Sickle Cell Disease Disorders Research Articles

#1174 Prevalence and factors contributing to erythropoietin hyporesponsiveness in CKD patients on hemodialysis: a single center, cross sectional study

Abstract Background and Aims Anemia, one of the most frequent early complications of CKD is associated with a reduced QOL, cardiovascular morbidity, accelerated CKD progression, and it is an independent predictor of mortality. The successful management of anemia is a vital part of patient care, that improves clinical outcomes. According to the literature, 90% of renal anemia patients responded in a dose-dependent manner to rHu EPO, whereas the remaining 5–10% of patients had either a blunted or absent response to this agent, despite high-dose therapy. Erythropoietin hyporesponsiveness is a strong, independent predictor of mortality risk. Various factors have been associated with ESA hypo responsiveness in different studies. Both the inability to achieve a target hemoglobin and administration of high dose epoetin -alpha are associated with increased risk of CVD complications. AIMS AND OBJECTIVES Method STUDY PERIOD: December 2021 to DECEMBER 2022 STUDY DESIGN: Observational cross sectional study. SAMPLE SIZE: N = 144: Patients older than 18 years old undergoing hemodialysis for at least 3 months before the study were enrolled. History of inpatient treatment, infection, bleeding or transfusion within the last month, hematologic disorders sickle cell disease, MDS and active malignancies were excluded. Required parameters were recorded on every month follow up;Demographic data, Cause of ESRD, Dialysis vintage, ESAs dose (Unit/week), type, Medications history; Dose (mg/week) of iron preparation & use of medication like ACEi, ARBs, dialysis adequacy(Kt/V), haemogram, Liver function test, Kidney function test Iron profile, Serum parathyroid hormone, Serum calcium & phosphorus, CRP, Anti EPO antibodies(if required). We used the European Best Practice Guideline (EBPG) II definition to define ESA hyporesponsiveness for our study purpose(Increase in erythropoietin dose ≥25% to maintain the same Hgb level or < 1 mg/dL gain in Hgb after 4 weeks. EHRI was calculated by dividing weekly ESA dose per kilogram of body weight (IU/Kg/W) by hemoglobin level (g/dL). Based on EHRI, patients were assigned or divided into 2 groups. Group I (EHRI<16) and Group II (EHRI ≥ 16). Patients in the Group II were labeled as erythropoietin hyporesponsive patients and they were compared with others in order to identify the impact of different factors on ESA. Results Among 144 patients, 80 were male and 64 females and 28.4% were diabetic. Mean EHRI were calculated for all patients and based on EHRI pts were divided into two study groups, Gr-I (EHRI<16) & Gr-II(EHRI ≥16). EHRI ≥16 group was considered as ESA hyporesponsive groups. The study parameters were compared between the groups and its statistical significance measured. The overall prevalence of ESA hyporesponsive in our study was 26.3%. Conclusion The overall prevalence of ESA hyporesponsive in our study was 26.3%. Iron deficiency anemia, inadequate dialysis, chronic inflammation, malnutrition, secondary hyperparathyroidism and increased dialysis vintage were the factors associated with ESA hyporesponsiveness.

Prevalence of Substance Use Disorders in Sickle Cell Disease Compared to Other Chronic Conditions: a Population-Based Study of Black American Adults.

Sickle cell disease (SCD) is a heritable chronic health condition characterized by pain symptoms throughout the life course that are routinely treated with opioids. This study examined differences in substance use disorders in Black American adults with SCD compared to those with other chronic conditions or with no chronic conditions. Data from a population-representative sample of Black Americans with SCD, other chronic conditions, and no chronic conditions were obtained from the National Survey of American Life (NSAL) database. Diagnosis of substance use disorder was determined by structured clinical interview. Hierarchical models controlling for covariates (demographics, socioeconomic status, self-rated health, and mood disorders) compared odds of diagnosis between the three groups. The sample included 4238 African-American and Black Caribbean participants from the NSAL study who were 18 years of age or older. Measures included age, sex, income, education, marital status, employment, possession of health insurance, health conditions, and substance use disorders diagnosed by structured clinical interview. Controlling for age, sex, and socioeconomic status, there were no differences in odds of a drug use disorder when comparing individuals with SCD to Black adults with other chronic conditions (OR = 1.12; p = 0.804) or no chronic condition (OR = 2.09; p = 0.102). SCD was, however, associated with greater odds of alcohol use disorders when compared to the groups with other chronic conditions (OR = 2.15; p = 0.01) and no chronic conditions (OR = 5.11; p < 0.001). This effect was not better accounted for by socioeconomic status, marital status, self-rated physical health, or the presence of a mood disorder. SCD was not a risk factor for drug use disorders. Further data will be needed to understand the factors contributing to increased risk of alcohol use disorders in SCD and the role uncontrolled pain symptoms may have in driving substance use.

Osteoarticular disorders in sickle cell disease

Different organs can be affected secondary to sickle cell disease, including the central nervous system, kidneys, gastrointestinal tract, respiratory system, cardiovascular system, bone, and joints. This can lead to increased morbidity and mortality events among the affected patients. Osteoarticular complications represent a severe set of events for patients with sickle cell disease. These complications might include gouty, septic, juvenile, and erosive arthritis, dactylitis, bone infarction, and osteomyelitis. These are the most common complications reported in the literature, and some case reports even reported other types of complications that develop secondary to the previously mentioned ones. Adequate diagnosis might be challenging in some cases. Therefore, clinicians must be crucial in determining the appropriate clinical and radiographic manifestations. Treating these cases is also challenging. Consequently, clinicians should be aware of these complications to enhance the prognosis of the affected patients. Further research is needed for the standardization of the diagnostic and management approaches in these events.

College students’ attitudes toward people with sickle cell disorders

ABSTRACT Sickle Cell Disease (SCD) is a serious hereditary blood disorder affecting millions of people around the world. Approximately 100,000 people have SCD and two and a half million have Sickle Cell Trait (SCT) in the United States. However, the literature on attitudes toward people with SCD is limited. The purpose of this study was to assess college student’s attitudes toward people with SCD disorders. The sample included 416 college students at a North Texas university. A descriptive, cross sectional research approach using a modified version of the Behavior toward SCD Scale was used in this study. The majority (78%) of the participants believed that everyone should know their carrier status however; only 26% indicated that they knew their carrier status at the time. Findings suggest that participants had positive attitudes toward people with SCD overall. The majority of participants indicated that they would be friends (86%), date (62%), or marry (49%) someone if they had SCD. Results support the need for improved knowledge of carrier status of both partners and the reproductive implications associated with being carriers.

The Emotional Impact of Sickle Cell Disease Symptoms: A Case Review

Background: Sickle Cell Disease (SCD) is a chronic and debilitating disease that can affect almost any organ system in the body; hence, it is associated with a broad range of complications and comorbidities that may have a profound impact on a patients’ quality of life through medical and mental health consequences. Psychosocial and affective comorbidities are prevalent in SCD and could considerably influence disease outcomes; however, treatment options for SCD psychosocial sequelae are suboptimal, and evidence on their effectiveness is limited. Case Report: We report a 21-year-old African American female with a history of SCD and recurrent hospital admissions due to acute SCD complications, who was referred to the consultation-liaison psychiatry service for evaluation of psychiatric comorbidities and management recommendations. Conclusion: This case demonstrates the complexity of the relationship between somatic complications and neuropsychiatric disorders in SCD and highlights the importance of early identification and management of mental health conditions in this patient population. We emphasize treatment challenges and the need for large scale research on pharmacotherapies and nonpharmacological interventions in treating psychosocial comorbidities associated with SCD.

Reduction of BCL11A in hematopoietic stem cells through gene editing: new strategy to ameliorate the severe β-globin disorders sickle cell disease

Reduction of BCL11A in hematopoietic stem cells through gene editing: new strategy to ameliorate the severe β-globin disorders sickle cell disease

Highly efficient therapeutic gene editing of human hematopoietic stem cells.

INTRODUCTORYRe-expression of the paralogous γ-globin genes (HBG1/2) could be a universal strategy to ameliorate the severe β-globin disorders sickle cell disease (SCD) and β-thalassemia by induction of fetal hemoglobin (HbF, α2γ2)1. Previously we and others have shown that core sequences at the BCL11A erythroid enhancer are required for repression of HbF in adult-stage erythroid cells but dispensable in non-erythroid cells2–6. CRISPR-Cas9 mediated gene modification has demonstrated variable efficiency, specificity, and persistence in hematopoietic stem cells (HSCs). Here we demonstrate that Cas9:sgRNA ribonucleoprotein (RNP) mediated cleavage within a GATA1 binding site at the +58 BCL11A erythroid enhancer results in highly penetrant disruption of this motif, reduction of BCL11A expression, and induction of fetal γ-globin. We optimize conditions for selection-free on-target editing in patient-derived HSCs as a nearly complete reaction lacking detectable genotoxicity or deleterious impact on stem cell function. HSCs preferentially undergo nonhomologous as compared to microhomology mediated end-joining repair. Erythroid progeny of edited engrafting sickle cell disease (SCD) HSCs express therapeutic levels of fetal hemoglobin (HbF) and resist sickling, while those from β-thalassemia patients show restored globin chain balance. NHEJ-based BCL11A enhancer editing approaching complete allelic disruption in HSCs is a practicable therapeutic strategy to produce durable HbF induction.

Transfusion Therapy in Sickle Cell Disease

Background: Blood transfusion is an important therapy in the management of sickle cell disease (SCD); especially in developing countries. Transfusion aids the restoration of the oxygen carrying capacity in patients with SCD and also prevents vaso-occlusion by dilution of the Hbs in circulation. However, there is paucity of information on transfusion as a therapy in the management of SCD. Aim and objective: This study is aimed at reviewing the available publications on transfusion as a therapy for SCD management. Materials and methods: Relevant literatures were searched on databases including PubMed, Google Scholar, Scopus, Cochrane and standard texts on haematology and transfusion medicine. The keywords used in the search are sickle cell disease, transfusion, simple and chronic transfusion, complications of transfusion, choice of blood for transfusion and guidelines for blood transfusion. The literatures gathered were reviewed, summarized and presented in this review. Results: Blood transfusion is a cornerstone in the management of patients with SCD. The management of SCD patients requires a multidisciplinary approach with a great deal of commitment been required from all the experts. Although, many hazards are associated with blood transfusion, it is pertinent that proper care is taken in the handling and administration of blood and blood products. Conclusion: Transfusion therapy still remains a cornerstone in SCD management and it tends to mitigate the severity and complication associated with SCD disorders. Adequate knowledge and information is needed by experts on the importance of transfusion therapy and its modalities in SCD.

14q32 and let-7 microRNAs regulate transcriptional networks in fetal and adult human erythroblasts

In humans, fetal erythropoiesis takes place in the liver whereas adult erythropoiesis occurs in the bone marrow. Fetal and adult erythroid cells are not only produced at different sites, but are also distinguished by their respective transcriptional program. In particular, whereas fetal erythroid cells express γ-globin chains to produce fetal hemoglobin (HbF), adult cells express β-globin chains to generate adult hemoglobin. Understanding the transcriptional regulation of the fetal-to-adult hemoglobin switch is clinically important as re-activation of HbF production in adult erythroid cells would represent a promising therapy for the hemoglobin disorders sickle cell disease and β-thalassemia. We used RNA-sequencing to measure global gene and microRNA (miRNA) expression in human erythroblasts derived ex vivo from fetal liver (n = 12 donors) and bone marrow (n = 12 donors) hematopoietic stem/progenitor cells. We identified 7829 transcripts and 402 miRNA that were differentially expressed (false discovery rate <5%). The miRNA expression patterns were replicated in an independent collection of human erythroblasts using a different technology. By combining gene and miRNA expression data, we developed transcriptional networks which show substantial differences between fetal and adult human erythroblasts. Our analyses highlighted the miRNAs at the imprinted 14q32 locus in fetal erythroblasts and the let-7 miRNA family in adult erythroblasts as key regulators of stage-specific erythroid transcriptional programs. Altogether, our results provide a comprehensive resource to prioritize genes that may modify clinical severity in red blood cell (RBC) disorders, or genes that might be implicated in erythropoiesis by genome-wide association studies of RBC traits.

162 Dysregulated NO Signaling in the Lower Genitourinary Tract: A Common Mechanism of Erection and Micturition Dysfunction in a Mouse Model of Sickle Cell Disease

Sickle cell disease (SCD) is a state of chronic nitric oxide (NO) deficiency. Priapism, a disorder of non-willful, excessive penile erection, is a highly prevalent complication of SCD. The principal molecular defects underlying priapism in SCD include reduced NO/cGMP/PDE5 bioavailability in the penis related to decreased endothelial NO synthase (eNOS) activity. Recently, urinary dysfunction, including nocturnal enuresis and overactive bladder, have been clinically observed in SCD patients, but the mechanisms underlying urinary dysfunction in SCD are unknown. We hypothesized that aberration in NO regulatory signaling is a common pathophysiologic mechanism for concomitant erection and voiding disorders in SCD. 3 month old SCD (Sickle) and wild type (WT) male mice were used. Erectile function measurement (intracavernosal pressure/mean arterial pressure) and cystometric studies were performed. Bladder and urethra were collected from separate groups of Sickle and WT mice for organ bath studies or measurement of protein expressions of phospho (P)-eNOS (Ser-1177) and P-nNOS (Ser-1412) protein expression by Western immunoblot.

Effect of Age on Blood Rheology in Sickle Cell Anaemia and Sickle Cell Haemoglobin C Disease: A Cross-Sectional Study.

ObjectivesBlood rheology plays a key role in the pathophysiology of sickle cell anaemia (SS) and sickle cell haemoglobin C disease (SC), but its evolution over the lifespan is unknown.Materials and MethodsBlood viscosity, red blood cell (RBC) deformability and aggregation, foetal haemoglobin (HbF) and haematocrit were measured in 114 healthy individuals (AA), 267 SS (161 children + 106 adults) and 138 SC (74 children + 64 adults) patients.ResultsOur results showed that 1) RBC deformability is at its maximal value during the early years of life in SS and SC populations, mainly because HbF level is also at its peak, 2) during childhood and adulthood, hydroxycarbamide treatment, HbF level and gender modulated RBC deformability in SS patients, independently of age, 3) blood viscosity is higher in older SS and SC patients compared to younger ones and 4) haematocrit decreases as SS patients age.ConclusionThe hemorheological changes detected in older patients could play a role in the progressive development of several chronic disorders in sickle cell disease, whose prevalence increases with age. Retarding these age-related haemorheological impairments, by using suitable drugs, may minimize the risks of vaso-occlusive events and chronic disorders.

Prevalence of Relative Systemic Hypertension in Ghanaian Adults with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is associated with an increased risk of premature death in adults. Relative systemic hypertension (RSH) is associated with increased risk of vascular disorders in SCD. While drugs targeting RSH may halt the development of sickle vascular disorders, the magnitude of this problem is unknown in many countries, including in Ghana, which has ~2% incidence rate of SCD. In this study, we examined the prevalence of relative hypertension in an adult SCD patient population of the Ghana Institute of Clinical Genetics (GICG), Korle-Bu, Accra, Ghana and described their demographic characteristics, genotypes and complications.Methods: With institutional ethics committee approval, we conducted a retrospective chart review of 1000 adults aged ≥ 18 years with SCD receiving regular care at the GICG. Charts were selected as patients visited the clinic for routine care over a ten month period. SCD patients 18 years or older who had 3 blood pressure (BP) measurements on separate clinic visits for at least one year were eligible for the study. RSH was defined as systolic BP (SBP) 120 mmHg to 139 mmHg and diastolic blood pressure (DBP) 70 mmHg to 89 mmHg on at least two consecutive routine visits or visits for mild illness. We collected data on demographics, genotypes, the three most recent consecutive BPs, blood counts done on days the BPs were recorded and documented complications of SCD. A data extraction manual was used to reduce inter-observer variability. Descriptive statistics were used for data analysis. The prevalence of relative systemic hypertension in the group was calculated.Results: There were 873 eligible cases involving 319 males (36.5%) and 554 females (63.5%). Homozygous SCD (SS) and Heterozygosity for sickle cell and hemoglobin D disease accounted for 56.9% of cases, Hb SC 39% and other genotypes (e.g. S-Beta Thalassemia, Hb SF) 4%. The overall prevalence of RSH was 40.4%; Hb SS 35.8% and Hb SC 47.7%. Among the 353 patients with RSH, 145 (41.1%) were male, and 208 (58.9%) were female. The predominant genotypes in the RSH group were SS (50.4%) and SC 46.2%. Other genotypes accounted for 3.4%. Median systolic BP (SBP) for the entire cohort was 116.6 (range 86.6 - 171.1) mmHg, and the median diastolic BP (DBP) was 70.3 (range 48 to 113.6) mmHg. Median blood pressures were higher in patients with Hb SC (males: 123/75, females: 122/76 mmHg) than those with Hb SS (males: 117.6/67, females 111/67mmHg). Complications were noted as follows; avascular necrosis (6.9%), other bone disease (1.1%) leg ulcers (6.3%), cholelithiasis (3.7%), cardiopulmonary 1%, and renal 1%. Pearson correlation coefficient showed associations between blood pressure, age, hemoglobin (Hb), and WBC. There was a positive correlation between SBP and age (r = 0.088, p = 0.009) and total Hb (r = 0.106, p = 0.002). Spearson's correlation revealed significant positive correlation between SBP and leg ulcers (r = 0.074, p ≤ 0.05); DBP and leg ulcers (r = 0.119, p ≤0.01); DBP and priapism (r = 0.075, p =0.026) and DBP and cholelithiasis (r = 0 .086, p=0.011).Conclusions: There is a 40.4% prevalence of RSH, which to the best of our knowledge represents the first estimate of this condition in the Ghanaian adult SCD population. The prevalence among Hb SS patients is 35.8% compared to the 44% previously reported in the US. There is significant positive correlation of BP with Hb, leg ulcers, priapism and cholelithiasis. Future prospective studies using standardized BP monitoring are warranted to validate preemptive treatment of RSH in SCD. DisclosuresNo relevant conflicts of interest to declare.

Generation of Non-Deletional Hereditary Persistence of Fetal Hemoglobin (HPFH) Beta-Yac Transgenic Mouse Models: -175 Black HPFH and -195 Brazilian HPFH

Fetal hemoglobin (HbF) is a major genetic modifier of the phenotypic heterogeneity in patients with the major β-globin disorders sickle cell disease (SCD) and β-thalassemia. Although the normal level of HbF postnatally is approximately 1% of total hemoglobin, some individuals have a condition known as hereditary persistence of fetal hemoglobin (HPFH), characterized by elevated synthesis of γ-globin in adulthood. HPFH is caused by small or large deletions in the β-globin locus (deletional HPFH), or point mutations in the Aγ-globin or Gγ-globin gene promoters (non-deletional HPFH). Pharmacological agents such as butyrate, decitabine, and hydroxyurea are effective in inducing HbF in vitro and in vivo. To date, hydroxyurea is the only drug approved for clinical use in sickle cell patients, although the efficacy level is variable between patients and the long-term effects of this drug remain uncertain. Therefore, current research has focused on elucidating the pathways involved in the maintenance/reactivation of γ-globin gene expression in adult life. Many studies have demonstrated the role of stage-specific transcription factors in β-like globin gene switching, indicating their potential as therapeutic targets in the treatment of β-hemoglobinopathies. In order to better understand the molecular pathways involved in the regulating γ-globin gene expression, we used β-YAC transgenic mice, produced with a 213 Kb β-globin locus yeast artificial chromosome, containing a 187 Kb human chromosomal insert encompassing the entire 82 Kb β-globin locus from 5'HS5 of the LCR to 3'HS1, approximately 20 Kb downstream from the β-globin gene. Four different transgenic mouse lines were included in this study: 1) wild β-YAC mice, with the normal sequence of the human β-globin locus; 2) mutant β-YAC mice with the Aγ-globin -117 G>A HPFH mutation 3) mutant β-YAC mice with the Aγ-globin -175 T>C HPFH mutation, and 4) mutant β-YAC mice with the Aγ-globin -195 T>C HPFH mutation. Adult -175 and -195 mutant β-YAC mice displayed an HPFH phenotype with an increased level of HbF. As measured by HPLC, -175 HPFH mice had the highest average level of γ-globin chains [16.4% γ/(γ+β)], followed by -195 HPFH mice (8.4%). Wild-type β-YAC control mice averaged 2.8% and -117 Greek HPFH β-YAC control mice displayed an average of 7.4%. Measurement of Aγ-globin mRNA by RNase protection analysis (RNAP) supported the HPLC data; γ/(γ+β) was 34%, 12.1%, 14.1% and less than 0.5% for -175 HPFH, -195 HPFH, -117 HPFH and wild-type β-YAC animals, respectively. Relative mRNA levels as determined by RT-qPCR were consistent with the RNAP results. Currently, we are examining our -175 and -195 HPFH mice for pancellular versus heterocellular distribution of HbF. To examine the molecular basis for the -175 and 195 HPFH phenotypes, fetal livers of these animals were collected on day E18 of gestation, after the fetal-to-adult β-like globin switch occurred, for chromatin immunoprecipitation (ChIP) analysis of transcription factor/co-factor binding, including YY1, PAX1, TAL1, LMO2 and LDB1. Previous unpublished DNA-protein array and ChIP data, comparing human primary erythroid cell cultures from normal donors and -195 HPFH individuals, showed a 6-fold enrichment of YY1 recruitment to the -195 region of the normal Aγ-globin promoter and a 5-fold enrichment of PAX1 recruitment to the HPFH mutant promoter, suggesting that YY1 may act as an A γ-globin gene repressor and PAX1 may be an activator when the -195 mutation is present. Preliminary ChIP experiments in β-YAC mice showed a similar pattern with YY1 enriched 2-fold in wild-type mice and PAX1 enriched 2-fold in -195 HPFH animals. Regarding -175 HPFH and wild-type β-YAC samples, we found occupancy enrichment of LMO2, TAL1 and LDB1 proteins (1.5-fold, 9-fold and 2.5-fold, respectively) in the -175 region of the Aγ-globin gene promoter in -175 HPFH β-YAC mice. Recently published studies in cell lines have shown that these three proteins form a complex with GATA-1 to mediate long-range interactions between the LCR and β-like globin genes. These mouse models provide additional tools for studying the regulation of γ-globin gene expression and may reveal new targets for selectively activating HbF. DisclosuresNo relevant conflicts of interest to declare.

Clinical predictors of sleep disorders in sickle-cell disease (SCD) patients in Cameroon

Clinical predictors of sleep disorders in sickle-cell disease (SCD) patients in Cameroon

Bedwetting and sleep disorders in sickle cell disease patients in Cameroon

Background: Bedwetting and enuresis are known predictive factors of sleep disorders in sickle-cell disease (SCD). Poor sleep affects functional status, quality of life and may precipitate acute painful crises. Data on bedwetting in SCD is limited in Africa and does not exist in Cameroon.

HbF-Associated Genetic Variation Marks an Erythroid Regulatory Element Essential for BCL11A Transcription and Subsequent Stage-Specific Globin Expression

Abstract 828Genome-wide association studies (GWAS) have identified common genetic variation within a 14-kb segment of intron-2 of the BCL11A gene that is associated with the level of fetal hemoglobin (HbF) and the clinical severity of the β-globin disorders sickle cell disease and β-thalassemia. Functional studies have validated BCL11A as a major repressor of HbF. Here, we explore the consequences of genetic variation on BCL11A expression. The HbF-associated variants overlap BCL11A sequences that possess an evolutionarily conserved enhancer chromatin signature, including the presence of H3K4me1 and H3K27ac and the absence of H3K4me3 histone modifications. Moreover, these sequences show a unique pattern of DNase I hypersensitivity in erythroid precursors compared to other BCL11A-expressing lineages including fetal brain and B-lymphocytes. Occupancy of the major erythroid transcription factors GATA1 and TAL1 is observed at these DNase I hypersensitive sites (DHS). Chromosome conformation capture studies demonstrate that these DHSs form a long-range interaction with the BCL11A promoter.To address the function of the putative regulatory element, we generated transgenic mice with the 12-kb intronic region attached to a minimal promoter and reporter gene. The element enhanced reporter gene expression in an erythroid-lineage restricted, definitive erythroid stage-specific manner. The minimal enhancer activity was mapped to the +58-kb DHS. Similar enhancer activity was observed in primary human erythroid precursors. To address the possible requirement of this element for BCL11A expression, we deleted the corresponding region in adult-stage murine erythroleukemia cells with TALEN-mediated gene targeting. Expression of BCL11A was dramatically reduced and embryonic globins Hbby and Hbb-bh1 were markedly derepressed with concomitant reduction of adult globin Hbb-b1. Analysis of heterozygous primary human erythroid precursors revealed that low-HbF haplotype alleles are preferentially occupied by GATA1 and TAL1 at sequences surrounding rs1427407. A composite half-E-box–GATA motif is disrupted at this SNP in the high-HbF allele. Furthermore, the low-HbF haplotype allele of BCL11A is expressed at a 1.7-fold higher level relative to the high-HbF allele. These data demonstrate that HbF-associated genetic variation in BCL11A modulates the function of a critical erythroid enhancer of BCL11A, and consequently expression of BCL11A itself. The quantitative level of BCL11A in turn regulates the relative expression of the stage-specific globin genes. The essential erythroid enhancer of the BCL11A gene might itself serve as a target for genetic manipulation as a novel approach to the human β-globin disorders. Disclosures:Porteus:Alex's Lemonade Stand Foundation: Research Funding.

Efficacy of homologous inositol hexaphosphate‐loaded red blood cells in sickle transgenic mice

Patients with sickle cell disease (SCD) can present several severe symptoms during their lifetime, including painful events due to vascular occlusion (VOC). Even though multiple factors are involved in VOC, hypoxia is the most important triggering factor. Inositol hexaphosphate (IHP) reduces the oxygen-haemoglobin affinity thus improving the oxygen release in the blood stream and in the tissues. Thus, IHP-loaded homologous red blood cells (IHP-RBCs) could be able to reduce disorders in SCD. The effectiveness of treatment was assessed in two types of SCD transgenic mice (BERK and SAD). The administration of four repeated injections of IHP-RBCs in BERK mice resulted in an improved survival rate and brain development, prevention of severe anaemia and a greatly lowered risk of VOC. After one injection of IHP-RBCs, SAD mice were subjected to acute hypoxic stress. Analysis of the lungs revealed significantly decreased mRNA levels of molecules involved in intravascular disorders. Our results showed that transfusion of homologous IHP-RBCs, by increasing the oxygen delivery, reduces SCD disorders in sickle transgenic mice.

Lipid, lipoproteins and atherogenesis profiles in sickle cell disease among Central African patients

Lipid and lipopproteins disorders are well established in sera from sickle cell disease (SCD) patients out of Central Africa. The present case-control study was conducted to compare serum levels of total cholesterol (TC), HDL-C, triglycerides (TG), LDL-C and TC/HDL-C ratio (atherogenic index) from SCD homozygotes (SS) in steady state, SCD heterozygotes (AS) and controls (AA) in Brazzaville, Congo. Significant reductions of TC and LDL-C vs. increase in TG were reported in SS. However, significant decrease in HDL-C and increase in atherogenic index were observed in AS. We recommend prevention of oxidative stress, dyslipidemia and atherosclerosis in SCD using hygiene-diet measures. Only longitudinal studies in large populations will provide pathophysiological basis of lipid and lipoproteins disorders in SCD.

Sickling Cells, Cyclic Nucleotides, and Protein Kinases: The Pathophysiology of Urogenital Disorders in Sickle Cell Anemia

Sickle cell anemia is one of the best studied inherited diseases, and despite being caused by a single point mutation in the HBB gene, multiple pleiotropic effects of the abnormal hemoglobin S production range from vaso-occlusive crisis, stroke, and pulmonary hypertension to osteonecrosis and leg ulcers. Urogenital function is not spared, and although priapism is most frequently remembered, other related clinical manifestations have been described, such as nocturia, enuresis, increased frequence of lower urinary tract infections, urinary incontinence, hypogonadism, and testicular infarction. Studies on sickle cell vaso-occlusion and priapism using both in vitro and in vivo models have shed light on the pathogenesis of some of these events. The authors review what is known about the deleterious effects of sickling on the genitourinary tract and how the role of cyclic nucleotides signaling and protein kinases may help understand the pathophysiology underlying these manifestations and develop novel therapies in the setting of urogenital disorders in sickle cell disease.

Psychiatric Diagnosis in Adolescents With Sickle Cell Disease: A Preliminary Report

Sickle cell disease (SCD), the most common genetic hemoglobin disorder, affects more than 70,000 Americans, primarily those of African and Mediterranean descent. SCD, characterized by chronic hemolytic anemia; recurrent, episodic painful episodes; vaso-occlusive complications affecting multiple organ systems; and increased risk of infections, is associated with a shortened life span for affected individuals. However, recent medical advances have significantly increased survivability and quality of life for individuals with SCD. Despite these advances, adolescents with SCD continue to face many challenges of living with a chronic condition that requires lifelong medical management that may place them at risk of psychiatric symptoms and disorders. Studies focusing on children and adolescents with SCD suggest greater risks for psychosocial difficulties and depressive and anxiety symptoms. This article describes findings from a structured psychiatric interview administered to 40 adolescents and their parents. The rates of reported psychiatric diagnosis were significantly higher than those reported for the general population. Awareness of risks for psychiatric disorders in SCD could lead to increased identification and interventions that may improve medical and psychiatric outcomes.