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.

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.

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

Resumo 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.

Abstract 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.

Prophylaxis of Venous Thromboembolism in Ankle and Foot Surgeries / Profilaxia do tromboembolismo venoso nas cirurgias do tornozelo e do pé

Abstract Venous thromboembolism (VTE) is among the most feared complications by orthopedists both for due to its potentially lethal outcome and the uncertainties related to its prevention. Despite the vast literature on VTE prevention in major orthopedic surgeries, little is known about it in ankle and foot procedures. In orthopedics, adequate thromboprophylaxis requires a careful assessment of the thrombotic and hemorrhagic risks based on the procedure to be performed, as well as and knowledge on anticoagulant agents. The presentis review has the goal of assessing the risk of developingdiscusses VTE risk assessment, the modalities of thromboprophylaxis modalities, and the drugs used, with an emphasis on foot and ankle surgeries.

Resumo O tromboembolismo venoso (TEV) é uma das complicações mais temidas pelos ortopedistas, tanto pelo seu desfecho potencialmente letal quanto pelas incertezas relacionadas à sua prevenção. Apesar da vasta literatura existente sobre a prevenção de TEV nas grandes cirurgias ortopédicas, pouco se sabe sobre sua prevenção nas cirurgias do tornozelo e do pé. Uma adequada prescrição da tromboprofilaxia em ortopedia exige criteriosa avaliação dos riscos trombóticos e hemorrágicos com base no tipo de cirurgia a ser realizada, além do conhecimento sobre os anticoagulantes. Esta revisão tem como objetivos abordar a avaliação do risco de desenvolver TEV, as modalidades de tromboprofilaxia, e os fármacos utilizados, tendo como ênfase as cirurgias do pé e do tornozelo.

Desmopressin acetate use in von Willebrand's disease: a survey on current practices in Brazil

ABSTRACT Introduction: von Willebrand's disease (VWD) is the most common inherited bleeding disorder. The 1-desamino-8-d-arginine vasopressin (DDAVP) is the treatment of choice for most responsive patients with VWD. The aim of this study was to evaluate DDAVP use in the management of VWD. Method: We implemented a survey targeting medical doctors involved in the management of VWD in Brazil. Data was collected during a national congress on Hematology in November 2017. Main results: A total of 51/80 (63.8%) questionnaires were collected. Most participants (76.2%) were hematologists who assisted adult patients and approximately 60% worked at hemophilia treatment centers (HTCs). Approximately half of participants who reported treating patients with VWD, assisted on average, less than 5 patients per month, and approximately 60% declared not having used any DDAVP for treating VWD in the previous year. However, most participants (70%) prescribed FVIII-containing VWF concentrate (VWF/FVIII) for 1-10 patients in the previous year. More than 80% of the participants recognized the main indications for DDAVP. Physicians who recognized indication for DDAVP for type 1 VWD more often had prescribed DDAVP in previous year (p = 0.03). Barriers for prescribing DDAVP varied and included unavailability of laboratory facilities and consumables for DDAVP testing and lack of skills on its prescription. Conclusion: The DDAVP is currently underused in Brazil, as opposed to the excessive use of VWF/FVIII in VWD patients. We suggest the adoption of measures targeting educational and auditing programs. Furthermore, availability of laboratory reagents is needed to evaluate response and increment the correct use of DDAVP.

Guidance on diagnosis, prevention and treatment of thromboembolic complications in COVID-19: a position paper of the Brazilian Society of Thrombosis and Hemostasis and the Thrombosis and Hemostasis Committee of the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy

ABSTRACT Hemostatic abnormalities and thrombotic risk associated with coronavirus disease 2019 (COVID-19) are among the most discussed topics in the management of this disease. The aim of this position paper is to provide the opinion of Brazilian experts on the thromboprophylaxis and management of thrombotic events in patients with suspected COVID-19, in the sphere of healthcare in Brazil. To do so, the Brazilian Society of Thrombosis and Hemostasis (BSTH) and the Thrombosis and Hemostasis Committee of the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy (ABHH) have constituted a panel of experts to carefully review and discuss the available evidence about this topic. The data discussed in this document was reviewed by May 9, 2020. Recommendations and suggestions reflect the opinion of the panel and should be reviewed periodically as new evidence emerges.

Standardization and evaluation of the performance of the thrombin generation test under hypo- and hypercoagulability conditions

ABSTRACT Background: In order to standardize a thrombin generation() protocol, we analyzed the analytical variables and sensitivity of this test to hypo/hypercoagulability states. Methods: The effect of the tissue factor concentration and the intra- and interassay precision were analyzed. To evaluate the hypercoagulability status, the plasma of women under an oral contraceptive was tested, while plasma from hemophilia A patients at 1, 3 and 7 days after recombinant FVIII infusion, and lyophilized plasma deficient in FVII or FVIII were used for the evaluation of hypocoagulability. Results: The intra-assay coefficient of variation was <10% with 1 and 5 pM of low and high TF. The oral contraceptive users showed increased thrombin generation in comparison to non-users, which was more pronounced with low TF (endogenous thrombin potential ETP) p = 0.0009; peak p = 0.0009; lagtime p = 0.0008). In relation to the FVIII-deficient plasma, a higher TG was observed as FVIII levels were increased and a better discrimination was obtained for different concentrations of FVIII with low TF (ETP p < 0.0001; peak p < 0.0001; lagtime p = 0.0004). Using low TF, plasma from hemophilia A patients showed higher TG values after 1 day of recombinant FVIII infusion vs after 3 days (ETP p < 0.0001; peak p < 0.0001; lagtime p = 0.0407), while the lowest values were observed after 7 days. With FVII-deficient plasma, thrombin generation was lower than normal plasma and a more pronounced difference was observed with high TF compared to low TF (ETP p < 0.0001; peak p < 0.0001; lagtime p < 0.0001). Conclusion: Under our conditions the thrombin generation test seems to be sensitive to evaluation of hyper/hypocoagulability states. Standardization of the thrombin generation test may have an application in the evaluation of bleeding and thrombotic disorders.

Eficácia da tromboprofilaxia não farmacológica em pacientes hospitalizados: estudo caso-controle aninhado / Non-pharmacological thromboprophylaxis efficacy in hospitalized patients: a nested case-control study

Introdução: a trombose venosa adquirida durante hospitalização (TV) é complicação potencialmente fatal, mas prevenível pela tromboprofilaxia primária (TP), que pode ser farmacológica ou não farmacológica (TPNF). A TPNF inclui mobilização precoce do paciente no leito, meias elásticas compressivas graduadas ou compressão pneumática intermitente de membros inferiores. O objetivo deste estudo foi avaliar a eficácia daTPNF em pacientes admitidos em hospital público, ajustando para confundimento por indicação. Material e método: este é um estudo com análise de caso-controle aninhado em coorte do programa de TP do Hospital Naval Marcílio Dias, Rio de Janeiro, entre 1995 e 2001. Os participantes foram pacientes hospitalizados maiores de 18 anos sem anticoagulação ou suspeita de TV à admissão. Casos foram participantes com TV. Cinco controles foram selecionados para cada caso com pareamento por sexo, idade e ano de internação. A medida de desfecho foi a razão de chances (OR) para TV sintomática, diagnosticada objetivamente em participantes submetidos à TPNF comparados a participantes sem TP. Resultados: houve 76 casos entre 21.067 participantes pareados a 379 controles. A OR não ajustada para TV foi de 0,41 (IC 95% 0,22-0,77) e a OR ajustada para confundimento foi de 0,42 (IC 95% 0,19-0,92). A taxa de incidência para TV entre participantes submetidos à TPNF foi de 1,6 por 1.000 internações e entre participantessem TP, 4,0 por 1.000 internações. Conclusão: após ajustes para fatores de confundimento, o risco de TV foi reduzido pela metade com medidas tromboprofiláticas não farmacológicas em relação a pacientes sem tromboprofilaxia.

Introduction: Hospital-acquired venous thrombosis (VT) is a potentially fatal but preventable complication. Thromboprophylaxis may include pharmacological or non-pharmacological strategies (NPTP). NPTP may include early patient ambulation, graduated elastic compressive stockings or compressive pneumatic compression of lower limbs. Our objective was to measure NPTP efficacy in a brazilian public hospital. Material and Method: This is a case-control study nested in a cohort comprising patients admitted to Hospital Naval Marcílio Dias from 1995 to 2001 who participated in the hospital TP program; Participants were over 18 years of age, without anticoagulation or suspected VT at admission. Cases were participants who developed VT during hospital stay. Five controls were matched by age, gender and date of VT to each index case. Outcome was evaluated by OR for VT comparing participants submitted to NPTB to no TP. Results: There were 76 cases matched to 379 controls out of 21,067 participants. Unadjusted OR for VT was 0.41 (95% CI 0.22-0.77) and the adjusted OR for confounding was 0.42 (95% CI 0.19-0.92). VT incidence was 1.6/1000 hospital admissions in participants receiving NFTP and 4.0/1000 hospital admissions in participants with no TP. Conclusion: After adjustment for confounding, venous thrombosis risk was halved by non-pharmacological thromboprophylaxis compared with no thromboprophylaxis.

Distúrbios tromboembólicos / Venous thromboembolism

Os distúrbios tromboembólicos compreendem um grupo de doenças caracterizado pela obstrução de artérias ou veias por coágulos formados localmente ou por trombos liberados na circulação sistêmica. Os distúrbios tromboembólicos compõem as principais causas de morbimortalidade no Brasil e no mundo. Sua apresentação clínica é variada e o diagnóstico e tratamento precoces dependem de alta suspeição clínica e de propedêutica adequada. Esta revisão abordará o diagnóstico e tratamento do tromboembolismo venoso. Não serão abordados, nesta revisão, os distúrbios tromboembólicos arteriais.

Tromboprofilaxia: recomendações médicas e programas hospitalares / Thromboprophylaxis: medical recommendations and hospital programs

O tromboembolismo venoso (TEV) é a principal causa evitável de óbito hospitalar. O TEV hospitalar está relacionado a mais de 50 por cento dos episódios de TEV, podendo ocorrer durante ou após a hospitalização. A tromboprofilaxia, em pacientes selecionados, é a abordagem recomendada para pacientes internados. A seleção de pacientes para tromboprofilaxia requer a estratificação do risco de TEV, que inclui a doença básica acrescida de fatores adicionais de risco ou modelos padronizados de avaliação de riscos (RAM). As categorias de risco orientam a seleção da tromboprofilaxia, que pode incluir medidas gerais, mecânicas, medicamentosa ou combinada. Embora os protocolos tromboprofiláticos existam há décadas, muitos pacientes em risco (20 por cento a 75 por cento) continuam a não receber a tromboprofilaxia recomendada. O objetivo deste estudo é alertar sobre a importância do tema e orientar a formulação de estratégias para a organização de programas de tromboprofilaxia hospitalar, em nosso meio.

Venous thromboembolism (VTE) is the most preventable cause of death in hospitalized patients. Hospital-related VTE is associated with more than half of the VTE burden in a community, either in-hospital or after discharge. Selective thromboprophylaxis is recommended for patients at risk. Patient selection for thromboprophylaxis requires proper VTE risk stratification. VTE stratification may be achieved by either risk assessment models (RAM) or by models based on patient's illness and associated risk factors. Whatever the model, a thromboprophylatic recommendation should be formulated for each VTE risk category. VTE thromboprophylaxis may include general measures, mechanic compression procedures, pharmacological intervention or a combined approach. After many decades of consensus statements, a large proportion of at risk patients (20 percent to 75 percent) still does not receive proper thromboprophylaxis. This study aims to alert to the relevance of thromboprophylaxis and to suggest hospital thromboprophylatic strategies in a Brazilian setting.

Distúrbios da hemostasia: doenças hemorrágicas / Disorders of homeostasis: bleeding disorders

As doenças hemorrágicas abrangem diversas condições clínicas, sendo caracterizadas por hemorragias de gravidade variável em diferentes locais do corpo. Podem ser de causa hereditária ou adquirida, relacionadas a doenças hematológicas ou a outras condições sistêmicas. Para o diagnóstico e tratamento adequados dessas doenças éfundamental a realização de anamnese detalhada e de testes laboratoriais, que podem ser complexos. Neste artigo serão abordadas as principais condições hemorrágicas, classificadas em doenças vasculares/doenças plaquetárias, coagulopatias e doenças hemorrágicas secundárias a doenças sistêmicas e uso de anticoagulantes.

The bleeding disorders include several clinical conditions, being characterized by bleeding of varying severity in different body sites. They can be either inherited or acquired disease - related to hematological diseases or other systemic conditions. For the diagnosis and treatment of these diseases, it is essential to conduct a detailed clinical history and laboratory tests, which may be complex. This article deals with the major hemorrhagic conditions, classified as vascular diseases/platelet diseases, coagulopathy and bleeding disorders secondary to systemic diseases and use of anticoagulants.

Hemovida Web Coagulopatias: um relato do seu processo de desenvolvimento e implantação. / Hemovida Web Coagulophaties: a report of its development andimplementation.

As coagulopatias hereditárias são doenças hemorrágicas decorrentes da deficiência de um ou mais fatores de coagulaçãosanguínea. A Coordenação da Política Nacional de Sangue e Hemoderivados, responsável pelo Programa Nacional deCoagulopatias Hereditárias, em parceria com o Departamento de Informática do Sistema Único de Saúde (SUS), desenvolveuo sistema informatizado Hemovida Web Coagulopatias, cujo objetivo é a sistematização do cadastro nacional dospacientes com coagulopatias e outras doenças hemorrágicas hereditárias. Esse cadastro reúne dados sobre o diagnóstico,tratamento e complicações das doenças, bem como o perfil sociodemográfico dos pacientes e os quantitativos de fatoresde coagulação a eles dispensados. Este artigo apresentou um relato sobre o desenvolvimento e implantação desse Sistema,considerando a descrição dos antecedentes, desenvolvimento, processamento dos dados, treinamento de pessoal esituação atual da implantação, além de apontar as potencialidades e perspectivas previstas para o seu aperfeiçoamento. Osistema está disponível na Internet desde janeiro de 2009 e conta com a adesão das Unidades da Federação, em estágiosdiferenciados de utilização. O uso potencial das informações produzidas nesse sistema é de grande necessidade, devido àpossibilidade de se realizar uma gestão eficiente às políticas públicas voltadas a essa população, em função de um gastopúblico de elevado valor na aquisição de hemoderivados.

Inherited coagulopathies are bleeding disorders characterized by the deficiency of one or more coagulation factors. The Coordenaçãoda Política Nacional de Sangue e Hemoderivados, in charge of the National Program of Inherited Coagulopathieshas developed, in conjunction with the Departamento de Informática do Sistema Único de Saúde (SUS), the system named Hemovida Web Coagulopatias, which role is to organize the national registry of patients with inherited coagulopathies and other bleedingdisorders. The registry compiles data on diagnosis, treatment and complications of the disorders, as well as the socioeconomic profile of thepatients and detailed treatment used. This article presented an evaluation of the development and implantation of this system, considering therational for its development, data processing, training of human resources and present situation of implantation. It also discussed its powerand perspectives for improvement. The system is available on the Internet since January 2009 with implantation in all States with differentlevels of utilization. The potential use of the system information is enormous, due to the need of implementing political actions directed to thispopulation of patients, due to a high value of public spending on the purchase of blood products.

As bases moleculares da hemofilia A

As hemofilias são doenças hemorrágicas resultantes da deficiência de fator VIII (hemofilia A) ou de fator IX (hemofilia B) da coagulação, decorrentes de mutações nos genes que codificam os fatores VIII ou IX, respectivamente. A hemofilia A é mais frequente que a hemofilia B e acomete aproximadamente 1:10.000 nascimentos masculinos. A gravidade e frequência dos episódios hemorrágicos está relacionado ao nível residual de atividade de fator VIII presente no plasma e este relaciona-se ao tipo de mutação associada à doença. A clonagem do gene do fator VIII tornou possível o conhecimento das bases moleculares da hemofilia A, sendo hoje conhecidas mais de 1.000 mutações associadas à doença. O conhecimento das bases moleculares da hemofilia A permite uma melhor compreensão da relação genótipo-fenótipo da doença, tomada de condutas clínicas diferenciadas em casos de mutações associadas a um maior risco de desenvolvimento de inibidor, determinação da condição de portadora de hemofilia em mulheres relacionadas aos pacientes, implementação de programa de aconselhamento genético/orientação familiar e melhor compreensão das relações estruturais-funcionais do gene-proteína. Este artigo propõe revisar as bases moleculares da hemofilia A, os métodos laboratoriais utilizados para a caracterização das mutações e as implicações clínicas envolvidas no diagnóstico molecular da hemofilia A.

Hemophilias are bleeding disorders due to deficiency of the blood coagulation factor VIII (hemophilia A) or factor IX (hemophilia B), resulting from mutation on the gene coding for factor VIII or factor IX. Hemophilia A is more frequent than hemophilia B and affects 1:10,000 male newborns. The severity and frequency of hemorrhagic episodes is related to residual activity of factor VIII present in the plasma and relates to the type of mutation associated with the disorder. Cloning of the factor VIII gene has enabled researchers to better understand the molecular basis of hemophilia A, accounting to date, for more than 1,000 mutations associated with the disease. This comprehensive knowledge permits an improved comprehension of the genotype-phenotype relation, establishment of clinical policies when mutations related to higher risk of inhibitors development are known, identification of hemophilia carriers in case of women related to patients, implementation of a program of genetic counseling and discovery of structural-functional relationship between gene-protein. This article aims to review the molecular basis of hemophilia A, laboratory techniques used to characterize mutations and clinical implications involved in the molecular diagnosis of hemophilia A.