Background Sickle cell disease (SCD) may cause several impacts to patients and the whole society. About 4% of the population has the sickle cell trait in Brazil, and 60,000 to 100,000 have SCD. ...However, despite recognizing the significant burden of disease, little is known about SCD costs. Objective To estimate SCD societal costs based on disease burden modelling, under Brazilian societal perspective. Methods A disease burden model was built considering the societal perspective and a one-year time horizon, including direct medical and indirect costs (morbidity and mortality). The sum of life lost and disability years was considered to estimate disability-adjusted life years (DALYs). Data from a public database (DATASUS) and the prevalence obtained from literature or medical experts were used to define complications prevalence and duration. Costs were defined using data from the Brazilian public healthcare system table of procedures and medications (SIGTAP) and the human capital method. Results Annual SCD cost was 413,639,180 USD. Indirect cost accounted for the majority of burden (70.1% of the total; 290,158,365 USD vs 123,480,816 USD). Standard of care and chronic complications were the main source of direct costs among adults, while acute conditions were the main source among children. Vaso-occlusive crisis represented the complication with the highest total cost per year in both populations, 11,400,410 USD among adults and 11,510,960 USD among children. Conclusions SCD management may impose an important economic burden on Brazilian society that may reach more than 400 million USD per year.
The cell adhesion molecule P‐selectin plays a key role in the pathogenesis of a vaso‐occlusive crisis (VOC) in patients with sickle cell disease (SCD). In the double‐blind, placebo‐controlled phase 2 ...SUSTAIN study, crizanlizumab (humanized, anti‐P‐selectin monoclonal antibody) 5 mg/kg significantly lowered the rate of VOC in patients with SCD by 45% vs placebo. In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. The primary endpoint was the annual rate of VOC with crizanlizumab vs placebo. This post hoc descriptive analysis evaluated the proportion of patients who did not experience a VOC during the study in the following subgroups: VOCs in the year prior to study entry (2‐4/5‐10), SCD genotype (HbSS/non‐HbSS), and concomitant hydroxyurea use (yes/no). More patients were VOC event‐free in the crizanlizumab 5 mg/kg arm than in the placebo arm, including those with more frequent prior VOCs (ie, 5‐10; 28.0% vs 4.2%), the HbSS genotype (31.9% vs 17.0%) and/or using concomitant hydroxyurea (33.3% vs 17.5%). Further analyses of secondary endpoints demonstrated that crizanlizumab treatment significantly increased time‐to‐first VOC vs placebo in these subgroups. The rates of treatment‐emergent adverse events were similar between treatment arms across all subgroups. This post hoc analysis of SUSTAIN shows that in patients with a high number of prior VOCs, on concomitant hydroxyurea and/or with the HbSS genotype, crizanlizumab treatment increases the likelihood of patients being VOC event‐free and delays time‐to‐first VOC.
Paroxysmal nocturnal hemoglobinuria is a chronic, multi-systemic, progressive and life-threatening 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.
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.
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.
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.
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.
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.
Hemochromatosis is currently characterized by the iron overload caused by hepcidin deficiency. Large advances in the knowledge on the hemochromatosis pathophysiology have occurred due to a better ...understanding of the protein of the iron metabolism, the genetic basis of hemochromatosis and of other iron overload diseases or conditions which can lead to this phenotype. In the present review, the main aims are to show updates on hemochromatosis and to report a practical set of therapeutic recommendations for the human factors engineering protein (HFE) hemochromatosis for the p.Cys282Tyr (C282Y/C282Y) homozygous genotype, elaborated by the Haemochromatosis International Taskforce.
The aim of this study was to describe maternal and perinatal outcomes in pregnant women with sickle cell disease (SCD) followed at Santa Casa de Sao Paulo over a 10-year period (between 2010 and ...2019).
Fifty-five records of pregnancies were analyzed among 35 women with SCD.
Among 29 newborns, 19 (65.5%) were full-term and 10 pre-term; 24 (82.7%) caesareans and 5 (17.2%) natural births were observed. The mean gestational age at birth and mother`s age were 36.6 weeks (30–40) and 26.7 years (17–39), respectively. No maternal death was observed. The main maternal obstetric and non-obstetric complications were: pre-eclampsia and gestational diabetes, and vaso-occlusive crisis, urinary tract infection and acute chest syndrome, respectively. Twenty-six (47.0%) fetal deaths were observed, 24 being intrauterine fetal (14 early abortions, 10 late abortions and 2 stillbirths). Regarding the red blood cell transfusion history, 40 (72.7%) out of 55 pregnancies received transfusion. Pregnant women who received 6 or more transfusions throughout pregnancy had a significantly lower number of abortions, i.e., no cases of early abortion and only 1 case of late abortion, versus 14 and 9 cases in pregnancies with 0–5 transfusions, respectively. Despite advances in the management of SCD, pregnant women with SCD (particularly those with HbSS) are at a high risk for maternal and fetal complications, even though they are followed in reference centers.
The lower risk of intrauterine fetal death for those women who received more transfusions throughout pregnancy observed in the current study leads us once more to raise the need for prospective, multicenter, randomized trials to determine whether the potential benefits balance the risks of prophylactic transfusions.
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