scholarly journals Insights from Comparative Serum Proteomic Profiling of Children with Sickle Cell Disease: The Effect of Hydroxyurea and Genotype on Protein Abundance

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1302-1302 ◽  
Author(s):  
Susanne Ragg ◽  
Melissa Key ◽  
Fernanda Rankin ◽  
Monica L. Hulbert
Keyword(s):  
Sickle Cell Disease ◽  
Serum Protein ◽  
Sickle Cell ◽  
Serum Proteins ◽  
Protein Abundance ◽  
Healthy Children ◽  
Cell Disease ◽  
Hydroxyurea Treatment ◽  
One Year ◽  
Restricted Maximum Likelihood Estimation

Abstract Introduction: Sickle cell disease (SCD) is a multisystem disease, with substantial variation in presentation and clinical course. Many protein biomarkers have been described in serum and plasma of children with homozygous sickle cell disease. In order to understand the effect of hydroxyurea and the hemoglobin SC genotype on serum protein levels, we compared the relative abundance of serum proteins in healthy children and children with SCD. Methods: The relative concentration of 140 different serum proteins was measured using liquid chromatography tandem mass spectrometry. Serum samples of healthy children and of children with SCD were collected at a baseline visit: 30 healthy African American children without sickle cell trait, 30 children with hemoglobin SS genotype, 30 children with hemoglobin SC (HbSC) genotype, and 30 children with hemoglobin SS (HbSS) genotype while adherent to hydroxyurea for at least one year. All groups were matched for age and gender. Type of SCD, hydroxyurea dose, laboratory values prior to starting hydroxyurea and at the time of sample collection were recorded. Disease and control samples were processed in a random block design stratified by disease, sex, and age to minimize the effect of sample preparation and technician processing. Samples were depleted of albumin and immunoglobulins. Tryptic peptides were analyzed on a linear ion-trap (LTQ) mass spectrometer. The acquired data was searched against the Human UniProt database using X!Tandem. Peptide identification and protein assignment were performed using the PeptideProphet and ProteinProphet in the Trans-Proteomic Pipeline. Alignment and quantification were done as described (Lai, X. et. al. 2011). Peptide-level quantitative information was analyzed for each protein using a mixed effects model fit with restricted maximum likelihood estimation to test the differential abundance of each protein. Within each comparison, the false discovery rate was controlled at 5% using the method of Benjamini and Hochberg. Results: Seventy-one serum proteins were significantly different between the children with HbSS disease and the healthy children. In contrast, between children with HbSS disease treated with hydroxyurea and healthy children, only 56 serum proteins were significantly different. Furthermore, in children with HbSC disease, only 25 serum proteins were significantly different compared to healthy children. In assessing the effect of hydroxyurea treatment on serum protein abundance, we found a total of 50 proteins that were significantly different between the 30 children with HbSS disease not prescribed hydroxyurea and the 30 children who were adherent to hydroxyurea (average 24 mg/kg/day) for at least one year (average 3.3 years). We also found a total of 41 proteins that were significantly different in comparing the 30 children with HbSS disease and the 30 children with HbSC disease. Conclusion: Due to the multisystem nature of sickle cell disease, proteins from many pathways are dysregulated, including inflammatory proteins, hemolysis-associated proteins, proteins involved in coagulation and complement regulation and apolipoproteins. Our findings indicate that the increase of HbF might not be the only beneficial effect of hydroxyurea treatment and that some of the clinical improvement might be due to decreased serum protein dysregulation. Disclosures Hulbert: Pfizer, Inc.: Other: spouse employment.

Serum Protein Abundance in Children with Sickle Cell Disease at Baseline, during Acute Pain Crisis, and on Hydroxyurea - Compared to Children with Other Pediatric Diseases

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4050-4050
Author(s):  
Susanne Ragg ◽  
Melissa Key ◽  
Fernanda Rankin ◽  
Mark E. Heiny ◽  
Monica L. Hulbert
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Acute Pain ◽  
Serum Proteins ◽  
Protein Abundance ◽  
Healthy Children ◽  
Cell Disease ◽  
Pediatric Diseases ◽  
Inflammatory Bowel ◽  
Pain Crisis

Abstract Introduction: Sickle cell disease (SCD) is a multisystem disease, with substantial variation in presentation and clinical course. Many biomarkers have been described both during steady state and with complications, but comparison between SCD and other pediatric disease are lacking. In this prospective study we used a multiplex dual antibody sandwich immunoassay and compared the abundance of 103 serum proteins in 130 children with SCD, 51 morbidly obese children (BMI percentile > 99%), 29 children with inflammatory bowel disease at initial diagnosis, 186 children with pediatric solid tumors and 151 healthy controls. Serum samples of children with SCD were either taken at baseline (59 samples), on the day of admission for pain crisis (27 samples), or while adherent to hydroxyurea for at least 9 months (44 samples). For each set of 5 disease samples, 3 healthy control samples were selected that were matched by age, gender and race. Type of SCD, laboratory values and disease severity based on history of SCD complication were recorded. Methods: The relative concentration of 103 different serum proteins was measured with a customized quantibody array (Raybiotech, Inc.). Disease and control samples were processed in a random block design stratified by disease, sex, and age to minimize the effect of sample preparation and technician processing. The slides were developed with Alexa Flour 555- conjugated streptavidin and the signal was quantified using a laser scanner (GenePix® 4000A, Molecular Devices Corporation). Measurements from the different PMT voltages were combined into a single composite scan, which was then background corrected and normalized by setting the mean of each array block to the global mean. A linear mixed effects model was constructed for each protein that included gender, race, and disease subgroups as fixed effects factors, with the sample (nested within subject) treated as a random factor. This model was fitted to each protein by restricted maximum likelihood using the lmer function in the R package lme4. Contrasts were constructed using the multcomp package to generate p-values for comparisons of interest. Within each comparison, the false discovery rate was controlled at 5% using the method of Benjamini and Hochberg. Results: Sixty-one serum proteins were significantly different between children with SCD and healthy subjects, 57 serum proteins between children with SCD and solid tumors, 38 serum proteins between children with SCD and obesity, and 14 serum proteins between children with SCD and inflammatory bowel disease. One-third of the serum proteins (19) were unique for SCD, as they were not significantly different from healthy children in any other of the pediatric diseases examined. Compared to serum of healthy children, 44 proteins were significantly different in children with severe SCD, 46 proteins in children with SCD suffering from an acute pain crisis, 45 proteins in children with SCD on hydroxyurea, and 42 proteins in children with clinically mild sickle cell disease (predominantly Hemoglobin SC disease). Surprisingly only one protein (CCL2) was significantly different between children with SCD at baseline and during an acute pain crisis. Hydroxyurea therapy only caused seven proteins to become significantly different from their pretreatment baseline; and only eight proteins were statistically different at a well baseline visit between children classified as having clinically mild versus severe disease. When compared to children with severe sickle cell disease, only 2 proteins (HGF and BDNF) were lower in both children with clinically mild SCD and in those taking hydroxyurea. Conclusion: Distinct SCD-specific abundance changes in serum proteins were identified compared to healthy controls and other pediatric disease. Perhaps most interestingly, the protein abundance profiles of the 103 studied proteins in pediatric SCD patients are almost identical between their baseline state and during an acute pain crisis; and minimal protein changes occurred in children with sickle cell disease who were stably taking hydroxyurea with an otherwise good laboratory response (increased MCV and Hgb F). Differences in serum protein abundance profiles could help distinguish mild from severe SCD and should be explored in larger studies. Disclosures No relevant conflicts of interest to declare.

Hydroxyurea for the Prevention of Stroke and Other Vasoocclusive Complications in Children with Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3792-3792 ◽  
Author(s):  
Markus Schmugge ◽  
Karin Zurbriggen ◽  
Manuela Albisetti ◽  
Marlies Schmid ◽  
Ralf W. Baumgartner ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Stroke Prevention ◽  
Stroke Recurrence ◽  
Healthy Children ◽  
Cell Disease ◽  
Therapeutic Alternative ◽  
Stop Trial ◽  
Hydroxyurea Treatment

Abstract Due to the immigration of families of Mediterranean, Asian and African origins to Switzerland an increasing number of children with Sickle Cell Disease (SCD) are being followed in our centers. The Swiss Pediatric Sickle Cell Disease Registry is aimed to study prognostic aspects and the outcome of different therapeutic approaches. Particularly, indications for hydroxyurea treatment and the effects of its long-term use are assessed. The risk of stroke in children with sickle cell disease (SCD) is approximately 200–300-fold greater compared to healthy children. 10% of children with SCD have a specially high risk for stroke with an incidence of 1 in 100 children per year. The US stroke prevention (STOP) trial has demonstrated the benefit of regular red cell transfusions for stroke prevention; however hemochromatosis is frequent and blood-borne infections can occur. Hydroxyurea (HU) can be a therapeutic alternative for the prevention of stroke in children with SCD and other severe vasoocclusive complications (VOC). From 52 children in our centers with SCD or with compound hemoglobinopathies 27 (median age 10.5, range 3.8–19 y) are treated with HU and were followed for 9–101 (mean 47) months. 16 received HU for recurrent VOC, including 4 children with chest syndrome. Two children recieved HU for silent cerebral infarctions and after stroke, respectively (Jehovas Witness). In 9 children HU was commenced for pathological transcranial dopppler ultrasonography (TCD) results according to the STOP trial criteria. TCDs were performed in all SCD patients once a year, in children with conditional TCDs every 6 months, and every 3 months in patients with pathological TCD results. Upon observation of two pathological TCDs at 2–3 months interval, HU was initiated with 10 to maximally 30 mg/kg/day. HU was well tolerated in all patients and no leuko- or neutropenia was observed. No stroke, stroke recurrence, chest syndrome or splenic sequestration was observed during HU treatment and the average number of hospital days/y before (9d) and after 12 months of HU (3d) were reduced significantly (P=0.002). However after 12–24 months, abnormal lung function and growth retardation did not improve significantly. Laboratory studies documented a significant increase in total Hb (mean 79 to 93 g/l; P=0.03), HbF (9 to 23%; P=0.0001) and MCV (83 to 94 fl; P=0.001) and a significant decrease of HbS (86 to 71%; P<0.0001), WBC (7,8 to 5.4; P<0.05) and bilirubin (54 to 36 umol/l; P<0.05) after 12 months of HU. In children that had received HU for pathological TCDs the increase of HbF resulted in a reduction of the middle cerebral arteries blood flow velocities as soon as after 5–7 months. We conclude that HU is a promising therapeutic alternative for the prevention of stroke and other VOC in SCD. Safety and efficacy of this treatment in children has to be assessed by further long-term studies.

Retinal microvascular analysis using Fundus Fluorescein Angiography in Egyptian sickle cell disease patients

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Nayera H El Sherif ◽  
Mahmoud A Kenny ◽  
Waheed S Elhalfawy
Keyword(s):  
Sickle Cell Disease ◽  
Blood Transfusion ◽  
Fluorescein Angiography ◽  
Sickle Cell ◽  
Large Sample Size ◽  
Cell Disease ◽  
Fundus Fluorescein Angiography ◽  
Transfusion Therapy ◽  
Hydroxyurea Treatment ◽  
Trans Cranial Doppler

Abstract Background Sickle cell disease can affect retina of eye via vaso-occulsive changes that occur in micro-vessels of retina which could be analysed by using Fundus Fluorescein Angiography. Aim To analyze macular microvascular alternation in patients with SCD by Fundus Fluorescein Angiography (FFA) and to assess the role of potentially contributory Clinico-pathological factors including Trans-Cranial Doppler, genotypes, hydroxyurea, transfusion therapy and finally iron overload state on the development of macular alterations. Method This was across-sectional study which included 30 Sickle cell disease patients randomly recruited from the Paediatric Haematology clinic, children Hospital, Ain Shams University, Cairo, Egypt. Complete blood count (CBC), Trans-Cranial Doppler (TCD) and Fundus Fluorescein Angiography. Results In our study, there were 30 patients with mean age (14.1± 4.02), 5 patients had abnormal/conditional Trans-Cranial, 15 patients had Vaso-occlusive crises, 11 patients were on regular simple blood transfusion; all 30 studied sickle cell disease patients had normal Fundus Fluorescein Angiography and eye examination and only one patient hadabnormal visual acuity;A 29 years oldgirl who had five attacks of cerebral strokes last year, on regular simple blood transfusion and Hydroxyurea treatment with abnormal TCD and recurrent Vaso-occlusive crises in last two years, Although her vision is hand movement yet Fundus Fluorescein Angiography was normal. Conclusion we didn’t find any Retinal microvascular alternation in our studied SCD patients using Fundus Fluorescein Angiography, we related our results to the fact that our studied SCD patients were young and all our studied patients were on hydroxyurea therapy with fair compliance, further studies using large sample size are warranted in order to illustrate the utility of Fundus Fluorescein Angiography (FFA) as a tool for better detection of sickle retinopathy.

scholarly journals Hydroxyurea Treatment for Sickle Cell Disease

2002 ◽  
Vol 2 ◽  
pp. 1706-1728 ◽  
Author(s):  
Martin H. Steinberg
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
Pharmacologic Therapy ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Globin Chains ◽  
Hydroxyurea Treatment ◽  
Erythroid Precursors

High fetal hemoglobin (HbF) levels inhibit the polymerization of sickle hemoglobin (HbS) and reduce the complications of sickle cell disease. Pharmacologic agents that can reverse the switch from γ- to β-chain synthesis — γ-globin chains characterize HbF, and sickle β-globin chains are present in HbS — or selectively increase the proportion of adult erythroid precursors that maintain the ability to produce HbF are therapeutically useful. Hydroxyurea promotes HbF production by perturbing the maturation of erythroid precursors. This treatment increases the total hemoglobin concentration, reduces the vaso-occlusive complications of pain and acute chest syndrome, and attenuates mortality in adults. It is a promising beginning for pharmacologic therapy of sickle cell disease. Still, its effects are inconsistent, trials in infants and children are ongoing, and its ultimate value — and peril — when started early in life are still unknown.

scholarly journals Prevalence and Predisposing Factors of Atrial Fibrillation in a Multi-Ethnic Society: The Impact of Racial Differences in Bahrain

2011 ◽  
Vol 4 ◽  
pp. OJCS.S8032 ◽  
Author(s):  
Taysir Garadah ◽  
Saleh Gabani ◽  
Mohamed Al Alawi ◽  
Ahmed Abu-Taleb
Keyword(s):  
Atrial Fibrillation ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Middle Eastern ◽  
Predisposing Factors ◽  
Cell Disease ◽  
Clinical Events ◽  
History Of ◽  
The Mean ◽  
One Year

Background The prevalence and epidemiological data of atrial fibrillation (AF) among multi-ethnic populations is less well studied worldwide. Aim Evaluation of the prevalence and predisposing factors of AF in patients who were admitted to acute medical emergencies (ER) in Bahrain over the period of one year. Methods Two hundred and fifty three patients with onset of AF were studied. The mean difference of biochemical data and clinical characteristics between Middle Eastern (ME) and sub continental (SC) patients was evaluated. The odds ratio of different predisposing factors for the development of clinical events in AF patients was assessed using multiple logistic regression analysis. Results Out of 7,450 patients that were admitted to ER over one year, 253 had AF based on twelve leads Electrocardiogram (ECG), with prevalence of 3.4%. In the whole study, the mean age was 59.45 ± 18.27 years, with 164 (65%) male. There were 150 ME patients (59%), and 107 (41%) SC, 55 (22%) were Indian (IND) and 48 (19%) were South Asian (SA). In the whole study clinical presentation was of 48% for palpitation, pulmonary edema was of 14%, angina pectoris on rest of 12%, 10% had embolic phenomena, 6% had dizziness, and 7% were asymptomatic. The odds ratio of different variables for occurrence of clinical events in the study was positive of 2.2 for history of hypertension, 1.8 for sickle cell disease, 1.2 for high body mass index (BMI) >30, 1.1 for mitral valve disease. The ME patients, compared with SC, were older, had significantly higher body mass index, higher history of rheumatic valve disease, sickle cell disease with high level of uric acid and lower hemoglobin. The history of hypertension, DM and smoking was higher among the SC patients. The rate of thyroid disease was equal in both groups. Conclusion The prevalence of atrial fibrillation was 3.4% with male predominance of 65%. Patients of sub continental origin were younger with a significantly high history of hypertension and ischemic heart disease. The patients of Middle Eastern origin had significantly high rate of rheumatic heart disease, and sickle cell disease. The history of hypertension was the most important independent clinical predictor of adverse events in patients presented with AF.

scholarly journals Salmonella osteomyelitis in a one year old Child without Sickle Cell Disease: A Case report

2014 ◽  
Vol 8 (2) ◽  
pp. 52-54 ◽  
Author(s):  
Saturveithan C ◽  
Arieff A ◽  
Premganesh G ◽  
Sivapathasundaram N
Keyword(s):  
Case Report ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease ◽  
One Year ◽  
Salmonella Osteomyelitis

Intrauterine Diagnosis for Sickle-Cell Disease

PEDIATRICS ◽  
1973 ◽  
Vol 52 (3) ◽  
pp. 463-463
Author(s):  
John M. Carr
Keyword(s):  
At Risk ◽  
Genetic Counseling ◽  
Family Planning ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Healthy Children ◽  
Cell Disease ◽  
Intrauterine Diagnosis

In Pediatrics, Volume 51, No. 4, April 1973, there is a commentary by Fost and Kaback entitled, "Why Do Sickle Cell Screening in Children?"1 On page 742 there appears this statement, "Genetic counseling might assist parents in family planning and the possibility of intrauterine diagnosis of sickle-cell disease would offer a more meaningful opportunity for parents at risk to bear healthy children." This statement seems vague and confusing in an otherwise reasonably straightforward article. If the authors are suggesting that such women either be aborted or counseled concerning the possibilities of this, why not come out and say so?

Health Related Quality of Life of Children with Sickle Cell Anemia and Their Parents; Quantitative Study in Albaha; Saudi Arabia

2021 ◽  
pp. 9-17
Author(s):  
Turki Alzahrani ◽  
Raed Alzahrani ◽  
Amer Alzahrani ◽  
Abdullah Alzahrani ◽  
Abdu Adawi ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Saudi Arabia ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Healthy Children ◽  
Health Related Quality ◽  
Cell Disease ◽  
Related Quality ◽  
Health Related

Aims: To gain a better understanding of the quality of life (QoL) of children and impact of this disease on parents QoL. Study Design: Cross-sectional study. Place and Duration of Study: The study was conducted in King Fahd Hospital, Albaha city, Albaha, Saudi Arabia, between March2020 and February 2021. Methodology: We included 95 responses. Two different tools were used for the purpose of this study. PedsQL™ Sickle Cell Disease Module was used to measure health-related quality of life (HRQoL) in healthy children and adolescents and those with acute and chronic health conditions. Moreover, PedsQL™ Family Information Form was completed by caregivers. Median and interquartile range were used for numerical variables since they were skewed. Bivariate analyses were carried out using non-parametrical tests and Pearson correlation. The prediction of QoL was accomplished through multivariate analysis. Results: A total of (95) responses were analyzed. Female respondents were 52.6%. The age median was 12 (IQR=10-14). Mothers represented the most frequent informant 46.3% in this current study. Significant association was found between QoL and certain independent factors, some of which is parental level of education (P< .001) and marital support (P< .001). Conclusion: Sickle cell disease (SCD) is a major condition accounts for a huge burden on variable levels. This study reported that low QoL among children affected by SCD. Higher education and current marital status of the parents were significantly associated with high QoL in SCD patients. Number of workdays affected due to child health was significantly correlated with low QoL.

Alterations of Hemoglobin Fractionation in a Sickle Cell Disease Patient on Voxelotor Therapy

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S100-S101
Author(s):  
S S Karimi ◽  
H Ni ◽  
L L Hsu
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Exchange Transfusion ◽  
Recent Literature ◽  
Disease Patient ◽  
Oxygen Affinity ◽  
Treatment Modalities ◽  
Cell Disease ◽  
Low Oxygen ◽  
Hydroxyurea Treatment

Abstract Introduction/Objective Voxelotor is a molecule that allosterically binds to the alpha-chain of hemoglobin, resulting in increased oxygen affinity. This allosteric inhibition leads to prevention of hemoglobin polymerization and sickling of red blood cells in response to low oxygen tension. Voxelotor has been used to treat patients with Sickle Cell Disease (SCD) and recent literature indicates it may contribute to complex hemoglobin fractionation (HF) elution patterns. We report a novel case of a SCD patient on concurrent Hydroxyurea, Voxelotor and chronic RBC exchange transfusion treatment and discuss the implications of these three treatment modalities on HF and monitoring of SCD. Methods A 17-year-old female with SCD complicated by frequent vaso-occlusive crisis, and avascular necrosis managed with chronic RBC exchange and Hydroxyurea. Her HF prior to initiation of Voxelotor treatment showed 3.2% HbA2, 51% HbA, 6.0% HbF, and 41% HbS. Voxelotor therapy was initiated at 1500mg/day and HF was performed 10 days later. Whole blood was collected and subjected to High Performance Liquid Chromatography (HPLC) with reflex to RBC solubility and Capillary Electrophoresis. Results HF performed post-Voxelotor therapy revealed positive sickle solubility with a complex pattern of 2.7% HbA2, 49.2% HbA, 5.3% HbF, 15.7% HbS, 0% HbC, and two additional peaks of a 6.3% peak in the window-D region (retention time of 4.34) and 20.8% of an atypical Hb peak pattern (at the retentuin time of 4.18). The results reflected a complex HF of a HbSS patient on concurrent chronic RBC exchange transfusion, hydroxyurea therapy, and Voxelotor treatment. Post Voxelotor-therapy HF revealed a reduction in HbS from 41% to 15.7% with the emergence of two additional peaks. Chronic RBC exchange transfusion and Hydroxyurea treatment account for the observed fractionation of HbA and HbF, respectively. Based on recent literature, we attribute the emergence of the two additional peaks to Voxelotor therapy. All three therapies led to reduction in HbS. Conclusion Routine HF serves as an essential modality in diagnosis and monitoring of SCD. Voxelotor treatment alters the HF profile and may cause difficulty for interpretation. With the emergence of novel therapies, it is imperative for clinicians to provide medication information to clinical laboratories and pathologists to be fully aware of the effects of current treatments to correctly interpret and monitor SCD.

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