Sandra F.M. Gualandro

Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease

Recent studies have recognised the importance of pulmonary hypertension (PH) in sickle cell disease (SCD). The aim of this study was to determine the prevalence and prognostic impact of PH and its features in patients with SCD. 80 patients with SCD underwent baseline clinical evaluation, laboratory testing, 6-min walk tests (6MWTs) and echocardiography. Patients with a peak tricuspid regurgitant jet velocity (TRV) of ≥2.5 m·s−1 were further evaluated through right heart catheterisation (RHC) to assure the diagnosis of PH. Our study evidenced a 40% prevalence of patients with elevated TRV at echocardiography. RHC (performed in 25 out of 32 patients) confirmed PH in 10% (95% CI 3.4–16.5%) of all patients, with a prevalence of post-capillary PH of 6.25% (95% CI 0.95–11.55%) and pre-capillary PH of 3.75% (95% CI -0.4–7.9%). Patients with PH were older, had worse performance in 6MWTs, and more pronounced anaemia, haemolysis and renal dysfunction. Survival was shorter in patients with PH. Our study reinforced the use of echocardiography as a screening tool for PH in SCD and the mandatory role of RHC for proper diagnosis. Our findings confirmed the prognostic significance of PH in SCD as its association to pronounced haemolytic profile.

Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease

Background The up‐regulation of P‐selectin in endothelial cells and platelets contributes to the cell–cell interactions that are involved in the pathogenesis of vaso‐occlusion and sickle cell–related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P‐selectin, were evaluated in patients with sickle cell disease. Methods In this double‐blind, randomized, placebo‐controlled, phase 2 trial, we assigned patients to receive low‐dose crizanlizumab (2.5 mg per kilogram of body weight), high‐dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell–related pain crises with high‐dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient‐reported outcomes were also assessed. Results A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high‐dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high‐dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high‐dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high‐dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high‐dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active‐treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. Conclusions In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell–related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361.)

Evaluation of 100 patients with dementia in São Paulo, Brazil : correlation with socioeconomic status and education

One hundred consecutive outpatients with dementia were prospectively studied to investigate the diagnoses of dementing diseases and to correlate these diagnoses with socioeconomic status and with education. Alzheimer disease was the most common cause of dementia (54%), followed by vascular dementia (20%). Eight patients presented with potentially reversible causes of dementia. These frequencies are similar to those reported by case register studies from Western Europe and the United States. We did not find differences in the frequencies of the dementing diseases according to socioeconomic status or education. Alzheimer disease was the most common cause of dementia in all socioeconomic classes. Potentially reversible dementias, vascular dementias, and other secondary dementias were not more frequent in the lower socioeconomic strata. There was a trend to a higher frequency of vascular dementia among patients with less education, but this was not statistically significant.

Two new mutations in the HIF2A gene associated with erythrocytosis

Congenital or familial erythrocytosis/polycythemia can have many causes, and an emerging cause is genetic disruption of the oxygen‐sensing pathway that regulates the Erythropoietin (EPO) gene. More specifically, recent studies have identified erythrocytosis‐associated mutations in the HIF2A gene, which encodes for Hypoxia Inducible Factor‐2α (HIF‐2α), as well as in two genes that encode for proteins that regulate it, Prolyl Hydroxylase Domain protein 2 (PHD2) and the von Hippel Lindau tumor suppressor protein (VHL). We report here the identification of two new heterozygous HIF2A missense mutations, M535T, and F540L, both associated with erythrocytosis. Met‐535 has previously been identified as a residue mutated in other patients with erythrocytosis; although, the mutation of this particular residue to Thr has not been reported. In contrast, Phe‐540 has not been reported as a residue mutated in erythrocytosis, and we present evidence here that this mutation impairs interaction of HIF‐2α with both VHL and PHD2. Am. J. Hematol. 2012.

Complicações cardiopulmonares das doenças falciformes

The lung is a major target organ for acute and chronic complications in sickle cell disease. Acute chest syndrome is the second most common cause of hospital admission resulting in considerable morbidity and mortality. The mainstay of successful treatment remains high quality supportive care. Fluid management, analgesia, oxygenation, bronchodilators, incentive spirometry and judicious use of transfusion therapy are essential elements of supportive care management. Pulmonary hypertension (PHT) has emerged as one of the most frequent and serious complications in these patients. The pulmonary artery pressure should be evaluated periodically by echocardiography. If the PHT diagnosis is positive the use of hydroxiurea, anticoagulation, transfusions and oxygen therapy should be considered. Cardiac manifestations are common including enlargement of the heart, myocardial ischaemia, ventricular dysfunction and cor pulmonale. The management of these complications follows the current guidelines.

Ethnic Differences in Cerebral Venous Thrombosis

Background: Cerebral venous thromboses (CVT) with distinct clinical presentations have been shown worldwide. However, there is little information regarding race-ethnic differences in this disease. Methods: We prospectively studied 50 CVT patients from Brazil, comparing clinical and laboratory data among white (W) and African-Brazilian (AB) patients. Results: Seventy percent of the patients were female, 26 W and 23 AB, mean age 34.7 years. Multiple sinus CVT, deep CVT and worse outcome were significantly more frequent in AB than in W patients. There was a trend towards a higher frequency of factor V Leiden and prothrombin mutation in W than in AB, and of protein C deficiency in AB. Conclusions: CVT was more severe in AB patients than in W patients. Race-ethnic differences may account for the heterogeneous distribution of inherited thrombophilia in this series.

RHD and RHCE genotyping by next-generation sequencing is an effective strategy to identify molecular variants within sickle cell disease patients

BACKGROUND The complexity of Rh genetic variation among sickle cell disease (SCD) patients is high. Conventional molecular assays cannot identify all genetic variants already described for the RH locus as well as foresee novel alleles. Sequencing RHD and RHCE is indicated to broaden the search for Rh genetic variants. AIMS To standardize the Next Generation Sequencing (NGS) strategy to assertively identify Rh genetic variants among SCD patients with serologic suspicion of Rh variants and evaluate if it can improve the transfusion support. METHODS Thirty-five SCD patients with unexplained Rh antibodies were enrolled. A NGS-based strategy was developed to genotype RHD and RHCE using gene-specific primers. Genotype and serological data were compared. RESULTS Data obtained from the NGS-based assay were gene-specific. Ten and 25 variant RHD and RHCE alleles were identified, respectively. Among all cases of unexplained Rh antibodies, 62% had been inaccurately classified by serological analysis and, of these, 73.1% were considered as relevant, as were associated with increased risk of hemolytic reactions and shortage of units suitable for transfusion. CONCLUSION The NGS assay designed to genotype RH coding regions was effective and accurate in identifying variants. The proposed strategy clarified the Rh phenotype of most patients, improving transfusion support.

Deficiência de ferro no idoso

Anemia e comum em idosos e e associada a significante morbidade e mortalidade. Mais de 10% dos individuos acima de 65 anos tem anemia. Com uma proporcao crescente da populacao mundial atingindo idade igual ou superior a 65 anos, a prevalencia de anemia certamente aumentara no futuro. O diagnostico precoce e importante para prevenir piora do quadro, diminuir progressao da doenca e melhorar a evolucao dos pacientes. Os criterios mais utilizados em estudos epidemiologicos para definir anemia em idosos sao os da OMS (hemoglobina<12 g/dL para mulheres e hemoglobina <13 g/dL para homens). Aproximadamente um terco dos idosos com anemia tem deficiencia de ferro, folato e/ou vitamina B12, um terco tem insuficiencia renal e/ou inflamacao cronica e o terco remanescente tem anemia inexplicada. A anemia ferropenica e microcitica e hipocromica e caracteriza-se por baixos niveis de ferritina serica, capacidade total de ligacao de ferro do plasma aumentada, saturacao da transferrina diminuida, concentracao do receptor soluvel da transferrina elevada e ausencia de ferro na medula ossea. E causada geralmente por perda de sangue pelo trato gastrointestinal devido a gastrite, ulceras, câncer de colo ou angiodisplasia. Anormalidades do trato gastrointestinal podem ser identificadas na maioria dos pacientes. Em alguns casos, ingestao ou absorcao inadequada de ferro pode contribuir para a anemia. Entretanto, em todos os casos deveria ser exaustivamente investigada e excluida perda de sangue antes de assumir que a deficiencia de ferro e devida a outras causas. O tratamento inclui parar o sangramento e repor o ferro.

Impact of allogeneic 2-RBC apheresis on iron stores of Brazilian blood donors

One limiting factor for automated two-red blood cells collections (2-RBC) is its potential iron depletion. We analyzed hematological parameters and iron balance before, two and four months after 2-RBC of 96 non-supplemented male donors. Four months after 2-RBC, ferritin level was significantly lower (P<0.01) than baseline levels and the number of donors who presented ferritin <30 ng/ml increased from 18 to 47. We concluded that four months was not sufficient for iron recuperation in the population studied. In an attempt to avoid iron depletion after 2-RBC, we recommend augmentation in the interval between blood donations and pre-donation ferritin measurement.

A associação anemia falciforme e hemoglobina fetal: [editorial]

403A anemia falciforme (AF) foi a primeira doenca mono-genica humana caracterizada a nivel molecular. Resulta deuma mutacao no gene da β-globina (HBB) que leva a subs-tituicao de acido glutâmico por valina na posicao 6 da cadeiada hemoglobina. As manifestacoes clinicas decorrem datendencia da hemoglobina anormal (HbS) se polimerizar noestado desoxigenado, deformando as celulas vermelhas, queassumem a caracteristica forma de foice.