Rodolfo D. Cançado

Sickle cell disease in Brazil

Ha mais de trinta anos, os segmentos sociais organiza-dos de homens e mulheres negras no Brasil vem reivindican-do o diagnostico precoce e um programa de atencao integralas pessoas com doenca falciforme (DF).O primeiro passo rumo a construcao de tal programafoi dado com institucionalizacao da Triagem Neonatal noSistema Unico de Saude do Brasil, por meio da Portaria doMinisterio da Saude de 15 de janeiro de 1992, com testespara fenilcetonuria e hipotireoidismo congenito (Fase 1).Em 2001, mediante a Portaria n

Iron deficiency in blood donors

CONTEXT Blood donation results in a substantial loss of iron (200 to 250 mg) at each bleeding procedure (425 to 475 ml) and subsequent mobilization of iron from body stores. Recent reports have shown that body iron reserves generally are small and iron depletion is more frequent in blood donors than in non-donors. OBJECTIVE The aim of this study was to evaluate the frequency of iron deficiency in blood donors and to establish the frequency of iron deficiency in blood donors according to sex, whether they were first-time or multi-time donors, and the frequency of donations per year. DESIGN From September 20 to October 5, 1999, three hundred blood donors from Santa Casa Hemocenter of São Paulo were studied. DIAGNOSTIC TESTS Using a combination of biochemical measurements of iron status: serum iron, total iron-binding capacity, transferrin saturation index, serum ferritin and the erythrocyte indices. RESULTS The frequency of iron deficiency in blood donors was 11.0%, of whom 5.5% (13/237) were male and 31.7% (20/63) female donors. The frequency of iron deficiency was higher in multi-time blood donors than in first-time blood donors, for male blood donors (7.6% versus 0.0%, P < 0.05) and female ones (41.5% versus 18.5%, P < 0.05). The frequency of iron deficiency found was higher among the male blood donors with three or more donations per year (P < 0.05) and among the female blood donors with two or more donations per year (P < 0.05). CONCLUSIONS We conclude that blood donation is a very important factor for iron deficiency in blood donors, particularly in multi-time donors and especially in female donors. The high frequency of blood donors with iron deficiency found in this study suggests a need for a more accurate laboratory trial, as hemoglobin or hematocrit measurement alone is not sufficient for detecting and excluding blood donors with iron deficiency without anemia.

Intravenous iron therapy: how far have we come?

Oral iron supplementation is usually the first choice for the treatment of iron deficiency anemia (IDA) because of its effectiveness and low cost. But unfortunately in many iron deficient conditions, oral iron is a less than the ideal treatment mainly because of adverse events related to the gastrointestinal tract as well as the long course required to treat anemia and replenish body iron stores. The first iron product for intravenous use was high-molecular-weight iron dextran. However, dextran-containing intravenous iron preparations are associated with an elevated risk of anaphylactic reactions, which made physicians reluctant to prescribe intravenous iron in the treatment of iron deficiency anemia for many years. In 1999 and 2001, two new intravenous iron preparations (ferric gluconate and iron sucrose) were introduced into the market as safer alternatives to iron dextran. Over the last five years, three new intravenous iron dextran-free preparations have been developed and have better safety profiles than the more traditional intravenous compounds, as none require test doses and all these products are promising in respect to a more rapid replacement of body iron stores (15-60 minutes/infusion) as they can be given at higher doses (from 500 mg to more than 1000 mg/infusion). The purpose of this review is to discuss some pertinent issues in relation to the history, pharmacology, administration, efficacy, safety profile and toxicity of intravenous iron for the treatment of iron deficiency anemia.

Anemia de Doença Crônica

The anemia of chronic disease (ACD) is usually defined as the anemia occurring in chronic infectious, inflammatory disorders, or neoplastic diseases, and is one of the most common syndromes in the clinical practice. Characteristically, ACD is a mild-to-moderate, normochromic/normocytic anemia, and is characterized by hypoferremia in the presence of adequate iron stores. The three principal pathologic mechanisms involved in ACD are: reduced erythrocyte survival, bone marrow failure to increase red blood cell production to compensate for the increase in its demand, and abnormal mobilization of reticuloendothelial iron stores. The central role of monocytes and macrophages, and the increased production of the cytokines that mediate the immune or inflammatory response, such as tumor necrosis factor, interleukin-1 and the interferons, are implicated in all three processes involved in the development of ACD. The aim of this article is to review the recent advances in the understanding of the pathophysiologic, diagnostic and therapeutic aspects of this syndrome.

Hereditary hemochromatosis: mutations in genes involved in iron homeostasis in Brazilian patients.

BACKGROUND p.C282Y mutation and rare variants in the HFE gene have been associated with hereditary hemochromatosis (HH). HH is also caused by mutations in other genes, such as the hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1). The low rate homozygous p.C282Y mutation in Brazil is suggestive that mutations in non-HFE genes may be linked to HH phenotype. AIM To screen exon-by-exon DNA sequences of HFE, HJV, HAMP, TFR2 and SLC40A1 genes to characterize the molecular basis of HH in a sample of the Brazilian population. MATERIALS AND METHODS Fifty-one patients with primary iron overload (transferrin saturation ≥50% in females and ≥60% in males) were selected. Subsequent bidirectional DNA sequencing of HFE, HJV, HAMP, TFR2 and SLC40A1 exons was performed. RESULTS Thirty-seven (72.5%) out of the 51 patients presented at least one HFE mutation. The most frequent genotype associated with HH was the homozygous p.C282Y mutation (n=11, 21.6%). In addition, heterozygous HFE p.S65C mutation was found in combination with p.H63D in two patients and homozygous HFE p.H63D was found in two patients as well. Sequencing in the HJV and HAMP genes revealed HJV p.E302K, HJV p.A310G, HJV p.G320V and HAMP p.R59G alterations. Molecular and clinical diagnosis of juvenile hemochromatosis (homozygous form for the HJV p.G320V) was described for the first time in Brazil. Three TFR2 polymorphisms (p.A75V, p.A617A and p.R752H) and six SLC40A1 polymorphisms (rs13008848, rs11568351, rs11568345, rs11568344, rs2304704, rs11568346) and the novel mutation SLC40A1 p.G204S were also found. CONCLUSIONS The HFE p.C282Y in homozygosity or in heterozygosity with p.H63D was the most frequent mutation associated with HH in this sample. The HJV p.E302K and HAMP p.R59G variants, and the novel SLC40A1 p.G204S mutation may also be linked to primary iron overload but their role in the pathophysiology of HH remain to be elucidated.

Expression levels of CD47, CD35, CD55, and CD59 on red blood cells and signal-regulatory protein-α,β on monocytes from patients with warm autoimmune hemolytic anemia

BACKGROUND: Animal models have shown that CD47‐deficient mice develop severe autoimmune hemolytic anemia (AIHA) because the binding of red blood cell (RBC) CD47 to signal‐regulatory protein (SIRP‐α) on macrophages contributes to the inhibition of phagocytosis. In contrast, complement‐inhibitory proteins such as CD35, CD55, and CD59 may protect RBCs against the lysis by complement.

Protocolo clínico e diretrizes terapêuticas para uso de hidroxiureia na doença falciforme

Hidroxiureia (HU) constitui o avanco mais importante no tratamento de pacientes com doenca falciforme (DF). Fortes evidencias confirmam a eficacia da HU em pacientes adultos diminuindo os episodios de dor intensa, hospitalizacao, numero de transfusoes e sindrome toracica aguda. Embora a evidencia da eficacia do tratamento com HU em criancas nao seja tao forte, os recentes resultados sao encorajadores. Os dados atuais em relacao aos riscos a curto e longo prazos da terapia com HU em adultos sao aceitaveis comparado aos riscos dos pacientes nao tratados com HU. Neste artigo, apresentamos revisao detalhada sobre os principais aspectos quanto a eficacia, efetividade, toxicidade e barreiras ao uso de HU em pacientes com DF e propomos um protocolo clinico e diretrizes terapeuticas para o uso de HU em pacientes com DF.

Uso de índices hematimétricos no diagnóstico diferencial de anemias microcíticas: uma abordagem a ser adotada?

OBJECTIVE To evaluate prospectively RBC indices as a diagnostic tool at a high complexity general hospital. METHODS We analyzed 2278 blood cell counts from the core laboratory of our service and we found 343(15%) microcytic anemias. Concomitant serum samples were found from 52 patients above 14 years-old, and ferritin measurement and hemoglobin electrophoresis were performed. We classified our patients in three groups: Iron-deficiency anemia (AF; 26 patients), beta-thalassemia minor (BTM; n=17) and non-iron-deficiency-non-beta-thalassemia (ANFNT; n=9). We evaluated the following RBC indices for group discrimination, with variance and ROC curve analysis: RBC, MCV, MCH, RDW, Englands index and Greens index. RESULTS None of the indices allowed complete discrimination of all groups. We have established limits for each of the indices, and sensitivity (S), specificity(E), positive and negative predictive values and test efficiency were determined. BTM was better distinguished from the other groups by RBC (above 5 millions/mL) and Englands index (<6), both with S=82.3% and E of 82.8%. A RDW above 16% was the best index of AF, with S=69.2% and E= 80.7%. CONCLUSIONS Presumptive diagnosis of AF is troublesome when using RBC indices; diagnosis should be based on complete laboratory evaluation. Elevated RBC levels, specially above 5 millions/microL, in anemic patients with microcytosis are important indicatives of BTM, and confirmatory tests are suggested.O diagnostico diferencial das anemias microciticas e complexo e sua investigacao laboratorial, de custo elevado. O uso de indices hematimetricos para racionalizar a abordagem diagnostica tem sido proposto para contornar essa problematica. OBJETIVO: Avaliar a utilidade diagnostica dos indices hematimetricos nas anemias microciticas, de modo prospectivo, em hospital geral de alta complexidade. METODOS: Foram analisados 2278 hemogramas realizados nos nossos servicos. Baseados em eletroforese de hemoglobina e ferritina, estratificamos 52 pacientes adultos com anemia microcitica em tres grupos: Anemia ferropriva (AF; n=26 pacientes), Beta-Talassemia Menor (BTM; n=17) e Anemia nao-ferropriva e nao-beta-Talassemia (ANFNT; n=9). Avaliamos o uso dos seguintes indices hematimetricos na discriminacao dos tres grupos, por analise de variância e curvas ROC: RBC, VCM, HCM, RDW, indices de England e de Green. RESULTADOS: Nenhum dos indices permitiu a separacao integral dos tres grupos. Determinamos valores de corte para cada um dos indices e calculamos sensibilidade (S), especificidade(E), valores preditivos positivo e negativo e eficacia, em funcao de sua melhor discriminacao. A discriminacao de BTM foi melhor realizada pelo RBC acima de 5 milhoes/mL, com S=82,3% e E=82,8%; enquanto a anemia ferropriva, pelo RDW acima de 16%, mas com S de apenas 69,2% e E=80,7%. CONCLUSOES: A anemia ferropriva apresenta dificil diagnostico presuntivo pelos indices, devendo ser realizada confirmacao laboratorial. Valores elevados de RBC em anemicos devem fazer suspeitar de traco talassemico, sendo recomendavel confirmacao diagnostica.OBJECTIVE: To evaluate prospectively RBC indices as a diagnostic tool at a high complexity general hospital. METHODS: We analyzed 2278 blood cell counts from the core laboratory of our service and we found 343(15%) microcytic anemias. Concomitant serum samples were found from 52 patients above 14 years-old, and ferritin measurement and hemoglobin electrophoresis were performed. We classified our patients in three groups: Iron-deficiency anemia (AF; 26 patients), beta-thalassemia minor (BTM; n=17) and non-iron-deficiency-non-beta-thalassemia (ANFNT; n=9). We evaluated the following RBC indices for group discrimination, with variance and ROC curve analysis: RBC, MCV, MCH, RDW, Englands index and Greens index. RESULTS: None of the indices allowed complete discrimination of all groups. We have established limits for each of the indices, and sensitivity (S), specificity(E), positive and negative predictive values and test efficiency were determined. BTM was better distinguished from the other groups by RBC (above 5 millions/mL) and Englands index (<6), both with S=82.3% and E of 82.8%. A RDW above 16% was the best index of AF, with S=69.2% and E= 80.7%. CONCLUSIONS: Presumptive diagnosis of AF is troublesome when using RBC indices; diagnosis should be based on complete laboratory evaluation. Elevated RBC levels, specially above 5 millions/mL, in anemic patients with microcytosis are important indicatives of BTM, and confirmatory tests are suggested.

Non-HFE hemochromatosis

Hereditary hemochromatosis (HH) is an autosomal recessive disorder classically related to HFE mutations. However, since 1996, it is known that HFE mutations explain about 80% of HH cases, with the remaining around 20% denominated non-HFE hemochromatosis. Nowadays, four main genes are implicated in the pathophysiology of clinical syndromes classified as non-HFE hemochromatosis: hemojuvelin (HJV, type 2Ajuvenile HH), hepcidin (HAMP, type 2B juvenile HH), transferrin receptor 2 (TFR2, type 3 HH) and ferroportin (SLC40A1, type 4 HH). The aim of this review is to explore molecular, clinical and management aspects of non-HFE hemochromatosis.

Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: results of a 1-yr Phase 2 study

This open‐label, prospective, phase 2 study evaluated the safety and efficacy of deferasirox (10 ± 5 mg/kg/d) in patients with hereditary hemochromatosis (HH) and iron overload refractory to or intolerant of phlebotomy. Ten patients were enrolled and all completed the 12‐month treatment period. There were significant decreases from baseline to end of study (i.e., 12 months) in median serum ferritin (P < 0.001), mean transferrin saturation (P < 0.05), median liver iron concentration (P < 0.001), and mean alanine aminotransferase (P < 0.05). The median time to achieve serum ferritin reduction ≥50% compared to baseline was 7.53 months. The most common adverse events were mild, transient diarrhea (n = 5) and nausea (n = 2). No patient experienced an increase in serum creatinine that exceeded the upper limit of normal. These data confirm that deferasirox was well tolerated and effective in reducing iron burden in patients with hereditary hemochromatosis and could be a safe alternative to phlebotomy in selected patients.