Assessment of Burden on Family Caregivers of Children With Sickle Cell Anemia in Al Madinah Al Munawwarah, Saudi Arabia.

Background Sickle cell anemia (SCA) results in various complications, necessitating continuous daily care and placing burdens on caregivers. Objectives This study aims to assess the burden on family caregivers of children with SCA and its associated factors. Materials and methods This analytical cross-sectional study was conducted in Madinah City, Saudi Arabia. We included family caregivers of children with SCA who were registered and treated at the Maternity and Child Hospital in King Salman Medical City. Data were collected from all registered files of children who received treatment for SCA. Data from participants was obtained using the validated Arabic version of the Zarit Burden Interview (ZBI). Descriptive statistics, chi-square tests, independent sample t-tests, and multivariate regression analysis were used in the statistical analysis. Results Overall, 124 caregivers participated out of 166 (response rate: 74.7%), among which 83 (66.9%) were fathers, 72 (58.1%) were aged ≥40 years, 96 (77.4%) held Saudi nationality, and 62 (50%) had a monthly income of <5000 SAR. The average daily caregiving hours were 5±4 hours, and 30 (24.2%) of children were diagnosed with associated physical or psychological diseases. The Zarit Burden Interview score indicated that 45 (36.3%) of caregivers reported no burden, whereas 51 (41.1%), 22 (17.7%), and 6 (4.8%) reported mild, moderate, and severe burden, respectively. Factors contributing to the burden included being a mother, low financial resources, non-Saudi nationality, children diagnosed with associated physical or psychological diseases, and caregiving hours. Conclusions The burden on SCA caregivers was higher for caregivers who were mothers, non-Saudis, those with lower income, and children with physical or psychological diseases, as well as more caregiving hours. Enhancing the overall well-being of families affected by the SCA burden involves creating targeted interventions and comprehensive support programs.

Epidemiological profile trends and cost of pediatric sickle cell disease in Brazil from 2008 to 2022.

OBJECTIVE: This study aimed to investigate the epidemiological trends of Pediatric Sickle Cell Disease (SCD) in Brazil over the period 2008-2022, with a focus on understanding the incidence, mortality rates, and associated healthcare costs. The study explored potential associations between patient characteristics and the occurrence of crises in pediatric SCD cases. METHODS: A cross-sectional study was conducted, analyzing national annual rates of pediatric SCD hospitalizations using data from the FioCruz platform. Descriptive and inferential analyses, including time series and ARIMA regression, were employed. Economic dimensions were assessed using cost categorization. The study followed STROBE reporting guidelines. RESULTS: Data on 81,942 pediatric SCD hospitalizations were collected, with a predominance of crisis-related cases (74.08 %). Males and children under five years old were most affected. Regional disparities were observed, with the Southwest region recording the highest hospitalization rates. ICU costs were higher for crisis-related hospitalizations. Mortality rates were significantly higher for crisis-related cases (p < 0.001), with ARIMA regression indicating a significant association between hospitalizations for crisis-related cases and mortality. CONCLUSION: This study highlights the significant burden of pediatric SCD in Brazil, particularly crisis-related cases, suggesting a need for focused interventions. By prioritizing early detection, equitable access to healthcare, and evidence-based interventions, Brazil can mitigate the burden of SCD and improve patient outcomes. These findings contribute to informing public health policies and interventions aimed at addressing the challenges of pediatric SCD management in Brazil.

Impact of oral health conditions on the quality of life of children and adolescents with sickle cell anemia: A cross-sectional study.

BACKGROUND: Sickle cell anemia (SCA) is the most common hemoglobinopathy in Brazil and worldwide and is part of a group of chronic genetic diseases resulting from abnormalities in the structure of hemoglobin. AIM: To evaluate the impact of oral health conditions on the quality of life (QoL) of children and adolescents with SCA. DESIGN: This is a cross-sectional study with a sample of 76 children and adolescents aged 8-14 years. For inclusion, they were required to have a diagnosis of HbSS SCA in their medical records, without a pain crisis or any dental emergency in the last three months. The children and adolescents with SCA were from Hematology and Hemotherapy Center of Maranhão. Demographic characteristics, socioeconomic status, oral hygiene, caries, malocclusion, and oral health-related quality of life (OHRQoL) were assessed. OHRQoL was assessed using the Child Perceptions Questionnaire. Descriptive statistics, Student's t and Mann-Whitney tests were performed (α = 5%). RESULTS: Brown race was the most prevalent for both age groups (8-10 years-63.2% and 11-14 years-57.9%). Predominant monthly family income for both age groups was below $106. Visible plaque and gingival bleeding were higher in children aged 8-10 years. Dental caries significantly impacted the QoL of adolescents through the domain "oral symptom" (p = .031). Malocclusion significantly impacted the QoL of adolescents ("total score," p = .026; "social well-being", p = .045). CONCLUSION: Oral health impairment negatively affected the QoL of adolescents with SCA.

Transcriptional regulators of fetal hemoglobin.

Sickle cell anemia is a hereditary disease caused by sickle-shaped red blood cells that can lead to vaso-occlusive crises. Treatment options are currently limited, highlighting the need to develop new clinical approaches. Studies demonstrated that elevated levels of fetal hemoglobin (Hb F) are associated with a reduction of mortality and morbidity in sickle cell anemia patients. In light of this, researchers have been trying to elucidate the transcriptional regulation of Hb F to develop new therapeutic interventions. The present study aimed to present the main transcription factors of Hb F and discuss the clinical feasibility of these molecular targets. Two search strategies were used in the PubMed, SciELO, and LILACS databases between July and August 2023 to conduct this review. Manual searches were also conducted by checking references of potentially eligible studies. Eligibility criteria consisted of clinical trials and cohort studies from the last five years that investigated transcription factors associated with Hb F. The transcription factors investigated in at least four eligible studies were included in this review. As a result, 56 eligible studies provided data on the BCL11A, LRF, NF-Y, GATA1, KLF1, HRI, ATF4, and MYB factors. The studies demonstrated that Hb F is cooperatively regulated by transcription factors with the BCL11A factor appearing to be the most specific target gene for γ-globin induction. Although these data are promising, there are still significant gaps and intervention limitations due to the adverse functions of the target genes. New studies that clarify the aspects and functionalities of Hb F regulators may enable new clinical approaches for sickle cell anemia patients.

Eosinophilic dialogues: a molecular exploration of sickle cell anemia severity.

Sickle cell anemia (SCA) is a genetically inherited hemoglobinopathy characterized by the abnormal morphology of red blood cells, resulting in vaso-occlusive events and diverse clinical complications. Recent investigations have unveiled a novel dimension in understanding SCA severity through the lens of eosinophilic dialogues. This review article synthesizes current knowledge on the molecular intricacies of eosinophils in the context of SCA, exploring their biology, molecular markers, and interactions with other cellular components. Eosinophil-mediated inflammation and oxidative stress are dissected to elucidate their impact on the disease course. Furthermore, the review evaluates potential therapeutic interventions and outlines future directions in this burgeoning field. The term "Eosinophilic Dialogues" encapsulates the multifaceted molecular exchanges that influence SCA severity, presenting a promising avenue for targeted interventions and improved clinical outcomes. This review serves as a comprehensive resource for researchers, clinicians, and healthcare practitioners engaged in unraveling the complex pathophysiology of SCA and exploring novel therapeutic avenues.

Therapeutic Gene Editing for Hemoglobinopathies.

In the last ten years, a consistent number of clinical studies have evaluated different gene approaches for the treatment of patients with sickle cell disease (SCD) and transfusion-dependent ß-thalassemia (TDT). Initial studies of gene therapy for hemoglobinopathies involved the use of lentiviral vectors to add functional copies of the gene encoding ß-globin in defective CD34 cells; more recently, gene editing techniques have been used involving either CRISPR-Cas9, transcription activation-like effector protein nuclease, zinc finger nuclease, and base editing to either induce fetal hemoglobin production at therapeutic levels or to genetically repair the underlying molecular defect causing the disease. Here, we review recent gene editing studies that have started the development of a new era in the treatment of hemoglobinopathies and, in general, monoallelic hereditary diseases.

Impaired phagocytosis and oxidative respiratory burst activity in sickle cell anemia leukocytes.

Objectives: This case-control study investigated the mode of leukocyte function in sickle cell anemia (SCA) to delineate the underlying immunopathology for early diagnosis and mitigate the increased bacterial infection risk in this patient population. Method: In total, 90 participants comprising 24 hemoglobin (Hb)-AA, 22 Hb-AS, 23 steady state Hb-SS and 21 vaso-occlusive crisis state Hb-SS subjects were recruited for this study. The subjects were further divided into the following six groups: Hb-AA and Hb-AS subjects as control groups, Hb-SS subjects at steady state, Hb-SS subjects in a vaso-occlusive crisis state, Hb-SS subjects undergoing medication (Meds), and Hb-SS subjects undergoing medication plus blood transfusion (Meds/BT) group, respectively. Hematological analysis, Hb electrophoresis, leukocyte ratios, and leukocyte functional assays were assessed with standard methods, and interleukin 8 (IL-8) and L-selectin levels were evaluated using enzyme-linked immunosorbent assays. Results: Total leukocyte and monocyte counts were increased in the Hb-SS groups compared to the control groups. However, the Hb-SS groups had lower lymphocyte counts than the other groups (p < 0.005). Leukocyte viability was increased in the SCA groups, while phagocytic activities and oxidative respiratory burst were both reduced in the SCA groups (p < 0.005). Increased IL-8 levels were observed in all SCA groups (p < 0.05), whereas L-selectin levels of the Hb-SS steady and Hb-SS on Meds groups were decreased compared to the other groups (p < 0.05). The neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, and platelet-to-lymphocyte ratio were higher in the SCA groups than the control groups (p < 0.05). Conclusion: Impaired leukocyte phagocytic and oxidative respiratory burst activities constitute altered leukocyte function in SCA, which can increase their susceptibility to infections and the risk of mortality, especially during the crisis state. Novel therapeutic approaches can be tailored specifically to enhance these leukocyte functions and mitigate the increased infection risk in SCA.

Targeted therapeutic management based on phytoconstituents for sickle cell anemia focusing on molecular mechanisms: Current trends and future perspectives.

The global epidemic of Sickle cell anemia (SCA) is causing thousands of children to die. SCA, a genetic disorder affecting the hemoglobin-globin chain, affects millions globally. The primary physiological issue in these patients is the polymerization of sickle hemoglobin within their red blood cells (RBCs) during their deoxygenating state. The RBC undergoes a sickle shape due to the polymerization of mutant hemoglobin within it and membrane deformation during anoxic conditions. To prevent complications, it is essential to effectively stop the sickling of RBCs of the patients. Various medications have been studied for treating SCA patients, focusing on antisickling, γ-globulin induction, and antiplatelet action. Natural and synthetic anti-sickling agents can potentially reduce patient clinical morbidity. Numerous clinical trials focused on using natural remedies for the symptomatic therapy of SCA. Medicinal plants and phytochemical agents have antisickling properties. Recent studies on plant extracts' natural compounds have primarily focused on in vitro RBCs sickling studies, with limited data on in vivo studies. This review discussed the potential role of phytoconstituents in the management of SCA.

Hydroxyurea in the sickle cell disease modern era.

INTRODUCTION: Sickle cell disease is an inherited disorder characterized by hemoglobin S polymerization leading to vaso-occlusion and hemolytic anemia. These result in a variety of pathological events, causing both acute and chronic complications. Millions around the world are affected by sickle cell disease with predominance in sub-Saharan Africa. Hydroxyurea was the first drug approved for use in sickle cell disease to reduce the occurrence of painful crises and blood transfusions in patients with frequent, moderate to severe painful crises. AREAS COVERED: With the development of new therapeutics, the role of hydroxyurea is evolving. This narrative review aims to provide clinical data, safety information, and supplementary evidence for the role of hydroxyurea in the current era of sickle cell disease. A comprehensive literature search of databases, including PubMed and Cochrane Library, was conducted from 1963 to 2024. EXPERT OPINION: Even though new medications have been approved for sickle cell disease, hydroxyurea remains the gold standard. Hydroxyurea is not only a disease modifier but it has additional clinical benefits, it is affordable, and its longevity has prompted expanded research in areas such as underutilization and pharmacogenomics. As the treatment landscape evolves, hydroxyurea's long-standing record of efficacy and safety continues to support its role as a key agent in disease management.

Genetic Patterns of Oral Cavity Microbiome in Patients with Sickle Cell Disease.

The Middle Eastern prevalence of sickle cell anemia, a genetic disorder that affects red blood cells, necessitates additional research. On a molecular level, we sought to identify and sort the oral microbiota of healthy individuals and those with sickle cell anemia. Furthermore, it is crucial to comprehend how changes in the genetic makeup of the oral microbiota impact the state of sickle cell anemia. Using next-generation sequencing, the 16S rRNA amplicon was examined using saliva samples from 36 individuals with sickle cell anemia and healthy individuals. These samples were obtained from sickle cell anemia patients (18 samples) and healthy control participants (controls, 18 samples). Various analyses are conducted using bioinformatic techniques to identify distinct species and their relative abundance. Streptococcus, followed by Fusobacterium nucleatum, Prevotella, and Veillonella were the most prevalent genera of bacteria in the saliva of the SCA and non-SCA individuals according to our findings. Rothia mucilaginosa, Prevotella scoposa, and Veillonella dispar species were the dominant species in both sickle cell anemia and non-sickle cell anemia subjects. Streptococcus salivarius, Actinomyces graevenitzii, Actinomyces odontolyticus, and Actinomyces georgiae spp. were the most prevalent bacterial spp. in the studied SCA cases. The sequencing of the 16S rRNA gene yielded relative abundance values that were visualized through a heatmap analysis. Alterations in the oral microflora's constitution can significantly affect the susceptibility of sickle cell anemia patients to develop more severe health complications. Salivary diagnosis is a potential tool for predicting and preventing oral microbiome-related diseases in the future.

Diagnostic and Therapeutic Challenges in Intravenous Mercury Poisoning: A Case Report.

Intravenous mercury poisoning is a rare but severe medical emergency, often resulting from accidental exposure or intentional self-harm. We present the case of a 30-year-old male with a history of sickle cell anemia who presented with high-grade fever, vomiting, giddiness, and breathlessness following intravenous mercury self-administration. Diagnostic challenges included distinguishing symptoms of acute mercury toxicity from those of his chronic condition of sickle cell trait. Markedly elevated serum mercury levels confirmed the diagnosis, with high-resolution computed tomography (HRCT) imaging studies revealing mercury deposits and alveolar lung injury. Management involved antidote of mercury poisoning, including non-invasive ventilation and transfusions, with consultations from multiple specialties. The patient demonstrated significant clinical improvement and was discharged with scheduled follow-ups. This case underscores the complexity of diagnosing and managing intravenous mercury poisoning, highlighting the importance of a comprehensive multidisciplinary approach for optimal patient outcomes.

Understanding Exercise (in)tolerance in Sickle Cell Disease: Impacts of Hemolysis and Exercise Training on Skeletal Muscle Oxygen Delivery.

Sickle cell disease (SCD) is characterized by central (cardiac) and peripheral vascular dysfunctions, significantly diminishing exercise capacity and quality of life. While central cardiopulmonary abnormalities in SCD are known to reduce exercise capacity and quality of life; the impact of hemolysis and subsequent cell-free hemoglobin (Hb)-mediated peripheral vascular abnormalities on those outcomes are not fully understood. Despite the recognized benefits of exercise training for cardiovascular health and clinical management in chronic diseases like heart failure, there remains substantial debate on the advisability of regular physical activity for SCD patients. This is primarily due to concerns that prolonged and/or high-intensity exercise might trigger metabolic shifts leading to vaso-occlusive crises. As a result, exercise recommendations for SCD patients are often vague or nonexistent, reflecting a gap in knowledge about the mechanisms of exercise intolerance and the impact of exercise training on SCD-related health issues. This mini-review sheds light on recent developments in understanding how SCD affects exercise tolerance, with a special focus on the roles of hemolysis and the release of cell-free hemoglobin in altering cardiovascular and skeletal muscle function. Also highlighted here is the emerging research on the therapeutic effects and safety of exercise training in SCD patients. Additionally, the review identifies future research opportunities to fill existing gaps in our understanding of exercise (in)tolerance in SCD.

Identification of genetic variants associated with clinical features of sickle cell disease.

Sickle cell disease (SCD) is an inherited blood disorder marked by homozygosity of hemoglobin S, which is a defective hemoglobin caused by a missense mutation in the ß-globin gene. However, clinical phenotypes of SCD vary among patients. To investigate genetic variants associated with various clinical phenotypes of SCD, we genotyped DNA samples from 520 SCD subjects and used a genome-wide association study (GWAS) approach to identify genetic variants associated with phenotypic features of SCD. For HbF levels, the previously reported 2p16.1 locus (BCL11A) reached genome significance (rs1427407, P = 8.58 × 10-10) in our GWAS as expected. In addition, we found a new genome-wide significance locus at 15q14 (rs8182015, P = 2.07 × 10-8) near gene EMC7. GWAS of acute chest syndrome (ACS) detected a locus (rs79915189, P = 3.70 × 10-8) near gene IDH2 at 15q26.1. The SNP, rs79915189, is also an expression quantitative trait locus (eQTL) of IDH2 in multiple tissues. For vasoocclusive episode (VOE), GWAS detected multiple significant signals at 2p25.1 (rs62118798, P = 4.27 × 10-8), 15q26.1 (rs62020555, P = 2.04 × 10-9) and 15q26.3 (rs117797325, P = 4.63 × 10-8). Our findings provide novel insights into the genetic mechanisms of SCD suggesting that common genetic variants play an important role in the presentation of the clinical phenotypes of patients with SCD.

Chronic automated red cell exchange therapy for sickle cell disease.

BACKGROUND: The data to support chronic automated red cell exchange (RCE) in sickle cell disease (SCD) outside of stroke prevention, is limited, especially in adults. STUDY DESIGN AND METHODS: A retrospective analysis was conducted of patients with SCD who were referred for chronic RCE at our institution over a 10-year period. Data that were evaluated included patient demographics, referral indications, and procedural details (e.g., vascular access, adverse events, etc.). In a subanalysis, the number of annual acute care encounters during 3 years of chronic RCE was compared with that in the year preceding the first RCE. RESULTS: A total of 164 patients were referred for chronic RCE: median age was 28 years (interquartile range [IQR] = 22-36) at referral and 60% were female. Seventy (42.6%) were naïve to chronic transfusion (simple or RCE) prior to referral. The leading indications for referral were refractory pain (73/164, 44.5%) and iron overload (57/164, 34.7%). A total of 5090 procedures occurred during the study period (median = 19, IQR = 5-45). Of the 138 patients who had central vascular access, 8 (6%) and 16 (12%) had ≥1 central-line-related thrombosis and/or infection, respectively. Of those who were not RBC alloimmunized at initiation of RCE, 12/105 (11.4%) developed new antibodies during chronic RCE. In those 30 patients who were adherent to therapy for 3 years, there was no significant difference in acute care encounters following initiation of RCE. CONCLUSION: Prospective clinical trials are needed to determine which patients are most likely to benefit from chronic RCE and refine selection accordingly.

Telomere Dynamics in Sickle Cell Anemia: Unraveling Molecular Aging and Disease Progression.

Sickle Cell Anemia (SCA) is a hereditary blood disorder characterized by the presence of abnormal hemoglobin, leading to the formation of sickle-shaped red blood cells. While extensive research has unraveled many aspects of the genetic and molecular basis of SCA, the role of telomere dynamics in disease progression remains a relatively unexplored frontier. This review seeks to provide a comprehensive examination of telomere biology within the context of SCA, aiming to elucidate its potential impact on molecular aging and the progression of the disease. The impact of oxidative stress on telomere dynamics in SCA is explored, with a particular focus on how increased reactive oxygen species (ROS) may contribute to accelerated telomere shortening and genomic instability. Furthermore, the potential relationship between telomere dysfunction and cellular senescence in SCA is investigated, shedding light on how telomere dynamics may contribute to the premature aging of cells in this population. The review concludes by summarizing key findings and proposing potential therapeutic strategies targeting telomere dynamics to mitigate disease progression in SCA. It also identifies gaps in current understanding and suggests avenues for future research, emphasizing the importance of further investigating telomere biology to advance our understanding of molecular aging and disease progression in Sickle Cell Anemia. This comprehensive exploration of telomere dynamics in SCA offers insights into potential mechanisms of molecular aging and disease progression, paving the way for targeted therapeutic interventions and improved disease management.

Differential sensitivity to hypoxia enables shape-based classification of sickle cell disease and trait blood samples at point of care.

Red blood cells (RBCs) become sickle-shaped and stiff under hypoxia as a consequence of hemoglobin (Hb) polymerization in sickle cell anemia. Distinguishing between sickle cell disease and trait is crucial during the diagnosis of sickle cell disease. While genetic analysis or high-performance liquid chromatography (HPLC) can accurately differentiate between these two genotypes, these tests are unsuitable for field use. Here, we report a novel microscopy-based diagnostic test called ShapeDx™ to distinguish between disease and trait blood in less than 1 h. This is achieved by mixing an unknown blood sample with low and high concentrations of a chemical oxygen scavenger and thereby subjecting the blood to slow and fast hypoxia, respectively. The different rates of Hb polymerization resulting from slow and fast hypoxia lead to two distinct RBC shape distributions in the same blood sample, which allows us to identify it as healthy, trait, or disease. The controlled hypoxic environment necessary for differential Hb polymerization is generated using an imaging microchamber, which also reduces the sickling time of trait blood from several hours to just 30 min. In a single-blinded proof-of-concept study conducted on a small cohort of clinical samples, the results of the ShapeDx™ test were 100% concordant with HPLC results. Additionally, our field studies have demonstrated that ShapeDx™ is the first reported microscopy test capable of distinguishing between sickle cell disease and trait samples in resource-limited settings with the same accuracy as a gold standard test.

Outcome of pregnancy in sickle cell anemia patients with COVID-19 infection.

Sickle cell anemia (SCA) is a multisystem disease, associated with increased risk for infection and thromboembolic disease, and pregnancy is a stressor for patients with SCA. In general, coronavirus disease 2019 (COVID-19) infection in SCA is associated with a favorable outcome. Literature of pregnancy in SCA with COVID is scarce. We report a case series study of pregnant women with SCA, who are confirmed positive for COVID-19 from May 2020 to March 2021. These patients showed generally mild-to-moderate disease and presented predominantly with fever and painful crisis. They showed a significant drop in Hb from baseline, and they received low-molecular-weight heparin prophylaxis (LMWH) and blood transfusion. The outcome of pregnancy is satisfactory, although the mean birth weight was significantly lower than that reported from the same SCA population.

Sex-disaggregated analysis of acute kidney injury in hospitalized children with sickle cell anemia in Uganda.

A growing body of research is categorizing sex differences in both sickle cell anemia (SCA) and acute kidney injury (AKI); however, most of this work is being conducted in high-resource settings. Here, we evaluated risk factors and clinical parameters associated with AKI and AKI severity, stratified by sex, in a cohort of children hospitalized with SCA and vaso-occlusive pain crisis (VOC). The purpose of this study was to explore sex disparities in a high-risk, vulnerable population. This study was a secondary analysis of data collected from a cohort of Ugandan children between 2 and 18 yr of age prospectively enrolled. A total of 185 children were enrolled in the primary study; 41.6% were female and 58.4% were male, with a median age of 8.9 yr. Incident or worsening AKI (P = 0.026) occurred more frequently in female compared with male children, despite no differences in AKI on admission. Female children also had altered markers of renal function including higher creatinine levels at admission (P = 0.03), higher peak creatinine (P = 0.006), and higher urine neutrophil gelatinase-associated lipocalin (NGAL) at admission (P = 0.003) compared with male children. Female children had elevated total (P = 0.045) and conjugated bilirubin at admission (P = 0.02) compared with male children and higher rates of hematuria at admission (P = 0.004). Here, we report sex differences in AKI in children with SCA and VOC, including increased incidence and worsening of AKI in female pediatric patients, in association with an increase in biological indicators of poor renal function including creatinine, estimated glomerular filtration rate, and NGAL.NEW & NOTEWORTHY In this study, we report an increased risk of developing acute kidney injury (AKI) during hospitalization, worsening AKI, and death among females with sickle cell anemia (SCA) hospitalized with an acute pain crisis compared with males. The sex differences in AKI were not explained by socioeconomic differences, severity of pain, or disease severity among females compared with males. Together, these data suggest that female children with SCA may be at increased risk of AKI.

Pharmacokinetic-Guided Hydroxyurea to Reduce Transfusions in Ugandan Children with Sickle Cell Anemia: Study Design of the Alternative Dosing And Prevention of Transfusions Trial.

INTRODUCTION: People with sickle cell anemia (SCA) may require frequent blood transfusions to treat acute and chronic complications. Hydroxyurea is a life-saving treatment for SCA that could also decrease the need for blood transfusions. Inadequate medication access and challenges in dose optimization limit the widespread use of hydroxyurea in Africa. If feasible, pharmacokinetic (PK) dosing might improve dose determination to minimize toxicities and maximize clinical benefits. The Alternative Dosing And Prevention of Transfusions (ADAPT, NCT05662098) trial will analyze the impact of hydroxyurea on transfusion rate and serve as a pilot study to evaluate the feasibility of PK-guided hydroxyurea dosing in Uganda. METHODS: Herein we describe the rationale and design of ADAPT, a prospective cohort study of ∼100 children with SCA in Jinja, Uganda. The primary hypothesis is that hydroxyurea will decrease blood transfusion use by ≥ 50%, comparing the transfusion incidence rate ratio between a 3-month pretreatment and a 12-month treatment period. A key secondary hypothesis is that our PK-dosing approach will generate a suitable hydroxyurea dose for ≥80% of participants. Every ADAPT participant will undergo hydroxyurea PK testing, and if a dose is generated within 15-35 mg/kg/day, participants will start on their individualized dose. If not, they will start on a default dose of 20 mg/kg/day. Hydroxyurea dose optimization will occur with periodic dose adjustments. CONCLUSION: Overall, demonstrating the reduction in blood transfusion utilization with hydroxyurea treatment would provide leverage to increase hydroxyurea access, and PK-guided hydroxyurea dosing should optimize the safe and effective treatment of SCA across sub-Saharan Africa.