thromboprophylaxis have rarely been reported in low-resourced countries. The aim of this study was to estimate the incidence of VTE and to evaluate the adequacy of thromboprophylaxis in acutely-ill medical hospitalized patients. METHODS: The PROFMiG is a prospective cohort study conducted in Brazil. We consecutively enrolled adult (> 18 years) acutely-ill hospitalized medical patients at admission. Risk assessment for VTE was evaluated by the IMPROVE7 (International Medical Prevention Registry on Venous Thromboembolism). Outcomes were death and VTE events during hospital stay up to 90 days after discharge. All VTE and death events were adjudicated. We also evaluated pulmonary embolism-related death and adequacy of thromboprophylaxis. VTE incidence was estimated by competing risk methods. RESULTS: A total of 2380 participants was included. Median age was 70 years, 56.1 % women, median length of hospital stay was 10 days. A total of 2052 (86.3 %) patients were classified as low-risk for VTE, 30 (1.3 %) patients had objectively confirmed VTE, and 1449 (60.8 %) received inadequate thromboprophylaxis. The overall mortality rate was 14.0 %. Cumulative incidence of VTE was 2.0 % (95 % confidence interval 0.9 %-3.8 %) at 130 days after admission when considering death as competing risk. CONCLUSION: The cumulative incidence of VTE in this cohort corroborates with that reported in high-resourced countries. Despite recommendation, thromboprophylaxis was mostly inadequate. We suggest the adoption of competing risk analysis to estimate the cumulative incidence of VTE in hospitalized patients.

Large deletions and small insertions and deletions in the factor VIII gene predict unfavorable immune tolerance induction outcome in people with severe hemophilia A and high-responding inhibitors.

INTRODUCTION: Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome. MATERIAL AND METHODS: We included people with severe hemophilia A (FVIII ˂ 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction, followed by F8 sequencing. RESULTS: We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6 years at ITI start. Intron 22 inversion was the most prevalent variant (53.6 %), followed by nonsense (16.1 %), small insertion/deletion (11.3 %), and large deletion (10.7 %). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (odds ratio [OR] 15.50; 95 % confidence interval [95 % CI] 4.59-71.30) and 4.25 times higher (95 % CI, 1.53-12.3) among carriers of F8 large deletions and small insertions and deletions, respectively. CONCLUSION: F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study to show F8 large deletions and small insertions/deletions as predictors of ITI failure.

International Society on Thrombosis and Haemostasis clinical practice guideline for treatment of congenital hemophilia A and B based on the Grading of Recommendations Assessment, Development, and Evaluation methodology.

BACKGROUND: Hemophilia is a rare congenital bleeding disorder that results from complete or partial deficiency of blood coagulation factor (F)VIII (hemophilia A) or FIX (hemophilia B) due to pathogenic variants in their coding genes. Hemophilia requires complex management. To date, there is no evidence-based clinical practice guideline on hemophilia treatment based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. OBJECTIVES: This evidence-based clinical practice guideline from the International Society on Thrombosis and Haemostasis aims to provide an overview of evidence and support patients, caregivers, hematologists, pediatricians, other clinicians, researchers, and stakeholders in treatment decisions about congenital hemophilia A and B. METHODS: The International Society on Thrombosis and Haemostasis formed a multidisciplinary guideline panel of physicians and patients with global representation, balanced to minimize potential bias from conflicts of interest. The panel prioritized a set of clinical questions and outcomes according to their importance for clinicians and patients. A methodological team supported the guideline development process, including searching for evidence and performing systematic reviews. The GRADE approach was used, including GRADE Evidence to Decision frameworks. The recommendations were subject to public comment. RESULTS: The panel selected 13 questions, of which 11 addressed the treatment of hemophilia A and 2 the treatment of hemophilia B. Specifically, the panel addressed questions on prophylactic and episodic treatment with FVIII concentrates, bypassing agents, and nonfactor therapy (emicizumab) for hemophilia A (with and without inhibitors) as well as immune tolerance induction for hemophilia A. For hemophilia B, the panel addressed questions on prophylactic and episodic treatment of bleeding events with FIX concentrates. Agreement was reached for all 13 recommendations, of which 7 (54%) were based on evidence from randomized clinical trials, 3 (23%) on observational studies, and 3 (23%) on indirect comparisons. CONCLUSION: Strong recommendations were issued for prophylactic over episodic treatment for severe and moderately severe hemophilia A and B. Only conditional recommendations were issued for the remaining questions. Future research should focus on direct treatment comparisons and the treatment of hemophilia B with and without inhibitors. Future updates of this guideline will provide an updated evidence synthesis on the current questions and focus on new FVIII and FIX concentrates, novel nonfactor therapies, and gene therapy for severe and nonsevere hemophilia A and B.

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.

Hypocoagulability in severe yellow fever infection is associated with bleeding: results from a cohort study.

Background: Severe yellow fever infection (YFI) may be complicated by a hemorrhagic diathesis. However, the hemostasis profile of YFI has rarely been reported. Objectives: The aim of this study was to characterize the hemostatic features of YFI by using a rotational thromboelastometry (ROTEM). Methods: We evaluated clinical, laboratory, and ROTEM parameters in adults with severe YFI and their correlation with hemostatic variables according to bleeding and death. Results: A total of 35 patients were included (median age, 49 years). ROTEM was performed in 22 patients, of whom 21 (96%) presented bleeding and 4 (18%) died. All patients who died had major bleeding. Patients who died presented prolonged clotting time (CT; median, 2326 seconds; IQR, 1898-2986 seconds) and reduced alpha angle (median, 12°; IQR, 12°-15°) in comparison with patients who had minor (median CT, 644 seconds; IQR, 552-845 seconds and alpha angle, 47°; IQR, 28°-65°) and major (median CT, 719 seconds; IQR, 368-1114 seconds and alpha angle, 43°; IQR, 32°-64°) bleeding who survived. In patients who had bleeding, CT showed a strong negative correlation with factor (F)V (r = -.68), FIX (r = -.84), and FX (r = -.63) as well as alpha angle showed a strong negative correlation with FIX (r = -.92). In patients who died, the correlations were even stronger. A total of 19/21 (90%) patients presented hypocoagulability assessed by ROTEM. Conclusion: Hypocoagulabitity is the hallmark of the bleeding diathesis of severe YFI. Abnormal CT and alpha angle associated with death and could be used as potential predictors of adverse outcome in severe YFI.

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.

Distinguishing ASH clinical practice guidelines from other forms of ASH clinical advice.

ABSTRACT: The American Society of Hematology (ASH) develops a variety of resources that provide guidance to clinicians on the diagnosis and management of blood diseases. These resources include clinical practice guidelines (CPGs) and other forms of clinical advice. Although both ASH CPGs and other forms of clinical advice provide recommendations, they differ with respect to the methods underpinning their development, the principal type of recommendations they offer, their transparency and concordance with published evidence, and the time and resources required for their development. It is crucial that end users be aware of the differences between CPGs and other forms of clinical advice and that producers and publishers of these resources use clear and unambiguous terminology to facilitate their distinction. The objective of this article is to highlight the similarities and differences between ASH CPGs and other forms of ASH clinical advice and discuss the implications of these differences for end users.

Venous Thromboembolism Prophylaxis in Foot and Ankle Surgery: A Worldwide Survey.

Current recommendations on thromboprophylaxis for foot and ankle (FA) surgery are often inconsistent and generally based on weak evidence. The aim of this survey study was to evaluate the current practice among orthopedic surgeons regarding venous thromboembolism (VTE) prophylaxis following FA surgery. From February 2019 to March 2020, an online questionnaire was sent by e-mail to orthopedic societies across the world. The questionnaire was hosted by the International Society of Thrombosis and Haemostais RedCAP platform. Topics of interest were VTE rates following FA surgery, duration and type of thromboprophylaxis, bleeding complications, VTE risk factors for prophylaxis and use of risk assessment. A total of 693 FA orthopedic surgeons from all continents completed the survey of whom 392 (57%) performed more than 200 FA procedures per year. A total of 669/693 (97%) respondents stated that thromboprophylaxis is necessary in FA surgeries. When thromboprophylaxis was prescribed, half of surgeons prescribed it for the duration of immobilization. Acetylsalicylic acid, low molecular weight heparin and direct-oral anticoagulants were, in this order, the preferred choice. Acetylsalicylic acid and low molecular weight heparin were predominantly prescribed in North America and Europe, respectively. Previous deep vein thrombosis, immobility, obesity and inherited thrombophilia were considered the main risk factors indicative of thromboprophylaxis use. In this survey, most surgeons agree that thromboprophylaxis is indicated for FA surgery, but the prescription, type and duration of prophylaxis differs greatly with a large intercontinental discrepancy. These survey results could be a foundation for developing uniform guidelines to optimize thromboprophylactic strategies in FA procedures around the world.

Electrocardiographic Findings Among Asymptomatic Adults With Haemophilia

Abstract Background: People with haemophilia (PwH) are living longer. Therefore, they can develop atherosclerotic cardiovascular disease (ASCVD). Electrocardiogram (ECG) alterations may be a sign of initial ASCVD before the occurrence of symptoms. Objective: To describe the prevalence of resting ECG alterations among PwH adults asymptomatic for ASCVD. Methods: PwH aged ≥ 30 years without previous ASCVD events were considered for the analysis. Resting ECG traces were analysed according to international reference values and the Brazilian Longitudinal Adult Health Study (ELSA-Brasil) results for asymptomatic Brazilian men. Based on the established normal values and using the QT index, we further described the altered ECGs as minor or major changes, according to the Minnesota Code. Differences between prevalences were evaluated by Pearson's χ2 test. Differences between medians were evaluated by the Mann-Whitney U test. A p-value < 0.05 was accepted as statistically significant. Results: A total of 64 PwH were included in the study. Median age was 44 years (interquartile range 35-52). Most patients had haemophilia A (81%) and 47% were severe. The prevalence of obesity, systemic arterial hypertension (SAH), diabetes mellitus (DM), and dyslipidaemia were 16%, 56%, 14%, and 72%, respectively. All the PwH had sinus rhythm, except for one, who had an implanted pacemaker due to idiopathic third-degree atrioventricular block. Altered ECGs were found in 25% and 30% of PwH, according to established criteria and ELSA-Brasil criteria, respectively. Major changes were found in eight (13%) PwH according to the Minnesota Code, including two ECGs with ischaemia-like wall inactivity. Conclusions: The prevalence of altered ECG varied from 25% to 30% among asymptomatic PwH.

Cardiovascular Risk Scores among Asymptomatic Adults with Haemophilia. / Escores de Risco Cardiovascular entre Adultos Assintomáticos com Hemofilia.

BACKGROUND: The mortality rate of Brazilian people with haemophilia (PwH) is decreasing, but the relative incidence of deaths associated with cardiovascular disease (CVD) is increasing. OBJECTIVES: We aimed to describe the CVD risk score of PwH according to Pooled Cohort Equations Risk (PCER) Calculator tool and its treatment recommendations. We also compared the PCER estimates with the respective Framingham Risk Score (FRS). METHODS: This cross-sectional study included male PwH ≥ 40 years treated at the Comprehensive Haemophilia Treatment Centre of Pernambuco (Recife/Brazil). PwH with a previous CVD event or a low-density lipid cholesterol ≥ 5.0 mmol/L were excluded. Interviews, medical file reviews, and blood tests were performed. The PCER tool was used to estimate the CVD risk and compare it with the respective FRS. A p-value < 0.05 was accepted as statistically significant. RESULTS: Thirty PwH were included. Median age was 51.5 [interquartile range-IQR; 46.0-59.5] years. The prevalence of obesity, systemic arterial hypertension, diabetes mellitus, hypertriglyceridaemia, hypercholesterolaemia, and hypoHDLaemia were 20%, 67%, 24%, 14%, 47%, and 23%, respectively. The median PCER score was 6.9% [IQR; 3.1-13.2], with 50% having a high risk (PCER ≥ 7.5%). Statin use was suggested for 54% of PwH. Blood pressure was poorly controlled in 47% of PwH. The agreement between PCER and FRS was 80% (κ = 0.60; p = 0.001). CONCLUSIONS: Half of the male people with haemophilia aged 40 years or older had a 10-year high risk of developing CVD with strong recommendations to improve control of dyslipidaemia and blood pressure.

FUNDAMENTO: A taxa de mortalidade de pessoas com hemofilia (PCH) no Brasil está diminuindo, mas a incidência relativa de mortes associadas a doenças cardiovasculares (DCV) tem aumentado. OBJETIVOS: Nosso objetivo foi descrever o escore de risco de DCV de PCHs de acordo com a ferramenta Pooled Cohort Equations Risk (PCER) Calculator e suas recomendações de tratamento. Além disso, foram comparadas as estimativas da PCER com o respectivo escore de risco de Framingham (FRS). MÉTODOS: Este estudo transversal incluiu PCHs do sexo masculino, com idade igual ou superior a 40 anos, tratados no Centro de Tratamento Integral de Hemofilia de Pernambuco (Recife/Brasil). PCHs com um evento cardiovascular prévio ou colesterol lipídico de baixa densidade ≥ 5,0 mmol/L foram excluídas. Entrevistas, revisões de prontuários médicos e exames de sangue foram realizados. A ferramenta PCER foi utilizada para estimar o risco de DCV e compará-lo com o respectivo FRS. Um valor de p < 0,05 foi aceito como estatisticamente significativo. RESULTADOS: Trinta PCHs foram incluídas. A idade mediana foi de 51,5 [intervalo interquartil-IIQ; 46,0-59,5] anos. A prevalência de obesidade, hipertensão arterial sistêmica, diabetes mellitus, hipertrigliceridemia, hipercolesterolemia e hipoHDLemia foi de 20%, 67%, 24%, 14%, 47% e 23%, respectivamente. O escore mediano da PCER foi de 6,9% [IIQ; 3,1-13,2], com 50% de alto risco (PCER ≥ 7,5%). O uso de estatina foi sugerido para 54% das PCHs. A pressão arterial estava mal controlada em 47% das PCHs. A concordância entre PCER e FRS foi de 80% (κ = 0,60; p = 0,001). CONCLUSÕES: Metade dos homens com hemofilia, com 40 anos de idade ou mais, teve um alto risco de desenvolver DCV em 10 anos, com fortes recomendações para melhorar o controle da dislipidemia e da pressão arterial.

The landscape of hematology research in Brazil: an analysis of data from citation databases

ABSTRACT Introduction: Scientometrics is the field concerned with measuring and analyzing academic literature, using specific metrics and data from bibliometric databases. Hematology is a broad area of science and medicine, from which several landmark scientific discoveries have emerged. Objective: The aim of this report is to provide a snapshot of the landscape of hematology research in Brazil, based on a comprehensive analysis of published studies in hematology whose authors were affiliated to Brazilian institutions from 1980 to 2020. Method: Articles, reviews and letters to the editor with at least one author affiliated to a Brazilian institution were retrieved from Incytes/Web of Science or Scopus databases. Importantly, only papers classified in the subject area "Hematology" by the embedded algorithms of each database were included. Results: Considering all published papers, Brazil is in the 22nd position, contributing with around 1.1% of papers in this period. A clear and sustained increase in publication output can be observed from the early 1990's to the present moment. Publicly-funded higher education institutions were the main contributors to the development and consolidation of the hematology scientific community, which has grown in diversity, with an increasing number of contributions from private institutions. In regard to funding, public agencies have been and remain by large as the most important funder of research in hematology in Brazil. Conclusion: We suggest that continuous monitoring of the temporal trends of some of the data compiled in our report could potentially contribute to a clearer picture of the development of hematology research in Brazil.

Reported prevalence of von Willebrand disease worldwide in relation to income classification.

INTRODUCTION: The diagnosis of von Willebrand disease (VWD) is complex and challenging, especially when diagnostic resources are limited. This results in a lack of consistency in identifying and reporting the number of people with VWD and variations in the VWD prevalence worldwide. AIM: To analyze the reported prevalence of VWD worldwide in relation to income classification. METHODS: Data on the VWD prevalence from the World Federation of Hemophilia Annual Global Survey, national registries of Australia, Canada, and the United Kingdom, and the literature were analysed. The income level of each country was classified according to the World Bank. RESULTS: The mean VWD prevalence worldwide was 25.6 per million people. The VWD prevalence for high-income countries (HIC) of 60.3 per million people was significantly greater (p < .01) than upper middle (12.6), lower middle (2.5) and low (1.1) income countries. The type 3 VWD prevalence for HIC of 3.3 per million people was significantly greater (p < .01) than lower middle (1.3) and low income (0.7) countries. The reported VWD prevalence was greater among females than males. CONCLUSION: The reported VWD prevalence varied considerably across and within income classifications. The variability of type 3 VWD prevalence was less than the VWD prevalence (all types). The variability in detection and diagnosis of type 1 VWD presents a challenge in forming a consistent prevalence value across countries and income classifications.