scholarly journals Genetic Analysis in the Tanzania Sickle Surveillance Study (TS3): Modifiers of Sickle Cell Disease and Identification of Hemoglobin Variants

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 988-988 ◽  
Author(s):  
Luke R. Smart ◽  
Emmanuela E. Ambrose ◽  
Mwesige Charles ◽  
Arielle G. Hernandez ◽  
Teresa S. Latham ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
G6pd Deficiency ◽  
Sickle Cell Trait ◽  
Cell Disease ◽  
Advisory Committees ◽  
Alpha Thalassemia ◽  
Hemoglobin Variants ◽  
Thalassemia Trait

Introduction. Based on sparse historical data, Tanzania ranks fourth globally for the estimated number of annual births with sickle cell disease. Northwest Tanzania is projected to have an especially high burden of sickle cell disease, but no contemporary surveillance data exist to verify this projection. We designed a large prospective study to determine the prevalence of both sickle cell trait and sickle cell disease in northwest Tanzania. Additional objectives included an analysis of two known genetic modifiers of sickle cell disease [alpha thalassemia trait and glucose-6-phosphate dehydrogenase (G6PD) deficiency], as well as genetic variants affecting fetal hemoglobin (HbF) expression and characterization of hemoglobin variants. Methods. The Tanzania Sickle Surveillance Study (TS3) is a prospective cross-sectional study to determine the prevalence of sickle cell trait and disease in an area projected to be at high risk. Dried blood spots (DBS) from all children born to HIV-infected mothers in the 9 regions across northwest Tanzania were collected by the HIV Early Infant Diagnosis (EID) program and transported to a central laboratory at Bugando Medical Centre, a teaching and consultancy hospital in Mwanza. DBS were tested by isoelectric focusing and scored as normal, trait, disease, or variant. Samples scored as disease or variant were retested for confirmation, and then frozen for subsequent genetic analysis. In the US, genomic DNA was extracted from each DBS, and sickle cell disease status was confirmed by PCR and TaqMan genotyping. All confirmed samples were then analyzed for alpha thalassemia trait (rightward -3.7 gene deletion) using quantitative real time PCR, and for G6PD deficiency using three real time PCR probes to distinguish A and B G6PD isoforms, to identify the G6PD A- variant, and to confirm the sex, respectively. Single nucleotide polymorphisms within 3 quantitative trait loci [BCL11A, the HBS1L-MYB intergenic polymorphism (HMIP) region, and the gamma-globin promoter XmnI site] that modify baseline HbF were analyzed using TaqMan genotyping. DBS with hemoglobin variants were investigated for the presence of common variants found in East Africa. Results. Between February 2017 and May 2018, a total of 232 IEF gels were completed by local staff in Tanzania. Among EID samples from children <24 months of age, the median age was 52 days (IQR 41-93 days), and 17,278 unique DBS samples were scored. With 20 samples uninterpretable and 54 samples with missing results, the primary analysis was performed on 17,204 samples. The overall prevalence of sickle cell trait and disease in the entire cohort was 20.3% and 1.2%, respectively, for a sickle allele frequency of 0.114 with Hardy-Weinberg equilibrium. There was some geographical variation between individual districts in both sickle trait (15.2-27.8%) and disease (0.0-4.3%). Hemoglobin variants were rare (0.1%) and included 4 Hb G-Pest, 2 Hb Kenya, and 1 Hb P-Nilotic. Of 143 DBS confirmed to have sickle cell disease and available for further testing, 61 (43%) had one-gene deletion alpha thalassemia trait and 21 (15%) had two-gene deletion. A- G6PD deficiency was detected in 19.2% of males, and 25.7% of females were heterozygous carriers. The minor allelic frequency for known modifiers of HbF were 32.2% C at rs11886868 (BCL11A), 26.6% T at rs1427407 (BCL11A), 32.5% A at rs4671393 (BCL11A), 23.8% G at rs28384513 (HMIP), 4.5% C at rs9399137 (HMIP), and 0% A at rs7482144 (XmnI). Conclusion. The prevalence of sickle cell trait and disease among infants in northwest Tanzania is very high, exceeding 20% trait and 1.2% disease. Regional prevalence data paired with region-specific crude birth rates predict 10,055 births annually in the northwest regions, more than doubling previous estimates. Concomitant alpha thalassemia trait and G6PD deficiency are frequently co-inherited and may affect the phenotype, as well as common genetic modifiers of HbF expression. Our detailed genetic analysis of a geographically representative surveillance cohort provides a foundation for future targeted screening and the introduction of hydroxyurea for treatment of sickle cell disease in northwest Tanzania. Disclosures Ware: Bristol Myers Squibb: Other: Research Drug Donation; Addmedica: Other: Research Drug Donation; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB.

scholarly journals Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3091-3091
Author(s):  
Michael Rabaza ◽  
Maria Armila Ruiz ◽  
Liana Posch ◽  
Faiz Ahmed Hussain ◽  
Franklin Njoku ◽  
...  
Keyword(s):  
Risk Factors ◽  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Avascular Necrosis ◽  
Sickle Cell ◽  
Research Funding ◽  
Medical Attention ◽  
Cell Disease ◽  
Advisory Committees ◽  
Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Crizanlizumab Therapy Is Associated with Lower Levels of Circulating Extracellular Vesicles in Sickle Cell Disease Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 955-955
Author(s):  
Cristiane Maria de Souza ◽  
Carolina Lanaro ◽  
Irene Pereira dos Santos ◽  
Oladele Olatunya ◽  
Sara T Olalla Saad ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Extracellular Vesicles ◽  
Sickle Cell ◽  
Treated Group ◽  
Clinical Severity ◽  
Cell Disease ◽  
Advisory Committees ◽  
Activated Platelets

Abstract Extracellular vesicles (EVs) are submicron structures released in blood circulation by different cell types which have been found to be increased in sickle cell disease (SCD) and are associated with clinical complications. The most abundant EVs in SCD patients derive from platelets, endothelial cells, and red blood cells (RBCs) and EVs have been explored as biomarkers of clinical severity. Crizanlizumab is a monoclonal antibody against P-selectin, an adhesion molecule expressed in activated platelets and endothelial cells. P-selectin facilitates the formation of heterocellular aggregates and is implicated in the pathophysiology of vaso-occlusive episodes (VOEs) in SCD. This study aimed to investigate the circulating levels of EVs in patients with SCD on standard of care or treated with crizanlizumab. We collected peripheral blood samples from 20 adults with SCD (Non treated group: 7 patients on hydroxyurea treatment and 7 without it. Treated group: 6 patients undergoing treatment with crizanlizumab in combination with hydroxyurea). Patients received the last dose of crizanlizumab at least a month prior to the study. EVs were identified by lactadherin+calcein stain and quantified by flow cytometry to determine the immunophenotype of their parent cell (platelet, endothelial cell, and RBC, with CD41+; CD146+/CD45-; CD235+, respectively). EV quantification was calculated in number per ml of blood as previously described by our group (Olatunya et al., 2019). We found that patients on crizanlizumab had lower total circulating EV counts than patients not receiving the drug (62.670.000,00 ± 15.600.000,00 vs 13.100.000,00 ± 3.513.000,00/mL, respectively, p=0,0076). The difference was statistically significant in platelet-derived EVs levels (5.397.000,00 ± 953.875,00 vs 2.413.000,00 ± 745.165,00/mL, p=0,0169), but not in endothelium-derived or RBC-derived EVs (345714 ± 101817 vs 220000 ± 64291, and 2.189.000,00 ± 1.648.000,00 vs 1.013.000,00 ± 572775, respectively). Crizanlizumab therapy has been shown to reduce the incidence of VOEs in SCD. EVs have been recognized as bio-effectors involved in VOEs, contributing to a hypercoagulable state, chronic inflammation, and endothelial damage. Our findings show an association between the use of crizanlizumab and lower EV levels, particularly of the platelet-derived type. While the anti-P-selectin activity of crizanlizumab could be expected to help remove platelets from circulation, clinical studies have not reported a reduction in platelet counts in patients treated with crizanlizumab. Therefore, we speculate that crizanlizumab may decrease the release of EV by activated platelets, reduce platelet activation, or contribute to EV removal from circulation. Our findings suggest that crizanlizumab therapy may modulate EV levels in the plasma of SCD patients and provide, for the first time, data to support exploring the use of extracellular vesicles as biomarkers to monitor the clinical response to this drug in patients. Further studies on EV expression of P-selectin and how crizanlizumab interacts with EVs and platelets may help clarify this particular effect of this drug. Disclosures Benites: Novartis: Honoraria. Fertrin: Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Costa: Novartis: Consultancy.

scholarly journals Student screening for inherited blood disorders in Bahrain

2021 ◽  
Vol 9 (3) ◽  
pp. 344-352
Author(s):  
S. Al Arrayed ◽  
N. Hafadh ◽  
S. Amin ◽  
H. Al Mukhareq ◽  
H. Sanad
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
G6pd Deficiency ◽  
High Performance ◽  
Sickle Cell Trait ◽  
Disease Incidence ◽  
Cell Disease ◽  
Blood Disorders ◽  
Inherited Disorders ◽  
Beta Thalassaemia

In Bahrain and neighbouring countries inherited disorders of haemoglobin, i. e. sickle-cell disease, thalassaemias and glucose-6-phosphate dehydrogenase [G6PD] deficiency, are common. As part of the National Student Screening Project to determine the prevalence of genetic blood disorders and raise awareness among young Bahrainis, we screened 11th-grade students from 38 schools [5685 students], organized lectures and distributed information about these disorders. Haemoglobin electrophoresis, high performance liquid chromatography, blood grouping and G6PD deficiency testing were performed. Prevalences were: 1.2% sickle-cell disease; 13.8% sickle-cell trait; 0.09% beta-thalassaemia; 2.9% beta-thalassaemia trait; 23.2% G6PD deficiency; 1.9% G6PD deficiency carrier. Health education, carrier screening and premarital counselling remain the best ways to reduce disease incidence with potentially significant financial savings and social and health benefits

scholarly journals Sex Based Differences in Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-37
Author(s):  
Rita V Masese ◽  
Dominique Bulgin ◽  
Mitchell Knisely ◽  
Liliana Preiss ◽  
Eleanor Stevenson ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Categorical Variables ◽  
Continuous Variables ◽  
Cell Disease ◽  
Advisory Committees ◽  
Blood Institute ◽  
National Heart Lung

Introduction Sickle cell disease (SCD) is the most common inherited blood disorders in the United States. The disease predominantly affects African Americans with 1 out of every 365 individuals born with SCD. The disease is characterized by vascular inflammation and vaso-occlusion leading to numerous complications and multi-organ dysfunction. Previous studies have shown women with SCD tend to outlive their male counterparts. Other than the increased life expectancy, sex-based clinical outcome differences in SCD remain largely unknown. To better characterize sex-based differences in SCD, we assessed sociodemographic characteristics, pain, treatment characteristics, laboratory measures and complications among males and females currently enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry. Methods The SCDIC consists of eight academic and comprehensive SCD centers, and one data-coordinating center that received funding from the National Heart Lung and Blood Institute to improve outcomes for individuals with SCD. Participants were eligible for the enrollment in the SCDIC registry if they were 15 to 45 years of age and had a confirmed diagnosis of SCD. Participants were excluded if they had sickle cell trait or had a successful bone marrow transplant. Enrolled participants completed surveys. Data were also abstracted from the participants' medical records. Data were entered into a REDCap database and analyzed using SAS version 9.4 (SAS Institute; Cary, NC). Categorical variables were presented as frequencies and percentages, continuous variables were presented as medians and interquartile ranges (IQR) or means and standard deviations. Categorical variables were analyzed using Chi-Square or Fisher exact tests when appropriate. Continuous variables were compared using the Mann-Whitney U test or independent sample t-tests depending on the distribution. A two-sided p-value less than 0.05 was deemed significant. Results A total of 2,124 participants were included in the study. The mean (SD) age of our participants was 27.8 (7.9) years. Almost all (95.6%) were Africa American, female (56%) and had hemoglobin SS (68.2%) SCD genotype. More males (55.4 % vs. 44.6%, p <0.0001) were taking hydroxyurea. Females had significantly worse reports of pain frequency and severity (p=0.0002 and <0.0001 respectively), more vaso-occlusive episodes (p=0.01) and a higher occurrence of 3 or more hospital admissions in the past year (30.9 % vs. 25.5, p= 0.03). Males had significantly more skin ulcers and respiratory, musculoskeletal, genitourinary and cardiovascular complications while females had more anxiety, depression and autoimmune conditions. Males also had significantly higher creatinine, blood urea nitrogen, albumin and liver enzymes (alkaline phosphatase, aspartate and alanine aminotransferases). Females had higher fetal hemoglobin levels with and without hydroxyurea use. There were no statistical differences in ethnicity, marital and employment status. Conclusion Key differences in SCD presentation and occurrence of complications exist among males and females. Females had higher rates of depression and anxiety while males had more chronic end-organ complications that are life threatening. Our findings emphasize the need for stratification of data analysis by sex in future SCD studies. Disclosures Hankins: Global Blood Therapeutics: Consultancy, Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; Novartis: Research Funding. Treadwell:UpToDate: Honoraria; Global Blood Therapeutics: Consultancy. King:Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company; RiverVest: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioline: Consultancy; Novimmune: Research Funding; Amphivena Therapeutics: Research Funding. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:bluebird bio, inc: Consultancy, Honoraria; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees. Glassberg:Eli Lilly and Company: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy. Shah:Bluebird Bio: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy; Alexion: Speakers Bureau.

scholarly journals The Optimal Cut-Off Level for Hemoglobin A2 to Differentiate between Sickle Cell Disease Genotypes

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2391-2391 ◽  
Author(s):  
Fayiz Al Shueili ◽  
Murtadha K. Al-Khabori ◽  
Salam Al-Kindi ◽  
Yasser Wali ◽  
Shoaib Al-Zadjali
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Roc Analysis ◽  
Beta Thalassemia ◽  
Cell Disease ◽  
R Program ◽  
Alpha Thalassemia ◽  
Thalassemia Trait ◽  
Hemoglobin A2 ◽  
Rbc Count

Abstract Objectives: Hemoglobin A2 (HbA2) is elevated in the presence of beta thalassemia trait and it is used as an indicator of its presence. High-Performance Liquid Chromatography (HPLC) overestimates HbA2 in patients with Sickle Cell Disease (SCD) due to the co-elution of HbS in HbA2 column. The optimal cut-off level of HbA2 to indicate the presence of beta thalassemia trait has not been well established in patients with SCD. We aim to define the optimal cut-off level of HbA2 to differentiate between SS and S/Beta SCD genotype variants. Methods: In this cross-sectional study, we included 241 patients with SCD who have either SS or S/Beta genotype based on their HPLC and the Sickledex test®. The diagnoses were confirmed by the direct sequencing of PCR amplified products of all exons, exon-intron junctions and promoter region of the beta globin gene. We retrieved the following clinical and laboratory variables from the electronic health records: age, gender, Hemoglobin (Hb), Mean Corpuscular Volume (MCV), Red Blood Cell (RBC) count and HbA2. We used the receiver operating curve (ROC) analysis to obtain the optimal cut-off level of HbA2 using the maximum sensitivity and specificity (Youden criteria). All descriptive and analytical statistics were performed using R program. The ROC analysis was performed with the "OptimalCutpoints" package available in R program. Results: Among the 241 patients included in the analysis, SS and S/Bthal patients were 81% and 19% respectively. Male to female ratio was 126:115. Fifty-two percent were using hydroxyurea. The median HbA2 level was 4.5% (Range: 0.0-6.5) in the SS group and 6.5% (Range: 3.5-8.2) in the S/Bthal group. The median Hb, MCV and RBC count was 9.4 g/dL (Range: 5.3 - 15.0), 75 fL (55 - 111) and 3.8 *1012/L (1.9 - 6.3) respectively for the SS group; while it was 9.7 g/dL (6.6 - 12.3), 68 fL (57 - 86) and 4.2 *1012/L (2.5 - 5.4) respectively for the S/Bthal group. The optimal cut-off level for HbA2 was estimated to be 5.7% using a sensitivity of 91% and a specificity of 92%. The positive and negative predictive values were 75% and 98% respectively. The discrimination estimated using the Area Under the Curve (AUC) was 0.936 (95% Confidence Interval: 0.878-0.994). Conclusions: The optimal cut-off HbA2 level to differentiate SCD with the S/Bthal genotype from the SS genotype is 5.7% with a high sensitivity, specificity and discrimination. The unexpected overlap in the MCV and the RBC count is likely related to the high rate of Alpha thalassemia trait in the analyzed population. Incorporation of the presence of alpha thalassemia trait in the analysis may improve the discrimination of MCV and RBC count. Disclosures No relevant conflicts of interest to declare.

scholarly journals Sickle-Cell Disease Patients' Attitudes Towards Their Treatment with Hydroxycarbamide

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1013-1013
Author(s):  
Frédéric Galactéros ◽  
Ersi Voskaridou ◽  
Anoosha Habibi ◽  
Giovanna Cannas ◽  
Laure Joseph ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Fetal Hemoglobin ◽  
Treatment Discontinuation ◽  
Cell Disease ◽  
Advisory Committees

Hydroxyurea (HU) is approved in the EU and USA for prevention of vaso-occlusive crises (VOC) including acute chest syndromes (ACS) in patients over 2 years with sickle-cell disease (SCD). The major benefits of HU in SCD are directly related to its abilities to increase HbF, decrease sickling of red blood cells and hemolysis, leading to reduction of vaso-occlusive episodes, need for blood transfusions and consequently reduction of morbidity and mortality. Adherence to the treatment is paramount for effectiveness, but in spite of proven benefits, barriers to adherence persist.[1] ESCORT-HU study (European Sickle Cell Disease COhoRT - HydroxyUrea), is a multicentric, prospective, non-interventional European study designed to evaluate the safety profile of HU in real life. Patients were enrolled from January 2009 to June 2017 with a follow-up of up to 10 years. All interruptions and resumptions of HU treatment exceeding 15 days were recorded in this study. We hereby present the analysis of the group of patients who self-discontinued HU at least once during the study before informing their caregiver, with a view to identify potential barriers to long-term adherence. In total, 1906 patients were enrolled in ESCORT-HU from 63 centers in France, Germany, Greece and Italy. Of these, 619 patients (32%) stopped HU for over 15 days at least once, and around a third (11% of all patients) were due to patient's will. The mean duration of HU treatment before the first discontinuation was 4.8 ± 5.1 years. Data are summarized in table 1. Compared to the rest of the cohort, the 'treatment discontinuation' group had similar distribution by gender and indication for HU prescription, but a higher proportion of adults stopped HU more than 15 days. It is notable that the proportion of patients with SC genotype was higher in the 'treatment discontinuation' group (4.5% vs 1.7%). The patients in the 'treatment discontinuation' group had more frequent SCD symptoms before enrolment in the study (table 2). Hematological and clinical improvement compared to the baseline was observed in both groups. However, average mean Corpuscular Volume (MCV) and Fetal Hemoglobin percentage (HbF%) were lower and mean percentages of patients with SCD symptoms were higher over the three years of follow-up in the 'treatment discontinuation' group, suggesting that HU daily dose was insufficient (table 2). Sixty patients have no treatment resumption date reported which suggest a permanent interruption of their treatment. Among them 32% preferred to switch to another HU medicinal product and 13% have safety issue (table 3). Understanding and managing self-discontinuation of HU before taking medical advice is challenging for the physician. It is tempting to speculate that it may be due, at least in part, to lack of effectiveness potentially due to an underdosage of the treatment. Resistance to the treatment may also be suggested based on past literature data revealing a great variability in the response (determined by HbF%) to HU therapy. There is evidence that genetic modifiers affect individual response to HU.[2],[3] Finally, weariness from long-term use may also explain the patient's wish to discontinue HU. But treatment at optimal effective should be the primary goal of caregivers. [1]Smaldone A., Manwani D., Green NS, Greater number of perceived barriers to hydroxyurea associated with poorer health-related quality of life in youth with sickle cell disease, Pediatr Blood Cancer. 2019 [2] Steinberg MH, Voskaridou E, Kutlar A, Loukopoulos D, Koshy M, et al. (2003). Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease. Am J Hematol 72: 121-126 [3] Ware RE, Despotovic JM, Mortier NA, Flanagan JM, He J, et al. (2011) Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood 118: 4985-4991 Disclosures Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Voskaridou:Celgene Corporation: Consultancy, Research Funding; Protagonist: Research Funding; Genesis: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees. Cannas:Addmedica: Membership on an entity's Board of Directors or advisory committees.

scholarly journals "Prevalence and Outcome of Avascular Necrosis of the Hip (AVN) Among Young Omani Patients with Sickle Cell Disease"

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3577-3577
Author(s):  
Iman Al Fadhali ◽  
Farah Al-Kindy ◽  
Naema Alshibli ◽  
Salam Alkindi ◽  
Murtadha Al-Khabori ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Avascular Necrosis ◽  
Sickle Cell ◽  
Tertiary Care ◽  
University Hospital ◽  
Average Dose ◽  
Cell Disease ◽  
Advisory Committees ◽  
Female Ratio

Background: Sickle cell disease is a common hemaglopinapthy worldwide and in Oman. Avascular necrosis (AVN) of the hip causes significant morbidity to patients with sickle cell disease and has a profound impact on their quality of life. This study aims to identify the prevalence and outcome of AVN among young Omani patients with sickle cell disease. Methods: The is a cross sectional study done in the main tertiary care and referral facility in Oman, Sultan Qaboos University Hospital. Out of 3000 registered patients 85 patients found to have clinical and radiological proven AVN, between June 2017-January 2019. Data obtained included demographics, the affected joint, uni or bilateral), radiological staging by FICAT (MRI), hydroxyurea use, dose and duration as well as laboratory data at time of diagnosis. Results: The prevalence of AVN among SCD Omani children and young adults is 2.8 %. Their age ranges between 5-25 (Mean 14.6 +3.4). Male to female ratio was 1.6:1. Based on FICAT system score, most of the cases (82%) are AVN grade 3 and above at diagnosis. Thirty-six patients (42%) were diagnosed to have stage IV AVN. Regarding the hydroxyurea use, 43 patients (50.6%) were already started on HU before the development of AVN. Their mean duration of HU use was 5.3 years, with an average dose of 15.7 mg/kg/day. Fifteen patients developed AVN and were started on HU as part of their management. The follow up MRI of 4 of them showed improvement of their AVN stage (from 4 to 2). Fifteen patients (17.6%) underwent joint replacement because of chronic pain and disability and almost half of them (7 patients) were on hydroxyurea. Conclusion: Prevalence of AVN in young patients with SCD in the main tertiary care referral facility in Oman is 2.8% which is less than the internationally reported. Patients are diagnosed at later stages (3 and above) indicating a possibility of underdiagnosis of asymptomatic stage one and 2 patients. Hydroxyurea use has improved the severity of the AVN in few patients. Disclosures Al-Khabori: SOBI: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Shire (Takeda): Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; NovoNardisk: Membership on an entity's Board of Directors or advisory committees. Wali:Sultan Qaboos University Hospital: Employment.

scholarly journals Effects of BCL11A Shmir-Induced Post-Transcriptional Silencing on Distributions of HbF in Single-RBCs and Reticulocytes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 967-967
Author(s):  
Nicolas Hebert ◽  
Erica B. Esrick ◽  
Myriam Armant ◽  
Christian Brendel ◽  
Marioara Felicia Ciuculescu ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Insertion Site ◽  
Fetal Hemoglobin ◽  
Fold Increase ◽  
Advisory Board ◽  
Cell Disease ◽  
Advisory Committees

Abstract NH and EE equally contributed. ADW and PB co-signed. The expression of fetal hemoglobin (HbF) is one of the main targets of sickle cell disease treatment, as it inhibits the polymerization of hemoglobin S. The hypothesis of an inhibitory threshold of HbF per red blood cell (RBC) has been suggested, 1 although not well defined, as the overall percentage of HbF does not reflect the heterogeneous distribution of HbF per cell. Likewise, the qualitative analysis of RBCs containing HbF, called F cells, is neither reproducible nor clinically interpretable, due to low expression. 2 We have developed a technique for measuring the amount of HbF per cell, to determine thresholds of HbF expression per RBC correlated with clinical and biological effects. 2 Among genes controlling its expression, BCL11A has a major repressive effect on the expression of gamma globin/HbF during the fetal to adult hemoglobin switch. Post-transcriptional silencing of BCL11A, using lentivirus expression of a shRNA embedded in a microRNA architecture (shmiR) to re-activate γ-globin expression, is safe and demonstrates high levels of %HbF in a pilot clinical study (NCT 03282656). 3 Here, we show the quantitative measurement of HbF per RBC and reticulocyte. Methods: During patient follow-up, HbF quantification per single cell RBC was performed using a fluorescent HbF antibody. 2 Addition of an anti-CD71 fluorescent antibody allowed selection of reticulocyte sub-populations for determining their HbF content. Fold-increase in percentage of RBC versus percentage of reticulocyte were calculated. Kinetics of HbF/RBC and HbF/Reticulocyte were modeled using mixed effects polynomial linear regression to account for the correlation between repeated data over time. Results: With a median follow-up of 15 months [12-20] after gene transfer, figure 1 shows the mathematical modeling of single-RBC HbF measurement representing RBC percentage containing at least 2, 4, 6, 8 and 10 pg of HbF. Percentage of RBC above each threshold was higher compared to 14 hydroxyurea treated patients for 6 months. Figure 2 shows fold increase between reticulocytes and RBCs with same thresholds of HbF/cell. For low thresholds, RBCs were found in same percentage as reticulocytes whereas RBCs containing increasing levels of HbF were found in higher percentage than reticulocytes, until 6pg/cell showing a clear selective advantage for red cells with a threshold ≥ 6pg/cell of HbF. Figure 3 shows different kinetics of HbF increase according to two different transduction strategies with 2 enhancers in patients 2-4 compared to one enhancer in patients 6-8. Conclusion: BCL11A down-regulation in six clinical trial subjects was associated with an in vivo selection process RBCs with ≥ 6pg HbF per cell attained with different engraftment kinetics, depending on transduction processes, and ultimately stable high level and broadly distributed HbF. 1 Steinberg MH, Chui DH, Dover GJ, Sebastiani P, Alsultan A. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood. 2014 Jan 23;123(4):481-5. 2 Hebert N, Rakotoson MG, Bodivit G, et al. Individual red blood cell fetal hemoglobin quantification allows to determine protective thresholds in sickle cell disease. Am. J. Hematol. 3 Esrick EB, Lehmann LE, Biffi A, et al. Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease. N. Engl. J. Med. 2021;384(3):205-215. Figure 1 Figure 1. Disclosures Esrick: bluebird bio: Consultancy. Audureau: GBT: Honoraria. Higgins: Sebia, Inc.: Honoraria; Danaher Diagnostics: Consultancy. Williams: BioMarin: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Advisory Board; Geneception: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Emerging Therapy Solutions: Membership on an entity's Board of Directors or advisory committees, Other: Chief Scientific Chair; Beam Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Alerion Biosciences: Other: Co-founder (now licensed to Avro Bio, potential for future milestones/royalties); Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Novartis ETB115E2201 (eltrombopag in aplastic anemia). Advisory fees donated to NAPAAC.; Orchard Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Membership on a safety advisory board (SAB): SAB position ended 05/20/2021. Co-founder , Patents & Royalties: Potential for future royalty/milestone income, X-SCID. Provided GMP vector for clinical trial, Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Analysis Advisory Board, Patents & Royalties: BCH licensed certain IP relevant to hemoglobinopathies to bluebird bio. The current license includes the potential for future royalty/milestone income. Bluebird has indicated they will not pursue this as a clinical program and BCH is negotiating return of, Research Funding. Bartolucci: AGIOS: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Jazz Pharma: Other: Lecture fees; Emmaus: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding; INNOVHEM: Other: Co-founder; Hemanext: Consultancy; GBT: Consultancy; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; Fabre Foundation: Research Funding.

scholarly journals Risk of Hospitalization for Vaso-Occlusive Episode in Patients with Sickle Cell Disease after out-Patient Exposure to Systemic Corticosteroids

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2048-2048
Author(s):  
Ondine Walter ◽  
Pierre Cougoul ◽  
Julien Maquet ◽  
Pablo Bartolucci ◽  
Maryse Lapeyre-Mestre ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
National Health Insurance System ◽  
Advisory Committees ◽  
Systemic Corticosteroids ◽  
Increased Risk ◽  
Case Period

Abstract Introduction : Sickle cell disease (SCD) is an inherited disorder which affects 300,000 newborns per year. Vaso-occlusive episodes (VOEs) cause an important morbi-mortality and a decreased quality of life in patients with SCD. Some risk factors of VOE are well known, like infection, cold exposure, stress, pulmonary diseases and dehydration. Exposure to systemic corticosteroids has been suspected to increase the occurrence of VOEs in few case reports or series. However, no comparative study has been conducted to demonstrate this risk which is still debated, resulting in discrepancies among guidelines on SCD management. This study aimed to assess the risk of hospitalization for VOE associated with out-hospital exposure to systemic corticosteroids in patients with SCD in France. Methods : Data source was the French national health insurance system database, named SNDS (Système National des Données de Santé) between 2010 and 2018. The SNDS links sociodemographic, out- and in-hospital data for the entire French population (>66 million inhabitants). The study population consisted in all patients with SCD with at least one hospitalization for VOE during the study period, identified with a primary discharge diagnosis of VOE (D57.0 code of the international classification of disease, 10 th version; positive predictive value: 98.6%). All genotypes (homozygous SS-SCD and double-heterozygous SCD) were included. Because we assessed out-hospital exposure to corticosteroids, patients hospitalized during the three months before the first VOE were excluded. We performed a case-case-time-control study (Figure 1). This self-controlled design results in self-adjustment for time-independent confounders, including genotype. The outcome was the first hospitalization for VOE. The exposure to oral and injectable corticosteroids, identified using out-hospital reimbursement data, was assessed during a case period (28 days before the outcome) compared to the exposure during a control period (28 days, starting 84 days before the outcome). The same comparison was made among future cases (matched patients hospitalized for VOE the year after the given case), in order to adjust for the trend of exposure to corticosteroids (calendar variations of corticosteroid exposure). Results : Overall, 5,151 cases of VOEs were included in the main analysis. Median age at first VOE was 16.9 years; 317 (6.2%) patients were exposed to corticosteroids during the case period. In the main analysis, corticosteroid exposure was significantly associated with the occurrence of hospitalizations for VOEs: adjusted Odds Ratio (aOR): 3.81, 95% confidence interval (95% CI): 2.44 to 5.61. In patients exposed to hydroxyurea, the aOR was 2.61, 95% CI: 1.07 to 6.39, compared with an aOR of 4.00, 95% CI: 2.53 to 6.30 in unexposed patients. In the subgroup analysis by age, the aOR was 2.81, 95% CI: 1.49 to 5.30 in children, and 4.45, 95% CI: 2.37 to 8.37 in adults. The results were consistent in all sensitivity analyses. Conclusion : This study showed an association between outpatient exposure to systemic corticosteroids with an increased risk of hospitalization for VOE, in both adults and children. Hydroxyurea may reduce this risk in adults. Figure 1 Figure 1. Disclosures Bartolucci: GBT: Consultancy; Emmaus: Consultancy; Fabre Foundation: Research Funding; AGIOS: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Jazz Pharma: Other: Lecture fees; INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; Hemanext: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding. Moulis: Argenx: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Prospective Newborn Screening for Sickle Cell Disease and Other Inherited Blood Disorders in Central Malawi

2021 ◽  
Vol 66 ◽  
Author(s):  
Gerald Tegha ◽  
Hillary M. Topazian ◽  
Portia Kamthunzi ◽  
Thad Howard ◽  
Zondwayo Tembo ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Newborn Screening ◽  
Sickle Cell ◽  
Early Identification ◽  
G6pd Deficiency ◽  
The United States ◽  
Sub Saharan Africa ◽  
Cell Disease ◽  
Hematological Disorders ◽  
Alpha Thalassemia

Objectives: Newborn screening in the United States and Europe allows early identification of congenital disorders but does not yet exist in most low-resource settings, especially in sub-Saharan Africa. Newborn screening can identify multiple inherited hematological disorders, but feasibility and effectiveness for Africa are not fully determined.Methods: Surplus dried blood spot collected in Central Malawi through the HIV Early Infant Diagnosis surveillance program were repurposed and tested by isoelectric focusing for sickle cell disease and trait. Additional genetic testing identified G6PD deficiency and alpha thalassemia.Results: Testing of 10,529 cards revealed an overall sickle cell trait prevalence of 7.0% (range 3.9–9.7% by district); 10 of 14 infants identified with sickle cell disease (prevalence 0.1%) were located and received care at a specialized clinic. Subsequent testing of 1,329 randomly selected cards identified alpha thalassemia trait in 45.7% of samples, and G6PD deficiency in 20.4% of males and 3.4% of females, with 29.0% of females as heterozygous carriers.Conclusion: Inherited hematological disorders are common in Central Malawi; early identification through newborn screening can improve clinical outcomes and should be supported throughout Africa.

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