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Examination of Reticulocytosis among Chronically Transfused Children with Sickle Cell Anemia.

ABSTRACT: Sickle cell anemia (SCA) is an inherited hemolytic anemia with compensatory reticulocytosis. Recent studies have shown that increased levels of reticulocytosis during infancy are associated with increased hospitalizations for SCA sequelae as well as cerebrovascular pathologies. In this study, absolute reticulocyte counts (ARC) measured prior to transfusion were analysed among a cohort of 29 pediatric SCA patients receiving chronic transfusion therapy (CTT) for primary and secondary stroke prevention. A cross-sectional flow cytometric analysis of the reticulocyte phenotype was also performed. Mean duration of CTT was 3.1 ± 2.6 years. Fifteen subjects with magnetic resonance angiography (MRA) -vasculopathy had significantly higher mean ARC prior to initiating CTT compared to 14 subjects without MRA-vasculopathy (427.6 ± 109.0 K/μl vs. 324.8 ± 109.2 K/μl, p<0.05). No significant differences in hemoglobin or percentage sickle hemoglobin (HbS) were noted between the two groups at baseline. Reticulocyte phenotyping further demonstrated that the percentages of circulating immature [CD36(+), CD71(+)] reticulocytes positively correlated with ARC in both groups. During the first year of CTT, neither group had significant reductions in ARC. Among this group of children with SCA, cerebrovasculopathy on MRA at initiation of CTT was associated with increased reticulocytosis, which was not reduced after 12 months of transfusions.

SUBMITTER: Kaushal M

PROVIDER: S-EPMC4845996 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Liver iron concentration measurements by MRI in chronically transfused children with sickle cell anemia: baseline results from the TWiTCH trial.

Project description:Noninvasive, quantitative, and accurate assessment of liver iron concentration (LIC) by MRI is useful for patients receiving transfusions, but R2 and R2* MRI techniques have not been systematically compared in sickle cell anemia (SCA). We report baseline LIC results from the TWiTCH trial, which compares hydroxyurea with blood transfusion treatment for primary stroke prophylaxis assessed by transcranial Doppler sonography in pediatric SCA patients. Liver R2 was collected and processed using a FDA-approved commercial process (FerriScan®), while liver R2* quality control and processing were performed by a Core Laboratory blinded to clinical site and patient data. Baseline LIC studies using both MRI techniques were available for 120 participants. LICR2* and LICR2 results were highly correlated (r(2) = 0.93). A proportional bias of LIC(R2*)/LIC(R2), decreasing with average LIC, was observed. Systematic differences between LICR2* and LICR2 were also observed by MRI manufacturer. Importantly, LICR2* and LICR2 estimates had broad 95% limits of agreement with respect to each other. We recommend LICR2 and LICR2* not be used interchangeably in SCA patients to follow individual patient trends in iron burden.

| S-EPMC4546569 | biostudies-literature

Airway hyperresponsiveness in children with sickle cell anemia.

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

Antibiotic Prophylaxis for Children With Sickle Cell Anemia.

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| S-EPMC7252515 | biostudies-literature

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| S-EPMC8158763 | biostudies-literature

Whole Blood Transcriptome Analysis in Children with Sickle Cell Anemia.

Project description:Whole transcriptome RNA-sequencing was performed to quantify RNA expression changes in whole blood samples collected from steady state sickle cell anemia (SCA) and control subjects. Pediatric SCA and control subjects were recruited from Atlanta (GA)-based hospital(s) systems and consented for RNA sequencing. RNA sequencing was performed on an Ion Torrent S5 sequencer, using the Ion Total RNA-seq v2 protocol. Data were aligned to the hg19 reference genome and analyzed in the Partek Genomics studio package (v7.0). 223 genes were differentially expressed between SCA and controls (± 1.5 fold change FDR p < 0.001) and 441 genes show differential transcript expression (± 1.5 fold FDR p < 0.001). Differentially expressed RNA are enriched for hemoglobin associated genes and ubiquitin-proteasome pathway genes. Further analysis shows higher gamma globin gene expression in SCA (33-fold HBG1 and 49-fold HBG2, both FDR p < 0.05), which did not correlate with hemoglobin F protein levels. eQTL analysis identified SNPs in novel non-coding RNA RYR2 gene as having a potential regulatory role in HBG1 and HBG2 expression levels. Gene expression correlation identified JHDM1D-AS1(KDM7A-DT), a non-coding RNA associated with angiogenesis, enhanced GATA1 and decreased JAK-STAT signaling to correlate with HBG1 and HBG2 mRNA levels. These data suggest novel regulatory mechanisms for fetal hemoglobin regulation, which may offer innovative therapeutic approaches for SCA.

| S-EPMC8793691 | biostudies-literature

Genetic predictors for stroke in children with sickle cell anemia.

Project description:Stroke is a devastating complication of sickle cell anemia (SCA), affecting 5% to 10% of patients before adulthood. Several candidate genetic polymorphisms have been proposed to affect stroke risk, but few have been validated, mainly because previous studies were hampered by relatively small sample sizes and the absence of additional patient cohorts for validation testing. To verify the accuracy of proposed genetic modifiers influencing stroke risk in SCA, we performed genotyping for 38 published single nucleotide polymorphisms (SNPs), as well as α-thalassemia, G6PD A(-) variant deficiency, and β-globin haplotype in 2 cohorts of children with well-defined stroke phenotypes (130 stroke, 103 nonstroke). Five polymorphisms had significant influence (P < .05): SNPs in the ANXA2, TGFBR3, and TEK genes were associated with increased stroke risk, whereas α-thalassemia and a SNP in the ADCY9 gene were linked with decreased stroke risk. Further investigation at these genetic regions may help define mutations that confer stroke risk or protection in children with SCA.

| S-EPMC3123027 | biostudies-literature

[Infectious complications after surgical splenectomy in children with sickle cell anemia disease].

Project description:To evaluate the frequency of infectious complications in children with sickle cell disease (SCD) after surgical splenectomy for acute splenic sequestration crisis.Retrospective cohort of children with SCD who were born after 2002 and were regularly monitored until July 2013. Patients were divided into two groups: cases (children with SCD who underwent surgical splenectomy after an episode of splenic sequestration) and controls (children with SCD who did not have splenic sequestration and surgical procedures), in order to compare the frequency of invasive infections (sepsis, meningitis, bacteremia with positive blood cultures, acute chest syndrome and/or pneumonia) by data collected from medical records. Data were analyzed by descriptive statistical analysis.44 patients were included in the case group. The mean age at the time of splenectomy was 2.6 years (1-6.9 years) and the mean postoperative length of follow-up was 6.1 years (3.8-9.9 years). The control group consisted of 69 patients with a mean age at the initial follow-up visit of 5.6 months (1-49 months) and a mean length of follow-up of 7.2 years (4-10.3 years). All children received pneumococcal conjugate vaccine. No significant difference was observed between groups in relation to infections during the follow-up.Surgical splenectomy in children with sickle cell disease that had splenic sequestration did not affect the frequency of infectious complications during 6 years of clinical follow-up.

| S-EPMC4516367 | biostudies-other

Hemodynamic responses to visual stimulation in children with sickle cell anemia.

Project description:Blood oxygenation level-dependent (BOLD) and cerebral blood flow (CBF)-based functional magnetic resonance imaging (fMRI) were used to measure primary visual cortex responses to photic stimulation in 23 children (12.4 ?± ?0.7 years old) with sickle cell anemia (SCA) and 21 clinical controls (11? ±? 1.0 years old). The objectives were to investigate the effect of SCA on detection of brain activation with fMRI and to explore the relationship between fMRI responses and global cognitive function. The BOLD responses were diminished in children with SCA. Clinical indicators of disease severity were greatest in patients without detectable visual cortex activation, but blood hemoglobin concentration and resting CBF were not predictive of BOLD signal amplitude in the SCA patients. Unexpectedly, the BOLD signal amplitude was positively associated (r(s)? ?? 0.8, p? ? ?0.05) with Wechsler Abbreviated Scale of Intelligence scores, suggesting that fMRI may help clarify medical, hemodynamic, and neural factors that mediate adverse effects of SCA on neurocognitive function.

| S-EPMC3620037 | biostudies-literature

Factors predicting future ACS episodes in children with sickle cell anemia.

Project description:While a doctor-diagnosis of asthma is associated with an increased risk of pain and acute chest syndrome (ACS) in children with sickle cell anemia (SCA), little is known about the relationship between specific asthma characteristics and clinical factors and future morbidity in children with SCA. We evaluated the relationship between (i) asthma risk factors at the time of a clinical visit (respiratory symptoms, maternal history of asthma, allergy skin tests, spirometry results) and (ii) the known risk factor of ACS early in life, on prospective pain and ACS episodes in a cohort of 159 children with SCA followed from birth to a median of 14.7 years. An ACS episode prior to 4 years of age, (incidence rate ratio [IRR] = 2.84; P < 0.001], female gender (IRR = 1.80; P = 0.009), and wheezing causing shortness of breath (IRR = 1.68; P = 0.042) were associated with future ACS rates. We subsequently added spirometry results (obstruction defined as FEV1 /FVC less than the lower limits of normal; and bronchodilator response, FEV1 ? 12%) and prick skin test responses to the model. Only ? 2 positive skin tests had a significant effect (IRR 1.87; P = 0.01). Thus, early in life ACS events, wheezing causing shortness of breath, and ? 2 positive skin tests predict future ACS events.

| S-EPMC4866602 | biostudies-literature

Acute silent cerebral ischemic events in children with sickle cell anemia.

Project description:BackgroundIrregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain.ObjectiveTo test the hypothesis that acute silent cerebral ischemic events (ASCIEs) are frequent and potentially transient.DesignCross-sectional and cohort study of children with SCA screened by magnetic resonance imaging (MRI) of the brain for a randomized clinical trial.SettingClinical trial setting in tertiary care centers.PatientsAsymptomatic children with SCA without known stroke, neurologic injury, or epilepsy not receiving treatment with transfusions or hydroxyurea.Main outcome measureIncidence of ASCIEs calculated using single diffusion-weighted MRI scans (acute ischemic events that occurred within 10 days of the MRI).ResultsAcute silent cerebral ischemic events were detected on 1.3% of MRIs (10 of 771) in 652 children (mean age, 10.0 years), with an incidence of 47.3 events per 100 patient-years (95% CI, 22.7-87.2). Two of 10 children with ASCIEs had follow-up MRIs of the brain; only 1 had silent cerebral infarction in the same location as the previously detected ASCIE.ConclusionsChildren with SCA experience ongoing (chronic, intermittent) cerebral ischemia, sometimes reversible, far more frequently than previously recognized. The brain in SCA is at constant threat of ischemia.

| S-EPMC3677221 | biostudies-literature

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