Joao Ricardo Friedrisch

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.)

High prevalence of anemia in children and adult women in an urban population in southern Brazil.

This population-based study was designed to detect the prevalence of anemia in a healthy population of children (18 months to 7 years) and women (14 to 30 years) tested in 2006–2007 in the state of Rio Grande do Sul, Brazil as part of an effort to tackle this massive problem that still affects so many people in the XXI century. Anemia was defined according to the WHO. Capillary blood was measured and socioeconomic status was determined according to the Brazilian Association of Market Research Agencies. The median prevalence of anemia in 2198 children was 45.4% and in 1999 women 36.4%. Anemia decreased with age during childhood; although significantly more prevalent in lower classes individuals, it was also high in the upper classes. There are indirect evidences that the lack of iron supplementation and/or iron fortified food may play a role in it. Professionals and society wise measures of education have to be implemented in order to address possible biologic factors involved in childhood psychosocial development in southern Brazil.

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.

Length of treatment and dose as determinants of mutagenicity in sickle cell disease patients treated with hydroxyurea.

Hydroxyurea (HU) is an antineoplastic drug widely used in the clinical management of patients with sickle cell disease (SCD), and many questions related with its use remain unresolved. Given the severity of SCD, HU benefits, although not thoroughly confirmed, seem to outweigh its potential carcinogenicity. This study aimed to assess the genotoxicity associated with HU dose and treatment length by evaluating mutagenicity in patients with SCD treated with HU (SCHU) using the cytokinesis-block micronucleus assay (CBMN) in white cells. The study was conducted with 35 individuals in the SCHU group and 34 controls matched according to age, sex and smoking habit. CBMN results showed an increase (p=0.032) in the number of micronuclei (MN), but not of nucleoplasmic bridges (NPB) or nuclear buds (NBUD) in the SCHU group. The increased frequency of MN in the SCHU group was significantly correlated with treatment length and final HU dose, which confirms that patients with SCD treated with HU should be carefully monitored to reduce the risk of carcinogenicity.

The role of BCL11A and HMIP-2 polymorphisms on endogenous and hydroxyurea induced levels of fetal hemoglobin in sickle cell anemia patients from southern Brazil.

High levels of fetal hemoglobin (HbF) reduce sickle cell anemia (SCA) morbidity and mortality. HbF levels vary considerably and there is a strong genetic component that influences HbF production. Genetic polymorphisms at three quantitative trait loci (QTL): Xmn1-HBG2, HMIP-2 and BCL11A, have been shown to influence HbF levels and disease severity in SCA. Hydroxyurea (HU) is a drug that increases HbF. We investigated the influence of single nucleotide polymorphisms (SNPs) at the Xmn1-HBG2 (rs7482144); BCL11A (rs1427407, rs4671393 and rs11886868); and HMIP-2 (rs9399137 and rs9402686) loci on baseline and HU-induced HbF levels in 111 HbSS patients. We found that both BCL11A and HMIP-2 were associated with increased endogenous levels of HbF. Interestingly, we also found that BCL11A was associated with higher induction of HbF with HU. This effect was independent of the effect of BCL11A on baseline HbF levels. Additional studies will be needed to validate these findings and explain the ample inter-individual variations in HbF levels at baseline and HU-induced in patients with SCA.

Prevalência de talassemias e hemoglobinas variantes em pacientes com anemia não ferropênica

To establish the frequency of hemoglobinopathies and thalassemias in patients with non-ferropenic anemia, 58 patients with confirmed non-ferropenic anemia and 235 non-anemic individuals (control group) were studied. All samples were obtained from the Hospital de Clinicas de Porto Alegre (HCPA), Rio Grande do Sul, Brazil. The techniques used were Alkaline pH cellulose acetate electrophoresis and cytological screening of Hb, Hl, HPLC, hemogram and ferritin. The data analysis showed that 63% of the patients with non-ferropenic anemia carried some type of inherited anemia: 25.9% of heterozygous a-thalassemia, 32.8% of heterozygous b-thalassemia, 3.4% of heterozygosity for hemoglobin S (Hb AS) and 1.7% of homozygosity for hemoglobin C (Hb CC). Inherited anemias were detected in 14.1% of the control group: 11.5% of a-thalassemia, 0.9% of b-thalassemia, 1.3% of heterozygosity for hemoglobin S (Hb AS) and 0.4% of heterozygosity for hemoglobin C (Hb AC). The results obtained showed that the prevalence of variant thalassemias and hemoglobins in the control group is coincident with that described in the literature. However, physicians and health services should be informed about the overwhelming prevalence of these inherited homeopathies in individuals with non-ferropenic anemia, due to its importance in the definitive diagnosis of anemia and for the correct therapeutic proceedings.

Prophylactic Iron Supplementation in Pregnancy: A Controversial Issue:

In our world today, iron deficiency (ID) is the most frequent nutritional deficiency and it is being considered as an epidemic public health crisis. Women of reproductive age and infants are at particular risk of ID, especially in underdeveloped countries. During pregnancy, iron deficiency anemia is a specific risk factor associated with negative maternal and perinatal outcomes. Many countries have iron supplementation (IS) programs—as recommended by the World Health Organization—during pregnancy; however, IS clinical benefits and risks are unclear. This review aims to discuss the threats and benefits of routine IS on maternal and infant outcomes.

Intravenous ferric carboxymaltose for the treatment of iron deficiency anemia.

Nutritional iron deficiency anemia is the most common deficiency disorder, affecting more than two billion people worldwide. Oral iron supplementation is usually the first choice for the treatment of iron deficiency anemia, but in many conditions, oral iron is less than ideal mainly because of gastrointestinal adverse events and the long course needed to treat the disease and replenish body iron stores. Intravenous iron compounds consist of an iron oxyhydroxide core, which is surrounded by a carbohydrate shell made of polymers such as dextran, sucrose or gluconate. The first iron product for intravenous use was the 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 use intravenous iron for the treatment of iron deficiency anemia over many years. Intravenous ferric carboxymaltose is a stable complex with the advantage of being non-dextran-containing and a very low immunogenic potential and therefore not predisposed to anaphylactic reactions. Its properties permit the administration of large doses (15 mg/kg; maximum of 1000 mg/infusion) in a single and rapid session (15-minute infusion) without the requirement of a test dose. The purpose of this review is to discuss some pertinent issues in relation to the history, pharmacology, administration, efficacy, and safety profile of ferric carboxymaltose in the treatment of patients with iron deficiency anemia.

Cirurgia e anestesia na doença falciforme

Individuals with sickle cell disease (SCD) have special perioperative concerns that must be considered before their anesthesia and surgery. During the perioperative period, these individuals are at risk for vaso-occlusive events, including acute chest syndrome, pain crises, priapism and stroke because they are exposed to hypoxia, acidosis, hypothermia, infections and hypovolemia. Several suggestions to reduce risk have been made, including a structural multidisciplinary approach, paying special attention to hydration and oxygenation, postoperative respiratory care and selection of less aggressive or extensive surgical procedures. Even with meticulous care, approximately 25% to 30% of individuals with SCD will have a postoperative complication. This article provides readers with information about the role of surgery in SCD and the measures that should be taken to ensure patients are well cared for in the perioperative period.

Long-term follow-up of kidney allografts in patients with sickle cell hemoglobinopathy

Embora a anemia falciforme e as sindromes falciformes frequentemente causem varias alteracoes funcionais renais, nao e comum a insuficiencia renal terminal. Nestes casos, o transplante renal e uma alternativa que se acompanha de resultados comparaveis aos obtidos em receptores sem hemoglobinopatias. Esta estrategia terapeutica tem sido, no entanto, pouco relatada para portadores de hemoglobinopatia SC. Este relato descreve a evolucao de dois pacientes portadores de hemoglobinopatia SC que foram submetidos ao transplante renal. No momento do transplante ambos apresentavam severa anemia e crises dolorosas frequentes. Os pacientes evoluiram com boa funcao do enxerto, parâmetros hematologicos quase normais e praticamente assintomaticos do ponto de vista da hemoglobinopatia, treze e oito anos apos o transplante. Estes casos ilustram que a insuficiencia renal terminal causada pela hemoglobinopatia SC pode ser tratada com sucesso pelo transplante renal, nao so do ponto de vista renal, propriamente dito, mas tambem em termos de sua doenca hematologica.