Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal hemoglobinuria is a chronic, multi-systemic, progressive and lifethreatening disease characterized by intravascular hemolysis, thrombotic events, serious infections and bone marrow failure. Paroxysmal nocturnal hemoglobinuria results from the expansion of a clone of hematopoietic cells that due to an inactivating mutation of the X-linked gene PIG-A are deficient in glycosylphosphatidylinositol-linked proteins. Early diagnosis, using flow cytometry performed on peripheral blood, the gold standard test to confirm the diagnosis of paroxysmal nocturnal hemoglobinuria, is essential for improved patient management and prognosis. The traditional therapy for paroxysmal nocturnal hemoglobinuria includes blood transfusion, anti-thrombosis prophylaxis or allogeneic bone marrow transplantation. The treatment that has recently become available is the complement blockade by the anti-C5 monoclonal antibody eculizumab. In this consensus, we are aiming to review the diagnosis and treatment of the paroxysmal nocturnal hemoglobinuria patients, as well as the early recognition of its systemic complications. These procedures express the opinions of experts and have been based on the best available evidence and international guidelines, with the purpose of increasing benefits and reducing harm to patients.

Association of HMIP1 C-893A polymorphism and disease severity in patients with sickle cell anemia

Abstract Introduction: Sickle cell anemia (SCA) is a Mendelian disorder with a heterogeneous clinical course. The reasons for this phenotypic diversity are not entirely established, but it is known that high fetal hemoglobin levels lead to a milder course of the disease. Additionally, genetic variants in the intergenic region HBS1L-MYB promote high levels of fetal hemoglobin into adulthood. Objective: In the present study, we investigated the HMIP1 C-839A (rs9376092) polymorphism, located at the HBS1L-MYB intergenic region block 1, in SCA patients. Method: We analyzed 299 SCA patients followed in two reference centers in Brazil. The HMIP1 C-839A (rs9376092) genotypes were determined by allele specific polymerase chain reactions. Clinical and laboratory data were obtained from patient interviews and medical records. Results: The median fetal hemoglobin levels were higher in patients with the HMIP1 C-839A (rs9376092) AA genotype (CC = 6.4%, CA = 5.6% and AA = 8.6%), but this difference did not reach significance (p = 0.194). No association between HMIP1 C-839A (rs9376092) genotypes and other clinical and laboratorial features was detected (p > 0.05). Conclusion: In summary, our data could not support the previously related association between the HMIP1 C-893A (rs9376092) polymorphism and differential fetal hemoglobin levels.

Mortality in children, adolescents and adults with sickle cell anemia in Rio de Janeiro, Brazil

Abstract Objective: To determine the mortality rate of children, adolescents and adults with sickle cell anemia in Rio de Janeiro, Brazil. Methods: The number of deaths, the mortality rate and the causes of deaths in patients with sickle cell anemia who were treated and followed up at our institution for 15 years were determined and compared to data available for the Brazilian population. Results: The overall number of deaths was 281 patients with a mortality rate of 16.77%. Survival probability was significantly higher in females. The number of deaths and the mortality rate were age-specific with a significant increase in the 19- to 29-year-old age group. The remaining life expectancy of the patients with sickle cell anemia was less than that of Brazilians at large. The gap between the two was about 20 years for ages between one and five years with this gap decreasing to ten years after the age of 65 years. The most common causes of death were infection, acute chest syndrome, overt stroke, organ damage and sudden death during painful crises. Conclusion: To the best of our knowledge, this is the first Brazilian study in a single institution in Rio de Janeiro; the mortality rate was 18.87% among adult patients with sickle cell anemia. The mortality rates in children and adults are higher than those reported in developed countries of the northern hemisphere.

Brazilian Thalassemia Association protocol for iron chelation therapy in patients under regular transfusion

In the absence of an iron chelating agent, patients with beta-thalassemia on regular transfusions present complications of transfusion-related iron overload. Without iron chelation therapy, heart disease is the major cause of death; however, hepatic and endocrine complications also occur. Currently there are three iron chelating agents available for continuous use in patients with thalassemia on regular transfusions (desferrioxamine, deferiprone, and deferasirox) providing good results in reducing cardiac, hepatic and endocrine toxicity. These practice guidelines, prepared by the Scientific Committee of Associação Brasileira de Thalassemia (ABRASTA), presents a review of the literature regarding iron overload assessment (by imaging and laboratory exams) and the role of T2* magnetic resonance imaging (MRI) to control iron overload and iron chelation therapy, with evidence-based recommendations for each clinical situation. Based on this review, the authors propose an iron chelation protocol for patients with thalassemia under regular transfusions.

Abnormal transcranial Döppler ultrasonography in children with sickle cell disease

BACKGROUND: Stroke is a potentially fatal complication of sickle cell disease in children between 2-16 years and transcranial Döppler has been recommended as a screening method in these cases. OBJECTIVE: The main goal of this study was to correlate transcranial Döppler results to complications related to stroke in sickle cell disease and baseline characteristics of the population. METHODS: This was an observational study of children and adolescents with ages between 2-16 years with sickle cell disease who were followed in three centers. RESULTS: From January 2008 to July 2009, 902 patients were enrolled in this study. The median age was 6.5 years (range: 1.8-15.8), 52.3% were male, 74.4% had hemoglobin SS; 221 (28.6%) had at least one complication associated with sickle cell disease. A total of 773 patients performed transcranial Döppler; in 91.2% this was a method of screening. Conditional or abnormal transcranial Döppler results were more common in patients with sickle cell disease complications versus those without complications (ODDS ratio = 3.18; 95% Confidence interval = 1.92-5.27). There was a significant difference in the frequency of conditional or abnormal transcranial Döppler results in patients with abnormal laboratory results compared to those without abnormalities (OR=4.03); 95% confidence interval = 2.30-7.06. CONCLUSIONS: Conditional or abnormal transcranial Döppler results were significantly more frequent in patients with complications of sickle cell disease confirming the increased risk of stroke in this subgroup of patients. This observation reinforces the recommendation of transcranial Döppler as a screening test for all patients with sickle cell disease with ages between 2 and 16 years.

The influence of hydroxyurea on oxidative stress in sickle cell anemia

OBJECTIVE: The oxidative stress in 20 sickle cell anemia patients taking hydroxyurea and 13 sickle cell anemia patients who did not take hydroxyurea was compared with a control group of 96 individuals without any hemoglobinopathy. METHODS: Oxidative stress was assessed by thiobarbituric acid reactive species production, the Trolox-equivalent antioxidant capacity and plasma glutathione levels. RESULTS: Thiobarbituric acid reactive species values were higher in patients without specific medication, followed by patients taking hydroxyurea and the Control Group (p < 0.0001). The antioxidant capacity was higher in patients taking hydroxyurea and lower in the Control Group (p = 0.0002 for Trolox-equivalent antioxidant capacity and p < 0.0292 for plasma glutathione). Thiobarbituric acid reactive species levels were correlated with higher hemoglobin S levels (r = 0.55; p = 0.0040) and lower hemoglobin F concentrations(r = -0.52; p = 0.0067). On the other hand, plasma glutathione levels were negatively correlated with hemoglobin S levels (r = -0.49; p = 0.0111) and positively associated with hemoglobin F values (r = 0.56; p = 0.0031). CONCLUSION: Sickle cell anemia patients have high oxidative stress and, conversely, increased antioxidant activity. The increase in hemoglobin F levels provided by hydroxyurea and its antioxidant action may explain the reduction in lipid peroxidation and increased antioxidant defenses in these individuals.

Brazilian Guidelines for transcranial doppler in children and adolescents with sickle cell disease

BACKGROUND: Sickle cell disease is the most common monogenic hereditary disease in Brazil. Although strokes are one of the main causes of morbidity and mortality in these patients, the use of transcranial Doppler to identify children at risk is not universally used. OBJECTIVE: To develop Brazilian guidelines for the use of transcranial Doppler in sickle cell disease children and adolescents, so that related health policies can be expanded, and thus contribute to reduce morbidity and mortality. METHODS: The guidelines were formulated in a consensus meeting of experts in transcranial Doppler and sickle cell disease. The issues discussed were previously formulated and scientific articles in databases (MEDLINE, SciELO and Cochrane) were carefully analyzed. The consensus for each question was obtained by a vote of experts on the specific theme. RESULTS: Recommendations were made, including indications for the use of transcranial Doppler according to the sickle cell disease genotype and patients age; the necessary conditions to perform the exam and its periodicity depending on exam results; the criteria for the indication of blood transfusions and iron chelation therapy; the indication of hydroxyurea; and the therapeutic approach in cases of conditional transcranial Doppler. CONCLUSION: The Brazilian guidelines on the use of transcranial doppler in sickle cell disease patients may reduce the risk of strokes, and thus reduce the morbidity and mortality and improve the quality of life of sickle cell disease patients.

Tratamento da anemia ferropriva com ferro por via oral: [revisão] / Treatment of iron deficiency anemia with oral iron: [review]

A anemia ferropriva permanece como uma das deficiências nutricionais mais frequentes e importantes no mundo. O tratamento com ferro deve ser iniciado preferencialmente por via oral e a investigação apropriada de sua causa é obrigatória. Os autores discutem os compostos com ferro atualmente disponíveis, o perfil de eficácia, segurança e tolerabilidade desses medicamentos, e o plano terapêutico mais adequado possível para o sucesso no tratamento dessa doença tão comum e importante.

Iron deficiency anemia remains one of the commonest and most important nutritional deficiencies in the world today. The treatment of iron deficiency should preferably be initiated with oral iron; an appropriate investigation of the cause of iron deficiency anemia is mandatory. The authors discuss the currently available iron preparations as well as their efficacy, safety and tolerability and the optimal therapeutic plan to successfully treat this common and important disease.

Tratamento da anemia ferropriva com ferro por via parenteral: [revisão] / Iron deficiency anemia treatment with parenteral iron: [review]

Embora o ferro por via oral seja considerado a primeira opção de tratamento da deficiência de ferro, em algumas situações específicas, a administração de ferro por via parenteral é uma opção terapêutica que deve ser considerada. Diferentemente do ferro dextran de alto peso molecular utilizado na década de 80 e lembrado como um composto associado ao alto risco de reação anafilática e morte, o desenvolvimento e comercialização de novos compostos com ferro para uso parenteral, sobretudo por via endovenosa - como o ferro sacarato, ferro gluconato e, mais recentemente, a carboximaltose férrica - , tem se tornado cada vez mais uma alternativa terapêutica segura e efetiva, e tem possibilitado ampliar o leque de indicações desta modalidade de tratamento além da nefrologia, como obstetrícia e ginecologia, cirurgia, pediatria, gastroenterologia, hematologia e hemoterapia. Os autores revisam as principais indicações do tratamento com ferro por via parenteral, analisam as principais drogas disponíveis para a correção da anemia ferropriva por via endovenosa e propõem uma estratégia de investigação diagnóstica, tratamento e seguimento laboratorial dos pacientes com indicação desta opção terapêutica.

Although oral iron is generally considered the first choice in the treatment of iron deficiency, in some specific situations, parenteral iron administration is a therapeutic option that should be considered. Different to the high-molecular-weight iron dextran utilized in the eighties and remembered as a compound associated with a high risk of anaphylaxis and death, the development and marketing of newer preparations for parenteral, in particular endovenous, administration, such as iron sucrose, ferric gluconate and more recently ferric carboxymaltose, are becoming a more effective and safe therapeutic alternative, that have extended the range of indications beyond nephrology to obstetrics and gynecology, surgery, pediatrics, gastroenterology, hematology and hemotherapy. The authors review the main indications of parenteral iron treatment, analyse the drugs available for the correction of iron deficiency anemia by intravenous iron administration and propose a new strategy of diagnostic investigation, treatment and laboratory follow up of the patient with indication for this therapeutic option.

Avaliação da analgesia de opioide tópico em úlcera de perna de paciente falcêmico / Evaluation of the topical application of opioid analgesia for a leg ulcer of a sickle cell disease patient

A doença falciforme é caracterizada por apresentar várias alterações clinicas e fisiopatológicas nos pacientes que por ela são acometidos. Uma dessas alterações é presença de úlceras de perna dolorosas e de difícil cicatrização, sendo necessário o apoio de equipe multiprofissional no seu manejo e tratamento. Com o objetivo de reduzir a dor associada a úlcera de perna, o paciente falcêmico faz uso de opioides parenterais e enterais que normalmente estão associados a efeitos colaterais indesejados. Com o objetivo de reduzir o uso desses opioides sistêmicos, avaliamos um gel de morfina, de fácil manipulação e baixo custo, que foi utilizado antes e após o processo de troca de curativo das úlceras de perna dos pacientes falcêmicos atendidos em nossa instituição. Baseados na escala analógica da dor foi avaliado o efeito analgésico do gel em 28 pacientes. Todos apresentavam dor grau 7 ou 8 antes da aplicação do gel. Vinte e quatro pacientes (85,7 por cento) apresentaram total ausência de dor por um período de 24 horas, não sendo necessário o uso de analgésicos sistêmicos. Em três pacientes (10,7 por cento) a ausência de dor durou um periodo de 12horas. Somente um paciente (3,6 por cento) não relatou analgesia apos o uso do gel. Os resultados demonstraram que o gel é altamente eficaz no controle da dor das úlceras de perna de pacientes falcêmicos.

Sickle cell disease is characterized by several clinical and pathophysiological changes including painful leg ulcers. These are difficult to heal and require the support of a multidisciplinary team in their management. The treatment of pain in these patients usually involves the use of opioids. In order to reduce the use of systemic opioids, we evaluated an easy-to-use low-cost morphine gel (0.12 percent) that was applied before and after changing leg ulcer dressings of sickle cell patients treated in Hemorio hospital. Based on the Analogue Pain Scale (APS) we evaluated the analgesic effect of the gel with 28 patients. All presented with a degree of pain of 7 or 8 before applying the gel. A total absence of pain was observed by 24 patients (85.7 percent) within thirty minutes of applying the gel, with the analgesia effect being maintained for a period of 24 hours and thus the use of other analgesics was not requiring. In 3 patients (10.7 percent) no pain was reported for a period of 12 hours. Only 1 patient (3.6 percent) reported no analgesic effect thirty minutes after the application of the gel. Our results indicate that the morphine gel was effective in controlling the pain of leg ulcers in this group of sickle cell patients. A controlled study should be designed to assess this important subject.

Protocolo clínico e diretrizes terapêuticas para uso de hidroxiureia na doença falciforme / Clinical protocol and therapeutic guidelines for the use of hydroxyurea in sickle cell disease

Hidroxiureia (HU) constitui o avanço mais importante no tratamento de pacientes com doença falciforme (DF). Fortes evidências confirmam a eficácia da HU em pacientes adultos diminuindo os episódios de dor intensa, hospitalização, número de transfusões e síndrome torácica aguda. Embora a evidência da eficácia do tratamento com HU em crianças não seja tão forte, os recentes resultados são encorajadores. Os dados atuais em relação aos riscos a curto e longo prazos da terapia com HU em adultos são aceitáveis comparado aos riscos dos pacientes não tratados com HU. Neste artigo, apresentamos revisão detalhada sobre os principais aspectos quanto à eficácia, efetividade, toxicidade e barreiras ao uso de HU em pacientes com DF e propomos um protocolo clínico e diretrizes terapêuticas para o uso de HU em pacientes com DF.

Hydroxyurea (HU) is an important major advance in the treatment of sickle cell disease (SCD). Strong evidence supports the effectiveness of HU in adults; severe painful episodes, hospitalizations, number of blood transfusions, and acute chest syndrome are reduced. Although the evidence of its effectiveness in the treatment of children is not as strong, the emerging data is encouraging. Current data on the risks of both short- and long-term HU therapy in adults are acceptable when compared to the risks of untreated SCD. In this article, we present a detailed review of the main aspects of the efficacy, effectiveness, toxicity, and barriers to the use of HU for SCD and propose a clinical protocol and therapeutic guidelines for the use of HU in patients with SCD.

Consenso brasileiro sobre atividades esportivas e militares e herança falciforme no Brasil - 2007 / Brazilian consensus of sickle cell trait in sports and army activities

A reunião de consenso brasileiro sobre atividades esportivas e militares e herança falciforme foi realizada no dia 3 de setembro de 2007, no Rio de Janeiro, e reuniu especialistas, representantes das Forças Armadas e de associações de pacientes de doença falciforme. Questões relativas à prática de esporte amador e profissional e do serviço militar foram amplamente discutidas, tendo como base a literatura científica e a experiência de cada um dos participantes. Ao final, algumas recomendações foram assim definidas: 1. O indivíduo portador de traço pode fazer qualquer modalidade de esporte, já que não há dados epidemiológicos consistentes que impeçam a prática de qualquer esporte; 2. Não é necessário fazer triagem para hemoglobinopatias em indivíduos que queiram praticar esportes, quer de natureza amadora ou profissional; 3. Para servir às Forças Armadas não é necessário fazer teste de triagem para hemoglobinopatias, o que equivale dizer que os portadores de traço falciforme podem serviràs Forças Armadas; 4. É fundamental que se esclareça entre os mais diferentes segmentos da sociedade que a heterozigose para a hemoglobina S não confere ao seu portador maior risco que a população geral no que tange às atividades físicas, desde que atendidas as condições básicas de hidratação e de descanso.

The Brazilian consensus meeting concerning sports and military activities and the sickle cell trait was held on September 3rd, 2007 in Rio de Janeiro and brought together experts, and members of the armed forces and sickle cell disease associations. Issues related to the practice of professional and amateur sports and military service were widely discussed based on the scientific literature and the experience of each participant. These were the final recommendations: 1. an individual with sickle cell trait can practice any type of sport because there is no consistent epidemiological data to recommend the contrary; 2. hemoglobin screening is not needed for individuals who want to practice sports, whether as amateur or professional sportspeople; 3. it is not necessary to undergo a screening test for hemoglobin to serve the armed forces, which means that the carriers of the sickle cell trait can serve the armed forces; 4. it must be made clear to the different segments of society that heterozygosis for hemoglobin S does not confer any specific risk to the practice of physical activities, provided the basic conditions of hydration and rest are observed.

Crises dolorosas na doença falciforme / Painful episodes in sickle cell disease

A doença falciforme é a enfermidade genética mais prevalente em todo o mundo. No Brasil, ela ocorre em um a cada 1.200 nascimentos. Por essa alta prevalência, ela representa, em nosso país, um importante problema de saúde pública. Além da hemólise, a vasoclusão é o achado central da doença e responsável pelas crises dolorosas, que correspondem à principal causa de internação nos adultos. Alguns pacientes evoluem com seis ou mais episódios dolorosos por ano. As crises graves e persistentes constituem, nesses pacientes, fator de mau prognóstico e um fator preditivo para morte precoce. Este artigo enfoca as abordagens terapêuticas das crises vasoclusivas nos pacientes de doença falciforme.

Sickle cell disease (SCD) is the most prevalent genetic disease in the world. In Brazil it occurs in one in every 1200 births. This high prevalence makes SCD a very important public health problem in Brazil. Vaso-occlusion and hemolysis are the hallmarks of the disease. Vaso-occlusion results in painful episodes which are the main cause of hospitalization among adults with SCD. Some patients experience episodes as often as 6 times per year. Persistent, severe sickle cell pain is a poor prognostic sign and a predictor for early death. The management of vaso-occlusion episodes is discussed here, as well as the related complications.

Tratamento da doença de Gaucher: um consenso brasileiro / Gaucher disease treatment: a Brazilian consensus

A doença de Gaucher (DG) é um erro inato do metabolismo do grupo das doenças lisossômicas de depósito, sendo a mais freqüente do referido grupo. É de herança autossômica recessiva, portanto com risco de 25 por cento a cada gestação de casal heterozigoto. A doença é resultante da deficiência da beta-glicosidase ácida ou beta-glicocerebrosidase, que leva ao acúmulo de glicolipídios nos macrófagos principalmente em baço, fígado, medula óssea e pulmão. As manifestações clínicas ou fenotípicas da DG vão depender do grau de deficiência da enzima, existindo três tipos: Tipo I, forma não neuropática, afeta crianças e adultos com hepatoesplenomegalia, anemia, trombocitopenia, leucopenia e lesões ósseas; Tipo II, forma neuropática aguda, afeta crianças com 4-5 meses com quadro neurológico grave, hepatoesplenomegalia e comprometimento pulmonar e o Tipo III, forma neuropática crônica, afeta crianças e adolescentes com quadro neurológico menos grave que o Tipo II e ainda pode comprometer fígado, baço e ossos. Um grupo de catorze médicos com experiência no tratamento da DG com reposição enzimática realizaram extensa revisão da literatura, confrontaram com os dados evolutivos dos pacientes brasileiros e chegaram a um consenso quanto aos critérios para iniciar o tratamento, a dose da enzima e freqüência das infusões, do acompanhamento ambulatorial, laboratorial e radiológico. O Grupo Brasileiro de Estudos em Doença de Gaucher e outras Doenças de Depósito Lisossômico (GBDDL) tem o objetivo de estabelecer diretrizes para o diagnostico, tratamento e acompanhamento de pacientes com doença de Gaucher no Brasil. Esta iniciativa pioneira visa uniformizar a conduta no país com relação ao tratamento de DG com reposição enzimática, tratamento de alto custo porém de grande eficácia

Triagem neonatal para hemoglobinopatias no Rio de Janeiro, Brasil / Neonatal screening for hemoglobinopathies in Rio de Janeiro, Brazil

OBJETIVO: Descrever os principais resultados do programa de triagem neonatal para a doença falciforme do Estado do Rio de Janeiro em 15 meses de funcionamento (agosto de 2000 a novembro de 2001). MÉTODOS: A partir de agosto de 2000, amostras de sangue passaram a ser coletadas de todos os recém-nascidos atendidos em postos de atençäo básica à saúde no Estado para triagem neonatal da doença falciforme. Essas amostras säo submetidas a cromatografia líquida de alta resoluçäo. Se o cromatograma resultante for compatível com a doença falciforme, a criança e seus pais säo encaminhados para confirmaçäo diagnóstica e tratamento. RESULTADOS: De agosto de 2000 a novembro de 2001, 99 260 recém nascidos participaram da triagem. Houve um caso de homozigose para Hb C. Um em cada 27 recém-nascidos triados pelo programa apresentou o traço falciforme (Hb AS). A doença falciforme foi constatada em 83 casos (um caso novo para cada 1 196 nascimentos): 62 Hb S, 18 Hb SC, 3 Hb SD. Uma criança näo compareceu para confirmaçäo diagnóstica. As 82 crianças acompanhadas apresentaram 15 intercorrências (infecçöes de vias aéreas superiores, febre, seqüestro esplênico, síndrome mäo-pé e crises de vaso-oclusäo), motivando sete internaçöes. Houve necessidade de transfusäo sangüínea em 15 crianças, mas nenhuma tornou-se alo-imunizada. Os demais bebês estäo evoluindo satisfatoriamente com o uso de penicilina profilática. CONCLUSÖES: Nossos dados evidenciam a importância do diagnóstico precoce da doença falciforme, de forma a prevenir e evitar as freqüentes complicaçöes infecciosas enfrentadas por esses pacientes