Sickle cell hepatopathy with spur cell anemia.
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SUBMITTER: Rice L
PROVIDER: S-EPMC8493973 | biostudies-literature | 2021 Jul
REPOSITORIES: biostudies-literature
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Project description:Sickle cell anemia (SCA) is a severe, inherited hemoglobin disorder affecting 100,000 persons in the US and millions worldwide. Hydroxyurea, a once daily oral medication, has emerged as the primary disease-modifying therapy for SCA. The accumulated body of evidence over 30 years demonstrates that hydroxyurea is a safe and effective therapy for SCA, but hydroxyurea remains underutilized for a variety of reasons.In this review, we summarize the available evidence regarding the pharmacology, clinical, and laboratory benefits, and safety of hydroxyurea therapy for the treatment of SCA. The purpose of this review is to provide the reader a comprehensive understanding of hydroxyurea and to reinforce the fact that hydroxyurea is a safe and effective medication for the treatment of SCA.In our opinion, hydroxyurea therapy should be considered standard-of-care for SCA, representing an essential component of patient management. Early initiation and broader use of hydroxyurea will alter the natural history of SCA, so affected children can live longer and healthier lives. In addition, hydroxyurea use should be extended to low-resource settings such as sub-Saharan Africa, where the burden of SCA and the need for hydroxyurea is arguably the greatest.
| S-EPMC5868345 | biostudies-literature
Project description:Proper management of sickle cell anemia (SCA) begins with establishing the correct diagnosis early in life, ideally during the newborn period. The identification of affected infants by neonatal screening programs allows early initiation of prophylactic penicillin and pneumococcal immunizations, which help prevent overwhelming sepsis. Ongoing education of families promotes the early recognition of disease-released complications, which allows prompt and appropriate medical evaluation and therapeutic intervention. Periodic evaluation by trained specialists helps provide comprehensive care, including transcranial Doppler examinations to identify children at risk for primary stroke, plus assessments for other parenchymal organ damage as patients become teens and adults. Treatment approaches that previously highlighted acute vaso-occlusive events are now evolving to the concept of preventive therapy. Liberalized use of blood transfusions and early consideration of hydroxyurea treatment represent a new treatment paradigm for SCA management.
| S-EPMC3721270 | biostudies-literature
Project description:Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of sickle cell disease, an effect mediated by its exclusion from the sickle hemoglobin polymer. Fetal hemoglobin genes are genetically regulated, and the level of HbF and its distribution among sickle erythrocytes is highly variable. Some patients with sickle cell disease have exceptionally high levels of HbF that are associated with the Senegal and Saudi-Indian haplotype of the HBB-like gene cluster; some patients with different haplotypes can have similarly high HbF. In these patients, high HbF is associated with generally milder but not asymptomatic disease. Studying these persons might provide additional insights into HbF gene regulation. HbF appears to benefit some complications of disease more than others. This might be related to the premature destruction of erythrocytes that do not contain HbF, even though the total HbF concentration is high. Recent insights into HbF regulation have spurred new efforts to induce high HbF levels in sickle cell disease beyond those achievable with the current limited repertory of HbF inducers.
| S-EPMC3139383 | biostudies-literature
Project description:In the 100 years since sickle cell anemia (SCA) was first described in the medical literature, studies of its molecular and pathophysiological basis have been at the vanguard of scientific discovery. By contrast, the translation of such knowledge into treatments that improve the lives of those affected has been much too slow. Recent years, however, have seen major advances on several fronts. A more detailed understanding of the switch from fetal to adult hemoglobin and the identification of regulators such as BCL11A provide hope that these findings will be translated into genomic-based approaches to the therapeutic reactivation of hemoglobin F production in patients with SCA. Meanwhile, an unprecedented number of new drugs aimed at both the treatment and prevention of end-organ damage are now in the pipeline, outcomes from potentially curative treatments such as allogeneic hematopoietic stem cell transplantation are improving, and great strides are being made in gene therapy, where methods employing both antisickling β-globin lentiviral vectors and gene editing are now entering clinical trials. Encouragingly, after a century of neglect, the profile of the vast majority of those with SCA in Africa and India is also finally improving.
| S-EPMC7613509 | biostudies-literature
Project description:Fetal hemoglobin (HbF) can blunt the pathophysiology, temper the clinical course, and offer prospects for curative therapy of sickle cell disease. This review focuses on (1) HbF quantitative trait loci and the geography of β-globin gene haplotypes, especially those found in the Middle East; (2) how HbF might differentially impact the pathophysiology and many subphenotypes of sickle cell disease; (3) clinical implications of person-to-person variation in the distribution of HbF among HbF-containing erythrocytes; and (4) reactivation of HbF gene expression using both pharmacologic and cell-based therapeutic approaches. A confluence of detailed understanding of the molecular basis of HbF gene expression, coupled with the ability to precisely target by genomic editing most areas of the genome, is producing important preliminary therapeutic results that could provide new options for cell-based therapeutics with curative intent.
| S-EPMC7685210 | biostudies-literature
Project description:More than 20 years ago, clinical trials and federal grant support for sickle cell disease (SCD) research were not on par with support for other genetic diseases. Faced with the opportunity to spur research and advance treatments for SCD, and at the recommendation of advisors, the Doris Duke Charitable Foundation (DDCF) offered an SCD research funding opportunity starting in 2009 through its Innovations in Clinical Research Awards (ICRA) program. Twenty-eight new grants of $450 000 for direct costs over 3 years and 7 renewals were awarded, for a total investment of $17 million. Only about half the research teams garnered follow-on funding directly related to their ICRA projects, but the financial return on the research investment was substantial (∼4 times the original $17 million or 300%). All but 1 of the ICRA investigative teams published original research reports that acknowledged DDCF as a source of funding; the median number of publications per team was 3. Major innovations in the diagnosis and treatment of SCD included but were not limited to a demonstration that genetic modification of BCL11A enhancer is a potentially important treatment modality, establishment that plerixafor mobilization is safe and effective for those with SCD, development and validation of a new diagnostic called SCD BioChip, and evidence that hydroxyurea treatment is safe and efficacious in African children. These outcomes show that relatively small research grants can have a substantial return on investment and result in significant advances for a disease such as SCD.
| S-EPMC8679676 | biostudies-literature
Project description:ObjectiveTo ascertain the prevalence of and risk factors for obstructive sleep apnea syndrome (OSAS) in children with sickle cell anemia (SCA).MethodsCross-sectional baseline data were analyzed from the Sleep and Asthma Cohort Study, a multicenter prospective study designed to evaluate the contribution of sleep and breathing abnormalities to SCA-related morbidity in children ages 4 to 18 years, unselected for OSAS symptoms or asthma. Multivariable logistic regression assessed the relationships between OSAS status on the basis of overnight in-laboratory polysomnography and putative risk factors obtained from questionnaires and direct measurements.ResultsParticipants included 243 children with a median age of 10 years; 50% were boys, 99% were of African heritage, and 95% were homozygous for β(S) hemoglobin. OSAS, defined by obstructive apnea hypopnea indices, was present in 100 (41%) or 25 (10%) children at cutpoints of ≥1 or ≥5, respectively. In univariate analyses, OSAS was associated with higher levels of habitual snoring, lower waking pulse oxygen saturation (Spo2), reduced lung function, less caretaker education, and non-preterm birth. Lower sleep-related Spo2 metrics were also associated with higher obstructive apnea hypopnea indices. In multivariable analyses, habitual snoring and lower waking Spo2 remained risk factors for OSAS in children with SCA.ConclusionsThe prevalence of OSAS in children with SCA is higher than in the general pediatric population. Habitual snoring and lower waking Spo2 values, data easily obtained in routine care, were the strongest OSAS risk factors. Because OSAS is a treatable condition with adverse health outcomes, greater efforts are needed to screen, diagnose, and treat OSAS in this high-risk, vulnerable population.
| S-EPMC4187233 | biostudies-literature
Project description:Severe chronic anemia is an independent predictor of overt stroke, white matter damage, and cognitive dysfunction in the elderly. Severe anemia also predisposes to white matter strokes in young children, independent of the anemia subtype. We previously demonstrated symmetrically decreased white matter (WM) volumes in patients with sickle cell disease (SCD). In the current study, we investigated whether patients with non-sickle anemia also have lower WM volumes and cognitive dysfunction. Magnetic Resonance Imaging was performed on 52 clinically asymptomatic SCD patients (age?=?21.4 ± 7.7; F?=?27, M?=?25; hemoglobin = 9.6 ± 1.6 g/dL), 26 non-sickle anemic patients (age?=?23.9 ± 7.9; F?=?14, M?=?12; hemoglobin?=?10.8 ± 2.5 g/dL) and 40 control subjects (age?=?27.7 ±?11.3; F?=?28, M?=?12; hemoglobin?=?13.4 ± 1.3 g/dL). Voxel-wise changes in WM brain volumes were compared to hemoglobin levels to identify brain regions that are vulnerable to anemia. White matter volume was diffusely lower in deep, watershed areas proportionally to anemia severity. After controlling for age, sex, and hemoglobin level, brain volumes were independent of disease. WM volume loss was associated with lower Full Scale Intelligence Quotient (FSIQ; P =?.0048; r2 =?.18) and an abnormal burden of silent cerebral infarctions (P =?.029) in males, but not in females. Hemoglobin count and cognitive measures were similar between subjects with and without white-matter hyperintensities. The spatial distribution of volume loss suggests chronic hypoxic cerebrovascular injury, despite compensatory hyperemia. Neurocognitive consequences of WM volume changes and silent cerebral infarction were strongly sexually dimorphic. Understanding the possible neurological consequences of chronic anemia may help inform our current clinical practices.
| S-EPMC6857783 | biostudies-literature
Project description:BackgroundThe high prevalence of airway hyperresponsiveness (AHR) among children with sickle cell anemia (SCA) remains unexplained.MethodsTo determine the relationship between AHR, features of asthma, and clinical characteristics of SCA, we conducted a multicenter, prospective cohort study of children with SCA. Dose response slope (DRS) was calculated to describe methacholine responsiveness, because 30% of participants did not achieve a 20% decrease in FEV1 after inhalation of the highest methacholine concentration, 25 mg/mL. Multiple linear regression analysis was done to identify independent predictors of DRS.ResultsMethacholine challenge was performed in 99 children with SCA aged 5.6 to 19.9 years (median, 12.8 years). Fifty-four (55%) children had a provocative concentration of methacholine producing a 20% decrease in FEV1<4 mg/mL. In a multivariate analysis, independent associations were found between increased methacholine responsiveness and age (P<.001), IgE (P=.009), and lactate dehydrogenase (LDH) levels (P=.005). There was no association between methacholine responsiveness and a parent report of a doctor diagnosis of asthma (P=.986). Other characteristics of asthma were not associated with methacholine responsiveness, including positive skin tests to aeroallergens, exhaled nitric oxide, peripheral blood eosinophil count, and pulmonary function measures indicating airflow obstruction.ConclusionsIn children with SCA, AHR to methacholine is prevalent. Younger age, serum IgE concentration, and LDH level, a marker of hemolysis, are associated with AHR. With the exception of serum IgE, no signs or symptoms of an allergic diathesis are associated with AHR. Although the relationship between methacholine responsiveness and LDH suggests that factors related to SCA may contribute to AHR, these results will need to be validated in future studies.
| S-EPMC3047289 | biostudies-literature
Project description:Background and objectiveSusceptibility to encapsulated bacteria is well known in sickle cell disease (SCD). Hydroxyurea use is common in adults and children with SCD, but little is known about hydroxyurea's effects on immune function in SCD. Because hydroxyurea inhibits ribonucleotide reductase, causing cell cycle arrest at the G1-S interface, we postulated that hydroxyurea might delay transition from naive to memory T cells, with inhibition of immunologic maturation and vaccine responses.MethodsT-cell subsets, naive and memory T cells, and antibody responses to pneumococcal and measles, mumps, and rubella vaccines were measured among participants in a multicenter, randomized, double-blind, placebo-controlled trial of hydroxyurea in infants and young children with SCD (BABY HUG).ResultsCompared with placebo, hydroxyurea treatment resulted in significantly lower total lymphocyte, CD4, and memory T-cell counts; however, these numbers were still within the range of historical healthy controls. Antibody responses to pneumococcal vaccination were not affected, but a delay in achieving protective measles antibody levels occurred in the hydroxyurea group. Antibody levels to measles, mumps, and rubella showed no differences between groups at exit, indicating that effective immunization can be achieved despite hydroxyurea use.ConclusionsHydroxyurea does not appear to have significant deleterious effects on the immune function of infants and children with SCD. Additional assessments of lymphocyte parameters of hydroxyurea-treated children may be warranted. No changes in current immunization schedules are recommended; however, for endemic disease or epidemics, adherence to accelerated immunization schedules for the measles, mumps, and rubella vaccine should be reinforced.
| S-EPMC4179098 | biostudies-literature