Clinical outcome and incidence of inhibitor development in severe hemophilia patients receiving low-dose prophylaxis: a 3-year follow-up study in Senegal, West Africa

ABSTRACT Introduction: In Africa, where access to diagnosis and treatment of hemophilia is the lowest in the world, prophylaxis is rarely used in preference to on-demand treatment. There are limited data of prophylaxis treatment from sub-Saharan Africa. The aim of this study was to evaluate clinical outcomes and inhibitor development in people with hemophilia receiving low-dose prophylaxis (LDP) in a sub-Saharan African setting. Methods: We conducted a three-year prospective study. A once or twice weekly prophylaxis regimen of 25 IU/kg of rFVIIIFc or 30 IU/kg of rFIXFc was given to Hemophilia A and B, respectively. We evaluated clinical outcomes and inhibitors occurrence, determined by screening and titration using the Nijmegen technique. Results: A total of 15 patients were included in the LDP regimen. The mean age was 6.3 years (1.5 - 10). A significant reduction was noted in the annualized bleeding rate, from 7.53 to 1.33 (p = 0.0001); the annualized joint bleeding rate passed from 3.6 to 1.4 (p = 0.001) and the proportion of severe bleeding, from 86.1% to 16.7% (p = 0.0001). The Hemophilia Joint Health Score (HJHS) moved from 9.6 to 3.4 (p = 0.0001) and the Functional Independence Score in Hemophilia (FISH) improved from 25.8 to 30.9 (p = 0.0001). School absenteeism decreased from 7.33% to 2.59%. Adherence to prophylaxis was 89.5% versus 60%. Consumption was 580 IU/kg/year versus 1254.6 IU/kg/year before and after prophylaxis, respectively. Incidence of inhibitors was 23% (3 /13 HA). Conclusion: The LDP in Hemophilia improves the clinical outcome without a surplus risk of inhibitor development. Using extended half-life clotting factor concentrates (CFCs) is better for prophylaxis in resource-limited countries, as they allow better compliance in treatment.

Prophylaxis in hemophilia

Hemophilia is an inherited X-linked coagulopathy defined by a deficiency or abnormality in the clotting function of factor VIII (Hemophilia A) or factor IX (Hemophilia B). Prophylaxis ­ the regular administration of therapeutic products to maintain hemostasis and prevent bleeding ­ is the mainstream of treatment. Addressing the development and scientific evidence for administrating prophylaxis is the goal of this review. Prophylaxis is the therapeutic modality of choice for people with severe hemophilia, being considered, in principle, a lifelong treatment. It should have an early onset, ideally as a primary, or at least secondary. Even lifelong tertiary prophylaxis seems to offer benefit, although further studies are still lacking. Individualized strategies should lead to an optimization of the dilemma between better joint outcomes versus involved costs.

Hemophilia: a biography on therapeutical approaches

The history of hemophilia is ancient, with descriptions dated to the 2nd century AD. The first modern narratives appeared in 1800s, when total blood transfusion was the only available treatment and life expectancy was remarkably low. Advances occurred with the use of plasma and cryoprecipitate, but only the discovered of factor concentrates revolutionized the treatment. The implantation of prophylaxis allowed hemophilic patients to prevent bleeding and the development of chronic arthropathy, although with a significant burdensome with the regular infusions. In the past 20 years, this field has witnessed major improvements, including the development of gene therapy and other pharmacological approaches.

Avaliação do perfil clínico-terapêutico e da resposta à profilaxia dos portadores de hemofilia A e B em um centro de referência no Ceará / Evaluation of the clinical-therapeutic profile and the response to prophylaxis of patients with hemophilia A and B in a reference center in Ceará

Objetivo: Avaliar o perfil clínico-terapêutico e a resposta à profilaxia em pacientes hemofílicos A e B em um centro de referência no Ceará. Métodos: Estudo de coorte retrospectivo, com dados de 133 hemofílicos A e B, em profilaxia entre 2016 e 2021, por meio de prontuários médicos e sistema Web Coagulopatias. Resultados: Os pacientes todos do sexo masculino em sua maioria foram hemofílicos A (93,2%), na forma grave, residentes em Fortaleza, com maior prevalência do município de Guaiúba. A maioria fazia uso de Fator VIII recombinante e em profilaxia secundária, em relação ao comprometimento articular a maioria não apresentou relato de hemartroses (66,9%), articulação-alvo (87,9%) ou artropatia (54,9%), porém os hemofílicos em profilaxia terciária apresentaram um maior comprometimento articular em relação a profilaxia primária e secundária. Verificou-se uma correlação negativa entre o tempo de profilaxia e a dose de fator utilizada, demonstrando que quanto maior o tempo de profilaxia menor a dose do fator utilizada. Um total de 13 hemofílicos A grave desenvolveram inibidor de fator VIII realizando imunotolerância (ITI) com sucesso total em 84,6%. Por meio da curva ROC, foi verificado uma associação entre a necessidade de ITI e a dose de fator de coagulação, com acurácia de 67,7% de que o uso de doses maiores de fator predispõe ao desenvolvimento de inibidores. Conclusão: Os dados do estudo permitem inferir que quanto mais precoce o tratamento de profilaxia menor é comprometimento articular, dose do fator utilizada e menor predisposição de desenvolver inibidores dos fatores da coagulação.

Objective: to evaluate the clinical-therapeutic profile and response to prophylaxis in hemophiliac A and B patients at a referral center in Ceará. Methods: Retrospective cohort study, with data from 133 hemophiliacs A and B, undergoing prophylaxis between 2016 and 2021, using medical records and the Web Coagulopathies system. Results: Most of the patients were male patients with severe hemophilia A (93.2%), residing in Fortaleza, with a higher prevalence in the city of Guaiúba. Most made use of recombinant Factor VIII and in secondary prophylaxis, in relation to joint involvement, the majority did not report hemarthroses (66.9%), target joint (87.9%) or arthropathy (54.9%). however, hemophiliacs on tertiary prophylaxis showed greater joint impairment in relation to primary and secondary prophylaxis. There was a negative correlation between the prophylaxis time and the factor dose used, demonstrating that the longer the prophylaxis time, the lower the factor dose used. A total of 13 severe A hemophiliacs developed factor VIII inhibitor performing immunotolerance (ITI) with total success in 84.6%. Using the ROC curve, an association was verified between the need for ITI and the dose of coagulation factor, with an accuracy of 67.7% that the use of higher doses of factor predisposes to the development of inhibitors. Conclusion: The study data allow us to infer that the earlier the prophylaxis treatment, the less joint impairment, the dose of the factor used and the less predisposition to develop coagulation factor inhibitors.

Caracterización clinicoepidemiológica de pacientes con hemofilia congénita de tipos A y B en Santiago de Cuba / Clinical epidemiological characterization of patients with types A and B congenital hemophilia in Santiago de Cuba

Introducción: La hemofilia es una enfermedad de origen genético, ligada al cromosoma X, que afecta la capacidad natural de la sangre para formar un coágulo, debido a la ausencia, disminución o un defectuoso funcionamiento de los factores VIII y IX, de ahí los tipos A y B, respectivamente. Objetivo: Describir las características clínicas y epidemiológicas de pacientes con hemofilia congénita de tipos A y B en Santiago de Cuba. Método: Se realizó un estudio descriptivo y transversal de los 41 pacientes con hemofilia congénita de tipos A y B (en una población pediátrica y de adultos) atendidos en la consulta de trastornos hemostáticos del Hospital General Docente Dr. Juan Bruno Zayas Alfonso de Santiago de Cuba, desde noviembre de 2017 hasta diciembre de 2018. Resultados: En la serie predominaron los adultos jóvenes con hemofilia A (56,1 %), la hemofilia moderada (58,6 %), la lesión articular ligera (36,6 %), el crioprecipitado como tratamiento más utilizado y el nivel de escolaridad secundario. Conclusiones: La hemofilia A fue la más frecuente, en adultos jóvenes residentes en el municipio de Santiago de Cuba, principalmente la de tipo moderada y con artropatía leve. No se encontraron diferencias en relación con los informes nacionales e internacionales y el estudio de las alteraciones genéticas y moleculares estuvo limitado por las condiciones tecnológicas del momento.

Introduction: The hemophilia is a disease of genetic origin, linked to chromosome X that affects the natural capacity of the blood to form a clot, due to the absence, decrease or a defective operation of the factors VIII and IX, hence the types A and B, respectively. Objective: To describe the clinical and epidemiologic characteristics of patients with types A and B congenital hemophilia in Santiago de Cuba. Method: A descriptive and cross-sectional study of the 41 patients with types A and B congenital hemophilia (in a pediatric and adults population) assisted in the hemostatic disorders service of Dr. Juan Bruno Zayas Alfonso Teaching General Hospital in Santiago de Cuba, was carried out from November, 2017 to December, 2018. Results: In the series there was a prevalence of young adults with hemophilia A (56.1 %), moderate hemophilia (58.6 %), light articular lesion (36.6 %), the cryoprecipitate as the most used treatment and the secondary school level. Conclusions: The hemophilia A was the most frequent, in young adults residents in Santiago de Cuba municipality, mainly that of moderated type and with light arthropathy. There were no differences related to the national and international reports and the study of the genetic and molecular disorders was limited by the technological conditions of the moment.

Autonomía y dignidad en personas que viven con hemofilia / Autonomy and dignity in people living with hemophilia

INTRODUCCIÓN. La hemofilia es una condición rara hereditaria, crónica, potencialmente discapacitante e incapacitante, caracterizada por frecuentes sangrados debidos al déficit del factor VIII coagulante, Hemofilia A o del factor IX Hemofilia B. Las evaluaciones de calidad de vida en personas con hemofilia, basadas principalmente en el aspecto biológico, llevaron a considerar un importante enfoque bioético que evalúe la afectación de la autonomía y dignidad debida a la enfermedad. OBJETIVO. Registrar la percepción de la autonomía y dignidad de personas que viven con hemofilia. MATERIALES Y MÉTODOS. Estudio descriptivo transversal. Población de 92 y muestra de 28 varones mayores de 18 años con diagnóstico de hemofilia, atendidos en la Clínica de Coagulopatías Congénitas del Hospital de Especialidades Carlos Andrade Marín en el periodo marzo 2021 a agosto del 2021. Se excluyó a varones menores de 18 años atendidos en otras instituciones del Sistema Nacional de Salud. Estudio basado en el desarrollo de las capacidades centrales descritas por Martha Nussbaum. Se aplicó el test The Hemophilia Well Being Index que evaluó calidad de vida con relación al bienestar personal asociado a salud, y la herramienta Body Mapping que analizó en base al interpretativismo fenomenológico. RESULTADOS. El 100% de personas presentaron afectación en algún área de la vida investigada por el Hemophilia Well Being Index, que se confirma con las expresiones escritas y gráficas recopiladas por el Body Mapping. CONCLUSIÓN. La autonomía y dignidad se encuentran afectadas en las personas que viven con hemofilia, al igual que las capacidades centrales; es importante valorar cómo estos parámetros afectan la consecución de logros, lo que se debe considerar en estudios futuros.

INTRODUCTION. Hemophilia is a rare hereditary, chronic, potentially disabling and incapacitating condition, characterized by frequent bleeds due to deficiency of clotting factor VIII, Hemophilia A or factor IX Hemophilia B. Quality of life assessments in people with hemophilia, mainly based on the biological aspect, led to consider an important bioethical approach that evaluates the impairment of autonomy and dignity due to the disease. OBJECTIVE. To record the perception of autonomy and dignity of people living with hemophilia. MATERIALS AND METHODS. Cross-sectional descriptive study. Population of 92 and sample of 28 males over 18 years of age with a diagnosis of hemophilia, attended at the Congenital Coagulopathy Clinic of the Carlos Andrade Marin Specialty Hospital in the period March 2021 to August 2021. Males under 18 years of age attended in other institutions of the National Health System were excluded. The study was based on the development of the central capabilities described by Martha Nussbaum. The test The Hemophilia Well Being Index was applied, which evaluated quality of life in relation to personal wellbeing associated with health, and the tool Body Mapping which analyzed based on phenomenological interpretivism. RESULTS. 100% of people presented affectation in some area of life investigated by the Hemophilia Well Being Index, which is confirmed by the written and graphic expressions collected by the Body Mapping. CONCLUSION. Autonomy and dignity are affected in people living with hemophilia, as are core capacities; it is important to assess how these parameters affect achievement, which should be considered in future studies.

Statements about hemophilia A in Brazil: an expert Delphi panel / Consensos em hemofilia A no Brasil: painel Delphi de especialistas

Objective: Understanding unmet needs related to hemophilia A management in Brazil is critical for supporting decision-making. Methods: A modified Delphi consensus panel was conducted. Hematologists with extensive experience treating hemophilia in the Brazilian Public Health System were invited to answer questions regarding indicators of severe hemophilia prophylaxis effectiveness, emicizumab treatment indications, and bypassing agents used to reduce bleeding in patients with inhibitors, immune tolerance induction (ITI) use, and adherence. The consensus was defined as ≥75% of votes in Round 1 or using a 5-point Likert-type scale (1 = strongly disagree, 2 = disagree, 3 = neither agree nor disagree, 4 = agree, and 5 = strongly agree) in Round 2, which included questions not reaching minimum cut-off in the first step. Results: Nine expert panelists with extensive experience in the Brazilian Public Health System participated. The panel reached an agreement on recommendations about prophylaxis, bleeding treatment patterns, and bleeding sites. From patients' perspectives, venous access and infusion frequency were the most significant barriers to improving patient treatment. According to most experts, emicizumab will not replace ITI or long-term factor VIII therapy. Still, emicizumab was thought to be a good therapeutic option for patients with difficult venous access, patients requiring central venous access, in the presence of inhibitors, or patients experiencing infusion-related pain. Conclusion: The information gleaned from this study may be helpful to both decision-makers and those in charge of developing healthcare economic models for the treatment of hemophilia A in Brazil.

Objetivo: É fundamental entender as necessidades não atendidas relacionadas ao manejo da hemofilia A no Brasil. Métodos: Foi conduzido um painel Delphi modificado. Foram convidados hematologistas com vasta experiência no tratamento de hemofilia no SUS para responder a perguntas sobre indicadores de eficácia da profilaxia, indicações de tratamento com emicizumabe, uso de agentes de bypass, uso de indução de tolerância imunológica (ITI) e adesão. O consenso foi definido como ≥75% dos votos na rodada 1 ou usando uma escala do tipo Likert de 5 pontos (1 = discordo totalmente, 2 = discordo, 3 = não concordo nem discordo, 4 = concordo e 5 = concordo totalmente) na segunda rodada, que incluiu questões que não atingiram o corte mínimo na primeira etapa. Resultados: Nove especialistas participaram e houve consenso sobre recomendações para profilaxia, padrões de tratamento de sangramento e locais de sangramento. O acesso venoso e a frequência da infusão foram identificados como as barreiras mais significativas para melhorar o tratamento do paciente. De acordo com a maioria, emicizumabe não substituirá a ITI ou tratamento com fator VIII de longo prazo. Emicizumabe foi considerado uma boa opção terapêutica para

Prevalencia de mutaciones metilentetrahidrofolato reductasa (MTHFR), protrombina (II G20210G/G20210A) y factor V Leyden en pacientes sometidos a estudio por perfil trombofílico en el Hospital San Vicente de Paúl, Costa Rica, 2017-2018 / Prevalence of mutations Methylentetrahydrofolate reductase (MTHFR), Prothrombin (II G20210G/G20210A) and Leyden V factor in patients undergoing studies by thrombophilic profile. Hospital San Vicente de Paul. Costa Rica, 2017 to 2018

Resumen Introducción: en los últimos años se han descrito alteraciones genéticas asociadas con un mayor o menor riesgo de padecer una enfermedad trombótica. El objetivo del presente estudio es conocer la prevalencia de las mutaciones para la metilentetrahidrofolato reductasa (MTHFR), la protrombina (II G20210G/G20210A) y el factor V Leyden en las muestras de pacientes sometidas a estudio por perfil trombofílico en el Hospital San Vicente de Paúl. Metodología: con la base de datos de muestras referidas del Hospital San Vicente de Paúl, se estudiaron los marcadores de riesgo para trombofilia: MTHFR, Ac Lúpico, mutación del Factor II y Factor V Leyden correspondientes al periodo comprendido entre abril de 2017 a abril de 2018. Resultados: se observó que la frecuencia de la solicitud de estudio por trombofilia era mayor para el sexo femenino, con un 83,7 % del total de análisis, mientras que, para el sexo masculino fue de un 16,3 %. La mutación más prevalente fue la MTHFR, seguida del factor V Leyden, además, ambas se presentaron superiormente en las mujeres. Conclusión: se ha demostrado en varios estudios la asociación de las alteraciones genéticas estudiadas con los eventos trombóticos, por lo tanto, conocer su prevalencia en determinada población es de gran importancia para ayudar al clínico a llegar a un diagnóstico adecuado.

Abstract Introduction: Genetic alterations associated with a higher or lower risk of thrombotic disease have been reported in recent years, the objective of this study is to understand the prevalence of mutations for methylentetrahydrofolate reductase (MTHFR), Mutation for prothrombin (II G20210G/G20210A) and Mutation for factor V Leyden, in the samples of patients undergoing studies by thrombophilic profile, at the Hospital San Vicente de Paul. Methodology: To carry out this study, we use the database of reference samples of the Hospital San Vicente de Paúl for the study of risk markers for thrombophilia: MTHFR, Ac Lúpico, Mutation of Factor II, Factor V Leyden in the period from April 2017 to April 2018. Results: From the analyses requested for thrombophilia study, the frequency in the thrombophilia study request was observed to be higher for female sex, with a frequency of 83.7% of total testing and 16.3% for the male sex. The most prevalent mutation is MTHFR, followed by the Mutation for factor V Leyden, and both mutations occur in greater numbers in women. Conclusion: The association of genetic alterations studied with thrombotic events has been shown in several studies so knowing their prevalence in a given population is of great importance to help the clinic arrive at an appropriate diagnosis.

Causes of death and mortality trends related to hemophilia in Brazil, 1999 to 2016

ABSTRACT Introduction Multiple cause of death methodology enhances mortality studies beyond the traditional underlying cause of death approach. Aim: This study aims to describe causes of death and mortality issues related to haemophilia with the use of multiple-cause-of-death methodology. Methods: Annual male haemophilia mortality data was extracted from the public multiple-cause-of-death databases of the Mortality Information System, searching deaths included in rubrics D66 "hereditary factor VIII deficiency" (haemophilia A), and D67 "hereditary factor IX deficiency" (Haemophilia B) of the International Classification of Diseases, Tenth Revision, and processed by the Multiple Cause Tabulator. Results: In Brazil, from 1999 to 2016, a total of 927 male deaths related to haemophilia occurred during the 18 year period, of which 418 (45,1 %) as underlying cause, and 509 (54,9 %) as associated cause of death. The leading associated cause of 418 deaths of haemophilia as underlying cause was hemorrhage (52.6%), half of which intracranial hemorrhage. Infectious and parasitic diseases accounted for 40,5% as the underlying causes of 509 deaths where haemophilia was an associated cause, where human immunodeficiency virus disease prevailed, however falling from 37,0% to 19.7%, and viral hepatitis increased from 6.0% to 7.9%; diseases of the circulatory system, increased from 13.5% to 18.4%, including intracranial hemorrhage from 5.7% to 7.0%, and neoplasms, from 8,5% to 13.2%, respectively from 1999-2007 to 2008-2016, followed as main underlying causes. Conclusion: Hemorrhages, mainly intracranial hemorrhage, human immunodeficiency virus disease, and viral hepatitis are the chief prevention goals aiming at the control of haemophilia mortality.

Epidemiological characteristics of hemophilia in the pre-primary prophylaxis era: a historical cohort

Introduction: Epidemiological studies on hemophilia in the Brazilian population are historically scarce. Despite the continuous effort made by the National Program of Inherited Bleeding Disorders to map this condition, little information is available, especially on the period prior to program conception. Therefore, the present study aims to assess the epidemiological, serological, and clinical characteristics of patients with hemophilia in the state of Rio Grande do Sul, Brazil. Methods: A total of 455 patients had their medical records reviewed from January 1, 2003 to December 31, 2007. Results: We observed a remarkable prevalence of hepatitis C virus (HCV) infection in patients with both hemophilia A and B, and this prevalence significantly increased along with age (p < 0.001). No positive anti-HCV results were observed among children younger than 5 years old. There was a significant correlation between the severity of hemophilia and the number of arthropathies in all age categories. Considering the presence of inhibitors, a significant difference was observed between age groups, as older patients had higher inhibitor titers. There was a significant correlation between mean coagulation factor consumption and the number of arthropathies in patients over 5 years old. Conclusions: This profile analysis of patients with hemophilia reflects a gradual improvement in treatment safety and efficiency, as well as the need for continued investment in this population. (AU)

Avaliação da Força Muscular em Adultos com Hemofilia de uma Associação de Pacientes em Brasília / Assessment of Muscle Strength in Adults with Hemophilia from an Association of Patients in Brasília / Evaluación de la fuerza muscular en adultos con hemofilia de una asociación de pacientes en Brasilia

Objetivo: avaliar a força muscular periférica em adultos portadores de hemofilia, por meio da dinamometria manual, e verificar a diferença da força muscular de acordo com a classificação de gravidade da hemofilia. Método: Participaram da pesquisa 20 homens divididos em 2 grupos, um com hemofílicos e um controle; foi aplicada uma ficha avaliativa seguida do teste de preensão palmar. Resultados: Quando comparados os dois grupos, foi observada diferença estatística significativa nas variáveis estatura (p=0,007) e força de preensão dos lados dominante (p=0,04) e não dominante (0,002), favorecendo o grupo controle; quando comparada a força de preensão dos hemofílicos com a doença leve e grave, houve diferença significativa para o lado não dominante (p=0,01). Conclusão: Pode-se associar a diminuição de força de preensão para o grupo de hemofílicos à sua condição de doença crônica hereditária. Entretanto, como o número de participantes foi pequeno, esses resultados sugestivos, mostram a necessidade de mais estudos sobre o tema

Objective: to evaluate peripheral muscle strength in adults with hemophilia, through manual dynamometry, and to verify the difference in muscle strength according to the classification of hemophilia severity. Method: Twenty men participated in the research, divided into 2 groups, one with hemophiliacs and one control; an evaluation form was applied, followed by the handgrip test. Results: When the two groups were compared, a statistically significant difference was observed in the variables height (p=0.007) and grip strength of the dominant (p=0.04) and non-dominant (0.002) sides, favoring the control group; when comparing the grip strength of hemophiliacs with mild and severe disease, there was a significant difference for the non-dominant side (p=0.01). Conclusion: The decrease in grip strength for the group of hemophiliacs can be associated with their condition of hereditary chronic disease. However, as the number of participants was small, these suggestive results show the need for more studies on the subject.

Objetivo: El objetivo del estudio fue evaluar la fuerza muscular periférica en adultos con hemofilia, mediante dinamometría manual, y verificar la diferencia en la fuerza muscular según la clasificación de severidad de la hemofilia. Método: Participaron de la investigación 20 hombres, divididos en 2 grupos, uno con hemofílicos y otro control; Se aplicó un formulario de evaluación, seguido de la prueba de agarre. Resultados: Al comparar los dos grupos, se observó una diferencia estadísticamente significativa en las variables altura (p = 0,007) y fuerza de agarre en los lados dominantes (p = 0,04) y no dominantes (0,002), favoreciendo al grupo control; al comparar la fuerza de agarre de los hemofílicos con la enfermedad leve y grave, hubo una diferencia significativa para el lado no dominante (p = 0,01). Conclusión: La disminución de la fuerza de prensión del grupo de hemofílicos puede estar asociada a su condición de enfermedad crónica hereditaria. Sin embargo, como el número de participantes fue pequeño, estos sugerentes resultados muestran la necesidad de más estudios sobre el tema.

Perfil dos hemofílicos provenientes de uma associação de pacientes / Hemophiliacs profile provided of a patient association / Perfil de hemofílicos de una asociación de pacientes

Objetivo: traçar o perfil epidemiológico de hemofílicos vinculados a uma associação de pacientes do estado de Goiás, Brasil. Método: pesquisa transversal realizada com indivíduos do gênero masculino acima dos 18 anos de idade. Catorze participantes foram submetidos a uma ficha de avaliação contendo questões sociodemográficas e clínicas. O presente estudo utilizou análises de frequências para descrição da amostra. Para as variáveis quantitativas rodou-se o teste de normalidade de Shapiro Wilk. Resultados: a média de idade encontrada foi de 32,64 anos ± 9,32. A maior parte dos indivíduos residia a menos de 30 km do centro de tratamento e apresentaram a forma grave da doença. Em relação às comorbidades, um indivíduo apresentou inibidor do fator de coagulação e as infecções virais estiveram ausentes em 71,4% dos participantes, em um período que não havia controle antiviral. As hemorragias articulares predominantes foram observadas no cotovelo e joelho e o hematoma muscular esteve presente em 50% da amostra. O tratamento mais utilizado pelos participantes foi a profilaxia secundária. Conclusão: a partir da caracterização dos pacientes hemofílicos cadastrados em uma associação é possível compreender mais sobre a patologia em estudo, demonstrando que as infecções virais se constituem em importantes comorbidades adquiridas por hemofílicos adultos.

Objective: to trace the epidemiological profile of hemophiliacs linked to a patient association in the state of Goiás, Brazil. Method: cross-sectional research conducted with male individuals over 18 years old. Fourteen participants were submitted to an evaluation form containing sociodemographic and clinical questions. The present study used frequency analysis to describe the sample. For quantitative variables, the Shapiro Wilk normality test was run. Results: the average age found was 32.64 years ± 9.32. Most individuals lived less than 30 km from the treatment center and had a severe form of the disease. Regarding comorbidities, one individual had a coagulation factor inhibitor and viral infections were absent in 71.4% of the participants, in a period when there was no antiviral control. The predominant joint hemorrhages were observed in the elbow and knee and muscle hematoma was present in 50% of the sample. The most used treatment by the participants was secondary prophylaxis. Conclusion: from the characterization of hemophiliac patients registered in an association, it is possible to understand more about the pathology under study, demonstrating that viral infections are important comorbidities acquired by adult hemophiliacs.

Objetivo: rastrear el perfil epidemiológico de hemofílicos vinculados a una asociación de pacientes en el estado de Goiás, Brasil. Método: investigación transversal realizada con varones mayores de 18 años. Se enviaron catorce participantes a un formulario de evaluación conteniendo preguntas sociodemográficas y clínicas. El estudio utilizó análisis de frecuencia describiendo la muestra. Para las variables cuantitativas se ejecutó la prueba de normalidad de Shapiro Wilk. Resultados: la edad promedio fue de 32,64 años ± 9,32. La mayoría de las personas vivían a menos de 30 km del centro de tratamiento y tenían una forma grave de la enfermedad. En cuanto a las comorbilidades, un individuo tenía un inhibidor del factor de coagulación y las infecciones virales estaban ausentes en el 71,4% de los participantes, en un período en el que no hubo control antiviral. Las hemorragias articulares predominantes se observaron en el codo y la rodilla y el hematoma muscular estuvo presente en el 50% de la muestra. El tratamiento más utilizado por los participantes fue la profilaxis secundaria. Conclusión: a partir de la caracterización de los pacientes hemofílicos, es posible conocer más sobre la patología en estudio, demostrando que las infecciones virales son importantes comorbilidades adquiridas por hemofílicos adultos.

The existing scenario of haemophilia care in Canada and China - A review

ABSTRACT Hemophilia is an X-linked recessive genetic disorder which affects approximately 400,000 people globally. Differing healthcare reimbursement systems, budgetary constraints and geographical and cultural factors make it difficult for any country to fully deliver ideal care. Although developed countries have sufficient treatment products available, they are burdened by the higher expectation of outcomes, coupled with insufficient supportive care to monitor adherence and outcomes and to implement regular follow-up. In contrast, developing regions may not have ready access to factor replacement, but have developed excellent physiotherapy and rehabilitation programs. Although there are multiple studies that have attempted to assess country-specific variations in hemophilia care, very few compare hemophilia care between economically unequal countries and the challenges in achieving optimal hemophilia care. This literature review tries to bridge this gap and throws light on the country-specific differences in epidemiology, standard of hemophilia care and challenges faced in Canada and China. Data sources resulted in 20 studies (11 from Canada and 9 from China), which were reviewed. In a developed country, the main advantages are: the early treatment of bleeding episodes and the presence of a specialized interdisciplinary and comprehensive treatment concept. This is not the case in most developing countries, where the government does not have the resources to buy the necessary quantities of coagulation factors in the face of more urgent health priorities and hardly a few patients can afford to pay for their own treatment, even the on-demand home therapy.

Atuação de médicos e enfermeiros no atendimento de emergência ao paciente hemofílico / Performance of doctors and nurses in emergency care for hemophiliac patients

Objetivo: descrever a atuação de médicos e enfermeiros no atendimento de emergência ao paciente hemofílico. Metodologia: estudo exploratório e qualitativo, realizado com enfermeiros e médicos do setor de emergência de uma Unidade Hospitalar de referência e de uma Unidade de Pronto Atendimento na região Centro-Sul do Ceará. Os dados foram coletados em setembro e outubro de 2018 por meio de questionário semiestruturado composto por questões abertas e fechadas. As respostas foram submetidas à análise de conteúdo. O estudo foi aprovado pelo Comitê de Ética. Resultados: evidenciou-se uma fragilidade no conhecimento dos profissionais acerca da hemofilia e uma insuficiência no suporte das unidades para oferta do cuidado ao hemofílico. As unidades não possuem um protocolo de atendimento para atender esses pacientes, dificultando a execução do cuidado direcionado ao hemofílico. A falta de capacitação dos profissionais, medicamentos específicos para hemofilia e de hematologista na equipe constituem dificuldades em ofertar a assistência. Conclusão: o estudo identificou a necessidade de educação permanente em saúde no atendimento aos pacientes hemofílicos, desburocratizar e tornar menos fragmentado o cuidado em redes, com vista a garantir a integralidade do cuidado.

Objective: to describe the role of doctors and nurses in emergency care for hemophiliac patients. Methodology: exploratory and qualitative research, carried out with nurses and doctors in the emergency department of a referral Hospital Unit and an Emergency Care Unit in the Center-South region of Ceará. Data collection took place from September to October 2018 using a semi-structured questionnaire composed of open and objective questions. The responses were submitted to content analysis. The study was approved by the Ethics Committee. Results: there was a weakness in the professionals' expertise about hemophilia and insufficiency in the support of units to provide care to the hemophiliac. The units do not have a flow protocol to assist these patients, making it difficult to carry out care directed to hemophiliacs. The lack of training of professionals, specific medications for hemophilia and a hematologist in the team represent difficulties in assisting. Conclusion: the research identified the need for permanent health education in the care of hemophiliac patients, reducing bureaucracy and making care in networks less fragmented, aimed at guaranteeing comprehensive care

Hemofilia B o enfermedad de Christmas / Hemophilia B or Christmas disease

La hemofilia B o enfermedad de Christmas se diferenció por primera vez de la hemofilia A en 1947. Su forma clásica consiste en un trastorno hereditario de la coagulación causado por mutaciones en el gen F9, que codifica para el factor IX de la coagulación. Su herencia está ligada al cromosoma X; las mujeres son portadoras, pero se manifiesta clínicamente en hombres, aunque se han descrito casos de mujeres portadoras sintomáticas. El factor IX activado es una proteína dependiente de vitamina K, sintetizada en el hígado, que forma parte del complejo tenasa, cuya función es formar la mayor cantidad de trombina en el nuevo modelo de la coagulación basado en células. De acuerdo a la actividad del factor IX, su deficiencia se puede clasificar en leve (5% a 40%), moderada (1% a 5%), o severa (<1%). Su diagnóstico se realiza con la presencia de un TPT alargado que corrige con plasma normal y con la determinación del nivel funcional del factor IX, y se confirma con el estudio molecular que demuestra la mutación en el gen F9. Su diagnóstico diferencial incluye otras patologías como la hemofilia A. El tratamiento con factor IX recombinante es el más utilizado en la actualidad, pero se vienen desarrollando nuevas terapias con virus adeno-asociados recombinantes que prometen mejorar la calidad de vida para algunos pacientes afectados. La profilaxis juega un papel fundamental, en particular en los casos de enfermedad moderada y severa.

Hemophilia B or Christmas disease was first differentiated from hemophilia A in 1947. Its classic form consists of an inherited bleeding disorder caused by mutations in the F9 gene, which codes for coagulation factor IX. Its inheritance is linked to the X chromosome; women are carriers, but it manifests clinically in men, although cases of symptomatic women carriers have been described. Factor IX activates a vitamin K-dependent protein, synthesized in the liver, which is part of the tenase complex whose function is to form the largest amount of thrombin (factor IIa) in the new model of cell-based coagulation. According to factor IX activity, its deficiency can be classified as mild (5% to 40%), moderate (1% to 5%), and severe (<1%). The diagnosis is made when there is a prolonged TPT that corrects with normal plasma, and by assessing the functional level of factor IX. The diagnosis is confirmed by molecular analysis that demonstrates the F9 gene mutation. Its differential diagnosis includes disorders such as hemophilia A. Treatment with recombinant factor IX is widely used, but also new therapies are being developed with recombinant adeno-associated viruses that promise to improve the quality of life for some of these patients. Prophylaxis plays an important role in cases of moderate and severe disease

Hemofilia adquirida A y B como manifestación inicial de linfoma no Hodgkin. Reporte de un caso y revisión de la literatura / Acquired Hemophilia A and B as an initial manifestation of Non-Hodgkin Lymphoma. Case report and literature review

Resumen La hemofilia adquirida es una complicación rara y potencialmente fatal en pacientes con neoplasias hematológicas (desórdenes linfoproliferativos) o tumores sólidos. Presentamos una paciente de 75 años de sexo femenino con antecedente de hipertensión arterial y anemia ferropénica que ingresa a urgencias por cuadro de dolor abdominal generalizado tipo cólico, asociado a episodios eméticos de contenido alimentario y deposiciones melénicas. Dentro de los estudios iniciales se encontraron: tiempos de coagulación prolongados, prueba de mezclas de aPTT con evidencia de anticoagulante circulante específico, factor IX, 0% y factor VIII, 0% con inhibidores de factor VIII y IX en 180 UB y 130 UB respectivamente. Se consideró que la paciente cursaba con hemofilia adquirida A y B con realización de estudios de extensión diagnosticándose linfoma no Hodgkin marginal esplénico.

Abstract Acquired hemophilia is a potentially fatal rare complication of patients with hematological malignancies (usually lymphoproliferative disorders) or solid tumors. We report a 75-year female patient with a history of arterial hypertension and iron deficiency anemia. Log in to the emergency department complaining of generalized cramping abdominal pain associated with emetic episodes and melenic stools. In initial studies found prothrombin time (PT) 19 seconds control: 11 seconds, INR 1.8 and activated partial thromboplastin time (aPTT) 45 seconds, control: 29 seconds. Mixing aPTT study with normal plasma was performed suggesting specific anticoagulation factor. Other tests were performed: Factor IX 0%, factor VIII and 0%. Factor VIII inhibitor: 180 UB, factor IX inhibitor: 130 UB. It was considered acquired hemophilia A and B and was studying with extension studies found a splenic marginal non Hodgkin lymphoma.

Perfil demográfico y epidemiológico de pacientes con Hemofilia y von Willebrand atendidos en el Área de Estomatología del Hospital de Especialidades Carlos Andrade Marín / Demographic and epidemiological profile of patients with Hemophilia and von Willebrand treated in the Stomatology Area of the Carlos Andrade Marín Specialties Hospital

INTRODUCCIÓN. Las alteraciones hereditarias de la hemostasia son patologías raras, dentro de estas se encuentran: Hemofilia A, Hemofilia B y von Willebrand. La hemofilia es un trastorno hereditario, ligado al cromosoma X, causado por ausencia o actividad reducida del factor VIII o IX. La enfermedad de von Willebrand es causada por la deficiencia del factor VIII. OBJETIVO. Determinar el perfil demográfico y epidemiológico de pacientes con Hemofilia y von Willebrand. MATERIALES Y MÉTODOS. Estudio observacional, descriptivo, transversal. La población de estudio fueron 133719 con una muestra de 144 pacientes, los criterios de inclusión fueron: pacientes de ambos sexos entre 2 a 88 años de edad, con diagnóstico de Hemofilia A, B, von Willebrand. Atendidos en la consulta externa del Área de Estomatología del Hospital de Especialidades Carlos Andrade Marín, en el periodo 2015-2018. Datos obtenidos del sistema AS400, analizados en el programa International Business Machines Statistical Package for the Social Sciences, Versión 22.0. RESULTADOS. El 77,0% (111; 144) perteneció al género masculino. El rango de edad fue entre 23 y 33 años con 24,0% (34; 144). Tuvieron Hemofilia A 62,0% (93; 144); Hemofilia B 6,0% (9; 144); von Willerbrand 28,0% (42; 144). El 50,0% (77; 144) recibieron tratamientos odontológicos; preventivos 15,0% (21; 144) y curativos 13,0% (18; 144); siendo la mayor patología caries dental. CONCLUSIÓN. Se determinó el perfil demográfico y epidemiológico de los pacientes con Hemofilia y von Willebrand que permitió brindar un tratamiento integral, interdisciplinario y oportuno.

INTRODUCTION. Hereditary abnormalities of hemostasis are rare pathologies, within these are: Hemophilia A, Hemophilia B and von Willebrand. Hemophilia is an inherited disorder, linked to the X chromosome, caused by absence or reduced activity of factor VIII or IX. Von Willebrand's disease is caused by factor VIII deficiency. OBJECTIVE. Determine the demographic and epidemiological profile of patients with hemophilia and von Willebrand. MATERIALS AND METHODS. Observational, descriptive, cross-sectional study. The study population was 133719 with a sample of 144 patients, the inclusion criteria were: patients of both sexes between 2 and 88 years of age, with a diagnosis of Hemophilia A, B, von Willebrand. Attended in the external consultation of the Stomatology Area of the Carlos Andrade Marín Specialty Hospital, in the period 2015-2018. Data obtained from the AS400 system, analyzed in the International Business Machines Statistical Package for the Social Sciences program, Version 22.0. RESULTS 77,0% (111; 144) belonged to the male gender. The age range was between 23 and 33 years with 24,0% (34; 144). They had hemophilia at 62,0% (93; 144); Hemophilia B 6,0% (9; 144); von Willerbrand 28,0% (42; 144). 50,0% (77; 144) received dental treatments; preventive 15,0% (21; 144) and curative 13,0% (18; 144); being the biggest dental caries pathology. CONCLUSION. The demographic and epidemiological profile of patients with Hemophilia and von Willebrand was determined, which allowed to provide a comprehensive, interdisciplinary and timely treatment.

Terapia secuencial: una opción en el paciente hemofílico que no responde al manejo con monoterapia con agentes puente, estudio observacional del GrHeCol (Grupo Hemofilia Colombia) / Sequential therapy: an option for hemophiliac patients not responding to monotherapy with bypassing agents. Observational study of the GrHeCol (Grupo Hemofilia Colombia)

RESUMEN Introducción: la hemofilia A y B severa son condiciones que predisponen al sangrado espontáneo. Una de las complicaciones de la terapia con concentrados de factores de coagulación es el desarrollo de anticuerpos o inhibidores contra los factores VIII o IX. El tratamiento en casos de inhibidores de título alto, para el control de la hemorragia, es la administración de agentes puente como el complejo protrombínico activado y Factor VII recombinante activado. La respuesta a cada uno de ellos no es predecible, en algunos casos puede ser necesario el uso de la terapia secuencial cuando esta estrategia falla. Objetivo: reportar cinco casos de hemofilia A severa e inhibidores de título alto con sangrado severo, sin respuesta clínica con monoterapia y que recibieron terapia secuencial. Métodos: estudio multicéntrico, descriptivo, observacional. Las variables cualitativas se presentan con frecuencias absolutas y relativas, y las cuantitativas se resumen con medidas de tendencia central. Resultados: cuatro pacientes evaluados que aportaron cinco eventos, la mediana de edad 20 años; mediana de días de monoterapia 10; 8,6 días de terapia secuencial, tiempo a resolver el sangrado cuatro días. Ausencia de complicaciones trombóticas. Conclusiones: la terapia secuencial es una opción para aquellos pacientes que no responden a la monoterapia y requieren control hemostático. En los cinco casos reportados, la terapia secuencial logró controlar el sangrado sin complicaciones.

SUMMARY Introduction and objectives: Patients diagnosed with severe hemophilia are at risk of developing inhibitors of low or high title, being the treatment of choice for this latter group of patients the immune tolerance therapy (ITI). In cases where the immune tolerance fails or presents bleeding events, we can use activated prothrombin complex (APCC) or Recombinant activated factor VII (rFVIIa); however, patients may fail to these agents as monotherapy. The aim of this paper is to report five cases of severe hemophilia and high titer inhibitors with mayor bleeding, which fail to respond to monotherapy and required sequential therapy. Methods: Case report study, qualitative variables are presented as absolute and relative frequencies and quantitative are summarized with measures of central tendency. Results: Five patients with median age 20 years; monotherapy treatment with median 10 days; 8.6 days of sequential therapy, time to control the bleeding: 4 days. There were no thrombotic complications. Conclusions: Sequential therapy is an option for patients who do not respond to monotherapy and requires hemostatic control. In all the cases of this report, the patients were responsive with bleeding control.

Alfanonacogue - Benefix® para hemofilia B em pacientes menores de 19 anos de idade / Alfanonacogue - Benefix® for hemophilia B in patients younger than 19 years of age

CONTEXTO: As coagulopatias hereditárias são doenças hemorrágicas resultantes da deficiência quantitativa e/ou qualitativa de um ou mais fatores da coagulação e se caracterizam pela ocorrência de hemorragias de gravidade variável, de forma espontânea e/ou pós-traumática. Segundo dados de 2014 do Sistema Hemovida Web ­ Coagulopatias do Ministério da Saúde, o número de pacientes com Hemofilia B era de 1.881 no Brasil. Como não há cura para as hemofilias, os objetivos de tratamento são prevenir e tratar hemorragias de modo a evitar artropatias incapacitantes e dano tecidual, e melhorar a qualidade de vida e a sobrevida. As modalidades de tratamento da hemofilia B são definidas pela periodicidade com que é realizada a reposição dos fatores de coagulação IX, podendo ser sob demanda (episódico) ou profilático. O fator IX de origem plasmática faz parte do rol de tecnologias ofertada pelo SUS para o tratamento de Hemofilia B. TECNOLOGIA: Alfanonacogue (Benefix®). INDICAÇÃO: Controle e prevenção de episódios hemorrágicos e para profilaxia de atividades rotineiras e cirúrgicas de pacientes com hemofilia B, menores de 19 anos de idade. PERGUNTA: O uso do Fator IX recombinante (BeneFIX®), além de tão eficaz quanto comparado às opções disponíveis atualmente no SUS, proporciona vantagens de segurança aos pacientes com Hemofilia B? EVIDÊNCIAS CIENTÍFICAS: Os estudos apresentados pelo demandante demonstram a eficácia do medicamento Benefix em aumentar a atividade de FIX e controlar sangramentos. Entretanto, não foi apresentado estudo de eficácia que comparasse os fatores IX plasmático e recombinante, o que impossibilita posicionar o fator IX recombinante como igual, melhor ou pior do que o fator IX plasmático ofertado pelo SUS. Apenas um estudo retrospectivo comparou o fator IX plasmático (medicamento atualmente ofertado pelo SUS) com o fator IX recombinante, e concluiu que a frequência de reações alérgicas e do desenvolvimento de inibidores entre os pacientes que receberam ambos os fatores IX foi bem similar (Recht et al., 2011). Na revisão sistemática incluída pelo DGITS sobre tipos e frequência das reações adversas - não trombóticas e não associadas a inibidor - relacionadas aos fatores de coagulação utilizados em pacientes com hemofilia A, hemofilia B e doença de von Willebrand, os autores concluíram que os dados por eles apresentados confirmam o elevado grau de segurança dos produtos atualmente utilizados para terapia de hemofilia A e B e doença da von Willebrand (Franchini et al., 2012). Assim, até o momento, não há comprovação de que os fatores IX de origem plasmática utilizados atualmente pelo SUS confiram algum risco conhecido e quantificável aos pacientes quando comparados ao Fator IX recombinante. AVALIAÇÃO ECONÔMICA: Na análise de custo-minimização, foram encontrados os seguintes custos incrementais: profilaxia primária - R$ 474.978,00; cirurgia de médio porte - R$ 27.802,00; tratamento de sangramentos espontâneos - R$ 5.014,00. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário de R$ 728 milhões a aproximadamente R$ 1,01 bilhão de reais considerando o horizonte de tempo de 5 anos possivelmente está subestimado e não se justifica frente falta de evidência de superioridade em termos de eficácia e segurança do Fator IX recombinante em relação ao Fator IX plasmático. RECOMENDAÇÃO INICIAL: Os membros presentes na reunião do plenário da Conitec realizada no dia 10 de novembro deliberaram que o tema fosse submetido à consulta pública com recomendação preliminar desfavorável a incorporação do alfanonacogue (fator IX recombinante) para o tratamento da Hemofilia B. Tal recomendação foi embasada na falta de evidências que demonstrem superioridade do medicamento Benefix frente à tecnologia já disponível no tratamento da hemofilia B, e assim, sendo, não se justificaria o impacto orçamentário apresentado. CONSULTA PÚBLICA: Foi recebido um total de 155 contribuições, sendo 146 contribuições provenientes do formulário de experiência/opinião e 9 do formulário técnico-científico. Nenhuma das contribuições apresentou evidências de superioridade do fator IX recombinante em relação ao plasmático. RECOMENDAÇÃO FINAL: Os membros presentes na reunião do plenário da Conitec realizada no dia 08 de março de 2017 mantiveram a recomendação desfavorável a incorporação do alfanonacogue (fator IX recombinante) para o tratamento da Hemofilia B. DECISÃO: Não incorporar o alfanonacogue para hemofilia B em pacientes menores de 19 anos de idade, no âmbito do Sistema Único de Saúde - SUS, dada pela Portaria nº 17, publicada no DOU nº 77, do dia 24 de abril de 2017, seção 2, pág. 57.(AU)

Hemarthrosis subtalar, a rare diagnosis / Hemartrose subtalar, um diagnóstico raro

ABSTRACT Type B hemophilia usually affects patients with a family history of this disease and has a typical clinical picture. However, in the present case it appeared in a patient outside the typical age with no family history of hematologic malignancies and with an unusual clinical picture.

RESUMO A hemofilia do tipo B afeta normalmente pacientes com história familiar positiva para a doença e se apresenta com quadro clínico típico. No presente caso, no entanto, o diagnóstico se deu em um paciente fora da idade típica, sem histórico familiar de doenças hematológicas e quadro clínico diferente do habitual.