Sickle Cell Disease Participants Research Articles

Genetic variants associated with white blood cell count amongst individuals with sickle cell disease.

Sickle cell disease (SCD) is a Mendelian disorder characterized by a point mutation in the β-globin gene that leads to sickling of erythrocytes. Several studies have shown that absolute neutrophil count is strongly associated with clinical severity of SCD, suggesting an apparent role of white blood cells (WBC) in SCD pathology. However, the mechanism by which genetic variants lead to WBC count differences in SCD patients remains unclear. Genome-wide association (GWA) analyses were carried out amongst a cohort of 2409 Brazil SCD participants. Association of WBC count and genetic markers were investigated in homozygous sickle cell anaemia participants and compound heterozygous sickle cell haemoglobin C participants. GWA analysis showed that variants in genes TERT, ACKR1, and FAM3C are associated with WBC count variation. The well-studied association between WBC count and Duffy null phenotype (variant in ACKR1) in healthy populations was replicated, reinforcing the influence of the SNP rs2814778 (T>C) in WBC count. Genetics plays an important role in regulating WBC count in patients with SCD. Our results point to possible mechanisms involved in WBC count variation and as increased WBC count is associated with more severe SCD, these results could suggest potential therapeutic targets for individuals with SCD.

Detectability of white matter cerebral blood flow using arterial spin labeling MRI in patients with sickle cell disease: Relevance of flow territory, bolus arrival time, and hematocrit.

Sickle cell disease (SCD) is the most common genetic blood disorder, characterized by red cell hemolysis, anemia, and corresponding increased compensatory cerebral blood flow (CBF). SCD patients are at high risk for cerebral infarcts and CBF quantification is likely critical to assess infarct risk. Infarcts primarily localize to white matter (WM), yet arterial spin labeling (ASL) MRI, the most common non-invasive CBF approach, has poor WM CBF sensitivity owing to low WM CBF and long WM bolus arrival time (BAT). We hypothesize that anemia, and associated cerebral hyperemia, in SCD leads to improved WM detection with ASL. We performed 3-Tesla multi-delay pulsed ASL in SCD (n = 35; age = 30.5 ± 8.3 years) and control (n = 15; age = 28.7 ± 4.5 years) participants and applied t-tests at each inversion time within different flow territories, and determined which regions were significantly above noise floor (criteria: one-sided p < 0.05). Total WM CBF-weighted signal was primarily detectable outside of borderzone regions in SCD (CBF = 17.7 [range = 12.9-25.0] mL/100 g/min), but was largely unphysiological in control (CBF = 8.1 [range = 7.6-9.9)] mL/100 g/min) participants. WM BAT was reduced in SCD versus control participants (ΔBAT = 37 [range = 46-70] ms) and BAT directly correlated with hematocrit (Spearman's-ρ = 0.62; p < 0.001). Findings support the feasibility of WM CBF quantification using ASL in SCD participants for appropriately parameterized protocols.

Exploring the role of viscosity-vaso-occlusion and haemolysis-endothelial dysfunction in pain sensitization among Jamaicans with sickle cell disease.

Viscosity-vaso-occlusion (VVO) and haemolysis-endothelial dysfunction (HED) are pathophysiological mechanisms and clinical subphenotypes of sickle cell disease (SCD). Recurrent vaso-occlusive crises (VOC) may lead to neuroplastic changes and pain sensitization. Among 257 SCD participants, we assessed the relationship of subphenotypes with pain sensitivity using quantitative sensory testing to identify heat pain thresholds (HPT) and pressure pain thresholds (PPT). VOC history and sleep, social and emotional functioning were assessed using the Adult Sickle Cell Quality of Life Measurement Information System. The 'elbow method' determined the optimal number of clusters as three. Clustering was performed using K-prototypes. Among clusters 2 and 3, VOC frequency and severity were higher. Clusters 1 and 3 had lower haemoglobin, higher reticulocytes and lactate dehydrogenase and more leg ulcers. In multivariate regression, cluster 3 was associated with approximately 13.6% lower PPT compared to cluster 1, and female sex was associated with decreases in PPT and HPT at the hands and feet (p < 0.001). Hydroxyurea use and unit increases in sleep functioning and age were associated with approximately 20.1% higher foot-PPT, 6.8% higher hand-PPT and 2.5% higher hand-HPT and foot-HPT respectively. Findings suggest that a third subphenotype with mixed VVO and HED features and worse pain sensitization may exist.

Investigation of parental socioeconomic status as a determinant of dietary habits and disease severity of sickle cell disease children

Background: Socioeconomic status (SES) impacts dietary choices and poor dietary pattern has been reported to play a role in the etio-pathogenic mechanisms that give rise to various diseases. Objective: The study is designed to explore the relationship between parental SES and both the dietary habits and disease severity markers among sickle cell disease (SCD) pediatric patients. Methods: Participants’ hemoglobin genotypes and hematocrit levels were determined using standard methods. Questionnaire was administered to the participants to obtain information on qualitative parameters. Descriptive and inferential statistics were used for data analysis. Significant level was set with P &lt; .05. Results: A high percentage of parents of SCD participants were of medium to high SES [73.33%- HbSC; 64.29%- HbSS]. While the rates of hospitalization of HbSS (92.85%) and HbSC (66.67%) were dissimilar, the rates of patients that had suffered vaso-occlusive crisis (VOC) in the last three months prior to the study were comparable [46.67%-HbSC; 53.57%-HbSS]. The daily fruit/vegetable consumption habits of 3 genotypes were poor ranging from 15-25%. The hematocrit levels of the 3 groups were significantly different. Conclusion: The study suggests that high percentage of patients belong to medium-high SES, signifying that educational background of parents did not impact prevalence of the disease.

Assessment of IL-2, IL-10 &TNF-〈 in sickle cell disease participants taking selenium supplement in their steady state

Assessment of IL-2, IL-10 &TNF-〈 in sickle cell disease participants taking selenium supplement in their steady state

Dental Caries in Children with Sickle Cell Disease and Its Association with the Use of Hydroxyurea and Penicillin Prophylaxis in Dar Es Salaam.

This comparative study sets out to report dental caries status among individuals with Sickle Cell Disease (HbSS) against those with sickle cell trait (HbSA) and those without the disease (HbAA) as controls. The study further assessed the impact of penicillin chemoprophylaxis and hydroxyurea use on dental caries among Sickle Cell Disease participants. This was a comparative cross-sectional study in which 93 children aged 30 to 60 months were recruited. There were 60 participating children who had SCD (HbSS), 17 with SCD trait (HbAS) and 16 were without SCD or SC trait (HbAA). A questionnaire was used to record sociodemographic details including mean age in months and sex and on haemoglobin genotype for all the participants. Specifically, for the participants with HbSS, information on their whether they are taking hydroxyurea (HU), and penicillin chemoprophylaxis was recorded. To assess the prevalence of dental caries, clinical examination of all primary maxillary and mandibular teeth to determine the presence or absence of dental caries lesions was also recorded. A total of 1197 teeth from 93 children were examined, whereby, 45 (2.4%) of them had dental caries. The participating children with HbAA genotype (6.6%, N=21) had more dental caries than their HbSS counterparts (2.0%, N=24), while none of the participants with HbAS exhibited dental caries. Among the participants with HbSS, males and those who use HU were 3.79 and 3.07 times more likely to have dental caries than their counterparts, female and non-users of HU, respectively. Dental caries was observed to be low among participants with HbSS when compared to those with HbAA. More research utilizing more robust methodologies is recommended.

Inflammation and autoimmunity are interrelated in patients with sickle cell disease at a steady-state condition: implications for vaso-occlusive crisis, pain, and sensory sensitivity.

ClinicalTrials.gov, Identifier: NCT05045820.

Abstract WP218: Risk Factors for Cerebral Aneurysms in Sickle Cell Disease

Introduction: Cerebral aneurysm frequency in sickle cell disease (SCD) is higher than in the general population. Specific risk factors explaining this difference have not been previously explored. We hypothesize that increased cerebral blood flow (CBF), low hemoglobin (Hb) levels, and documented risk factors for aneurysms in the general population would be associated with aneurysm development in SCD. Methods: Children and young adults with SCD defined as HbSS and HbSβ0 thalassemia were recruited from SCD clinics at an academic medical center and a community health clinic from 2014-2022 along with age and race-matched controls. Written consent and assent were required. Inclusion: ages 6-45 years, study MRI and MRA of the brain, risk factor data collected. MRAs were reviewed and aneurysms were confirmed by consensus of 2 neuroradiologists. CBF was assessed via MRI with pseudo-continuous arterial spin labeling. Results: The study population included 183 SCD participants, including 13 (7.1%) with aneurysms. The healthy control group included 77 participants, 3 (3.9%) of these participants had aneurysms, all women. In the SCD sample, 10 of 13 (76.9%) aneurysms occurred in males while 76 of 170 (44.7%) without aneurysms were male (p=0.025). In the aneurysm group, 3 of 13 (23.1%) were smokers versus 8 of 170 (4.7%) without aneurysms (p=0.035). In the SCD aneurysm group, median age was older, 30.9 years versus 17.2 years without aneurysm, (p&lt;0.001). Systolic blood pressure and Hb levels were not different in SCD participants with and without aneurysms, p=0.074 and p=0.358, respectively. However, SBP was 119.7±14.9 with aneurysms vs 113.2±12.3mmHg without aneurysms. Mean gray matter CBF for the SCD group with aneurysms was higher at 86.7± 25.9ml/100g/min compared to 80.8 ± 20.3ml/100g/min in the SCD group without aneurysms, though not significantly (p=0.325). Discussion: Increased CBF and low hemoglobin levels were not risk factors for cerebral aneurysms in SCD in this relatively small cohort. Like the general population, age and smoking are risk factors for aneurysm development in SCD. In contrast to the general population, male sex rather than female sex in SCD is an aneurysm risk factor. Based on these data, a larger consortium to study aneurysms in SCD is needed.

Global White Matter Changes and Associations with Cognition in Pediatric Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is a genetic blood disorder affecting multiple organ systems, particularly the brain (Pinto, V.M. et al 2019). Neurocognitive deficits can occur in the presence or absence of overt brain injury, such as stroke or silent cerebral infarction (SCI). Using diffusion tensor imaging (DTI) metrics, multiple studies have identified widespread white matter alterations in individuals with SCD. DTI abnormalities, such as decreased fractional anisotropy (FA) and increased mean diffusivity (MD), have been associated with decreased processing speed in this population (Stotesbury et al. 2018). The goals of this study are to 1) define developmental differences in diffuse (brain-wide) white matter microstructure between SCD and control pediatric participants and 2) determine medical and neurocognitive characteristics of pediatric participants with SCD and abnormal DTI metrics. Methods: Thirty-eight participants between 8 to 12 years of age with no prior known history of stroke, SCI, or seizures were recruited for a prospective longitudinal study. Study groups consisted of 28 participants with SCD and 10 sibling or unrelated control participants. This study was a cross-sectional analysis of participants who completed DTI scans and neuropsychological testing at study entry (n=35). DTI was obtained on a 3T Philips research scanner 2.2mm nominal isotropic resolution; 32 diffusion directions obtained at b=700 s/mm 2. Preprocessing, tensor estimation, and calculation of FA and MD maps were performed using DTI Studio/MRICloud and its pediatric DTI atlas. Neurocognitive evaluation was performed and interpreted by a trained psychology associate with supervision from a board-certified neuropsychologist and included intelligence testing (Weschler Intelligence Scale for Children, WISC-5). Statistical analyses were performed using STATA 18 and MATLAB 2022a. We examined cohort-level demographics using chi-square tests, T-tests, and Wilcoxon rank sum tests (Table 1). To examine diffuse differences in white matter microstructure development, we used 19 bilateral white matter regions of interest [ROIs] shown in prior research to be important in patients with SCD with and without SCI. We examined MD and FA values within ANOVA models (each in terms of Group*Age + ROI) to assess group-level differences (SCD vs. control) and group x age interactions. We used ANOVA loadings to compute global MD and FA scores and computed 95% prediction intervals by age based on control participants. We identified participants with SCD with global scores suggestive of white matter microstructural differences (high MD and/or low FA) and compared their overall neurocognitive profiles. Results: The SCD and control participants were similar with regards to age, sex, and full-scale IQ. SCD participants had significantly lower median hemoglobin levels than control participants. There was one control participant who met criteria for SCI. SCD vs. control group status, age, and group x age interactions all significantly impacted our MD model (explaining 0.8%, 1.1%, and 0.8% of total variance, respectively; all p&amp;lt;0.001). MD decreased with age in the combined cohort (β=-9.3±1.6e-7/month) with significant flattening of this trend in children with SCD (group x age interaction: β=+7.9±2.0e-7/month). In contrast, only age significantly impacted our FA model (p&amp;lt;0.001, explaining 1.1% of variance); group status and group x age interactions each explained &amp;lt;0.2% of variance in FA. Four children with SCD had global DTI metrics suggestive of white matter injury (one with high MD and low FA; two with high MD only; one with low FA only). All 4 participants with abnormal DTI metrics had abnormal MRIs, three of whom had SCI and one of whom had lesions that did not meet the size criteria for SCI. Three participants had full scale IQs 1 standard deviation below the expected mean of 100 (&amp;lt;85). Conclusion: We identified differences in global white matter microstructural indices between SCD and control participants with an apparent blunting of expected decreases in mean diffusivity with age. Our continuing longitudinal study will explicitly assess DTI trajectories and implications for neurocognitive functioning in children with SCD.

Identifying Geriatric Syndromes in Adults with Sickle Cell Disease Using the Sickle Cell Disease Functional Assessment (SCD-FA): The Sickle Cell Disease Functional Assessment Validation and Refinement (SILVR) Study

Introduction As people with sickle cell disease (SCD) age, they experience accelerated functional decline. Since historically survival for SCD has been limited to middle age, geriatric syndromes in adults with SCD remains understudied. Chronological age does not accurately represent a person's health status; thus, valid functional measures for adults with SCD are required. Geriatric assessments are commonly used to measure function in older adults in the general population. We previously demonstrated feasibility, safety, and acceptability of a geriatric assessment battery called the Sickle Cell Disease Functional Assessment (SCD-FA) in adults with SCD. The SCD-FA includes physical performance test and surveys evaluating multiple health domains. The purpose of this study was to evaluate the construct validity of the SCD-FA. Methods We enrolled younger (age 18-39) and older (age ≥ 40 years) adults with SCD in a single center prospective study. We assessed construct validity of each SCD-FA measure by determining known-group validity. Specifically, we evaluated whether the SCD-FA could distinguish between participants known to differ based on the following: age (&amp;lt; 40 vs ≥ 40), SCD genotype non-severe (HbSC/HbSβ +-thalassemia) vs severe (HbSS/HbSβ 0-thalassemia), and dependence in Activities of Daily Living/Instrumental Activities of Daily Living (no ADL/IADL deficit vs ≥ 1 ADL/IADL deficits). We used Student's t-tests and Wilcoxon rank sum test to gauge significant differences between groups. Results We performed the SCD-FA in 111 adults with SCD at steady state, with 93 (84%) having complete data. Most participants (58%) were female. The mean age of all participants was 44 ± 14 (range 19-82 years), with most (56%) age ≥ 40 years. The mean age for younger adults (18-39 years) was 30 ± 5.8 and 54 ± 9.3 for older adults (≥ 40 years). When evaluating SCD-FA measures by age, older adults had lower scores on PROMIS Physical Function (younger 52 ± 6.9 vs older 46 ± 8.4; p&amp;lt;0.001). Although there was no difference in number of falls by age, there were several participants with ≥ 1 fall (15%) or near fall (36%) in the last 6 months. Older adults had higher scores on the Social Support Survey (implying better support) (younger 69 ± 30 vs older 80 ± 20; p&amp;lt; 0.05). Older adults had more non-SCD comorbidities (younger 0.5 ± 0.7 vs older 1.7 ± 1.7; p&amp;lt;0.001), with no younger adults with ≥ 3 comorbidities vs. 33% of older adults with ≥ 3 comorbidities, more SCD conditions (younger 2.0 ± 1.5 vs older 2.7 ± 1.7; p&amp;lt; 0.05), and more reports of fair or poor hearing (0% younger vs 8% older; p = 0.01). Older adults took more prescribed medications (younger 3.9 ± 2.4 vs older 6.3 ± 3.9; p = 0.001) and were more likely to meet criteria for polypharmacy (defined as ≥ 5 prescribed medications) with 30% of younger adults vs 64% of older adults (Figure). Most participants (64%) had HbSS/HbSβ 0 (severe genotype) and 36% had HbSC/HbSβ + (non-severe genotype). When comparing groups by genotype, participants with severe genotypeshad a lower body mass index (severe25 ± 5.8 vs non-severe 31 ± 8.4 kg/m2; p &amp;lt; 0.005) and fewer non-SCD comorbidities (severe 0.75 ± 1.0 vs non-severe 1.9 ± 1.8; p&amp;lt; 0.005). There was no difference in physical performance, falls, psychological state, SCD conditions, and number of medications by genotypes. Of all participants, 34% reported dependence in ≥ 1 ADL/IADL. When comparing groups by ADL/IADL dependence, those who were dependent in ≥ 1 ADL/IADL had worse physical performance for all measures (gait speed, grip strength, 6-minute walk, Timed Up and Go test, and 30-Second Chair Stands). ADL/IADL dependent participants had more falls, higher PHQ-9 scores, lower MiniCog scores, more non-SCD comorbidities, and were more likely to report fair or poor vision. There was no difference in reported hearing deficits. (Table) Conclusion The SCD-FA was able to distinguish between known-groups by age and ADL/IADL dependence and identify deficits in adults with SCD such as falls, polypharmacy, comorbidities, and sensory deficits. Geriatric syndromes did increase with age in adults with SCD and were more common than in the general population (34% ADL dependent SCD participants vs 15% of middle-aged U.S. adults). Therefore, there is a need for early initiation of interventions to improve function and quality of life. We are currently adapting geriatric interventions for older adults with SCD. In future studies we will assess the predictive validity of the SCD-FA.

Effects of L-Glutamine on Biomarkers of Response in Sickle Cell Disease: A Pharmacokinetics-Pharmacodynamics Analysis

OralL-glutamine (Endari®) has been approved by the US-FDA to reduce the acute complications of sickle cell disease (SCD) in patients at least 5 years of age. L-glutamine has several roles in the body including de novo synthesis of intracellular glutathione which acts as an antioxidant. However, the mechanisms of action by which L-glutamine could reduce complications in SCD require further investigation. Additionally, there are no known biomarkers to assess response to L-glutamine therapy. We conducted an open-label, dose-ascending trial (NCT04684381) of L-glutamine in pediatric (n=4) and adult (n=4) participants with SCD as well as in adult healthy volunteers (n=4) (Table 1). Over a three-week trial period with 4 study visits, serial blood samples were collected to define the pharmacokinetics (PK), pharmacodynamics (PD), and PK-PD interactions of L-glutamine using a broad panel of laboratory investigations including amino acid concentrations, blood counts, percentage of dense red blood cells (%DRBC), whole blood viscosity, osmotic and oxygen gradient ektacytometry, and reactive oxygen species (ROS) of reticulocytes (ROS retic) and mature red blood cells (ROS RBC). In PK-PD analysis of amino acids, we focused analysis on arginine (Arg), citrulline (Cit), and ornithine (Orn) based on the hypothesis that L-glutamine improves endothelial function by increasing arginine bioavailability and augmenting nitric oxide (NO) production. Peak arginine concentration was directly correlated with both the maximum L-glutamine concentration (C max p=0.001) and area-under-the curve (AUC) (p=0.047) indicating improvement in arginine bioavailability, but there was no significant linear correlation with either the Arg:Orn or Arg:(Orn+Cit) ratios. In PK-PD analysis of osmotic gradient ektacytometry, L-glutamine C max was directly correlated with the elongation maximum (EI max), noted in all participants at visit 4 (p=0.033). In SCD participants, L-glutamine C max was inversely correlated with O hyper (osmolality at EI max/2) at visits 3 (p=0.044) and 4 (p=0.004). In PK-PD analysis of oxygen gradient ektacytometry in SCD participants, L-glutamine C max was inversely correlated with the point of sickling (POS) at visit 3 (p=0.005) but not at visit 4 (p=0.054). Together, these findings suggest that although L-glutamine may decrease cellular hydration (decreased O hyper) it may increase RBC deformability (increased EI max) and delay the onset of sickling after hypoxia (decreased POS). In PK-PD analysis of viscometry, higher L-glutamine C max was associated with higher whole blood viscosity measurements at all shear rates (p&amp;lt;0.05). However, L-glutamine C max was also directly correlated with hematocrit-to-viscosity ratio (HVR) at the highest shear rates in the overall population at visit 4 (p&amp;lt;0.05). In addition, L-glutamine C max for SCD participants was associated with increased hemoglobin concentration, an effect that was observed at visit 4 (p=0.025), and increased %DRBC, an effect detected at visits 3 (p=0.008) and 4 (p=0.007). In PK-PD analysis of ROS, L-glutamine AUC was inversely correlated with ROS Retic (p=0.024), but not ROS RBC, in all participants at visit 3. When considered as total ROS Retic (calculated as ROS retic × absolute reticulocyte count), there was a similar inverse correlation with glutamine AUC in SCD participants, although not statistically significant. In contrast to all other biomarkers, L-glutamine C max was not correlated with any ROS measurement. This PK-PD analysis of L-glutamine reveals biological effects that alter RBC characteristics and could modify SCD-related complications, with a complex interplay summarized in Figure 1. Prospective studies can validate these biomarkers and be used to monitor the effects of L-glutamine therapy in SCD patients.

Myocardial Fibrosis in Sickle Cell Anemia

Introduction Cardiovascular disease is a leading cause of morbidity and mortality in patients with sickle cell disease (SCD) as they age.Contrast-enhanced cardiac MRI has been utilized to evaluate myocardial fibrosis by calculating the extracellular matrix volume fraction (ECV) from pre and post-contrast T1 mapping. Recent research in both animal and human models reveal that SCD patients have elevated ECV suggestive of myocardial fibrosis and is associated with diastolic dysfunction. The effects of current first-line therapies, chronic transfusions (CTT) or hydroxyurea (HU), on myocardial fibrosis are unknown and at present, there is conflicting data regarding their benefits. At our institution, SCD patients are treated early with either hydroxyurea, chronic transfusions, or both. We aimed to determine whether current disease-modifying therapies differentially affect myocardial fibrosis. Methods This was a single-center, retrospective cohort study of chronically transfused SCD patients and SCD patients on HU and/or CTT at Children's Hospital of Los Angeles between 2017 and 2022 aiming to assess clinical biomarkers associated with elevated ECV in sickle cell disease. This study was reviewed and approved by the Children's Hospital Los Angeles Institutional Review Board. All patients underwent cardiac MRI for clinical assessment of myocardial iron, cardiac enlargement, and myocardial fibrosis. Continuous variables are expressed as mean±standard deviation for normally distributed data and median [interquartile range] for non-normally distributed data. Parametric and non-parametric testing were used where appropriate and c-square testing was used for categorical variables. Results A total of 63 SCD patients, mean age 17.3±5.9 years (range 5-36yo), who underwent contrast-enhanced cardiac MRI imaging between 2017 and 2022 were included in this study: 27 CTT; 43 HU; and 7 healthy participants, mean age 15.4±2.4 years. There was no difference in age between treatment groups, nor healthy and SCD participants. There were 6 SCD patients not on any therapy and 13 patients on both. The ECV was elevated in SCD versus healthy (31.3% [27.9, 35] vs 26% [23.7,27.2], P=0.0003). There was no significant difference between the ECV values of patients on CTT, HU, both or no therapy, P=0.56 (Fig.1A). There was no difference in average length of therapy between CTT or HU, mean 10.4±4.9 vs 10.2±5.2 years and no association between length of therapy and ECV. We found positive correlation of E/A ratio with ECV in patients with SCD regardless of therapy (Spearmans rho 0.34, P=0.008), suggesting an association with left ventricular (LV) restrictive physiology. ECV was associated with increased WBC count (rho +0.28, P=0.03), AST (rho +0.3, P=0.02), decreased GFR (P=0.02), and decreased hemoglobin (rho -0.41, P=0.0013) (Fig.1B), while there was a trend toward increased urine microalbumin (rho +0.41, P=0.09). Discussion Fibrosis is likely due to prolonged, continuous exposure to inadequate myocardial oxygen supply and cardiac microvascular disease. Amelioration of myocardial fibrosis likely requires consistent, effective CTT or HU therapy as suggested by the Cincinnati/CHLA study. The HU patients in that study had documented high MCV or HbF over many years before ECV was measured. St Jude's study was prospective but follow-up was only 2 years and not compared to an untreated or poorly treated cohort. The sum of these studies suggests that protection from fibrosis may only be seen with continual protection from anemia/microvascular disease. This hypothesis remains to be proven. While we did not see a differential effect of hydroxyurea vs. chronic transfusion therapy, it is important to put this data into the context of SCD therapies and their indications. CTT is generally reserved for the most severe vascular disease phenotypes, such as stroke. Hydroxyurea is often prescribed but not always adhered to. The ECV range in our cohort was lower than that found in the original Cincinnati cohort, mean 44%±8, but similar to that found in the St. Jude cohort, median 30% [IQR 28,34] (Fig.1A). Lastly, elevated ECV correlates with anemia, a modifiable risk factor; restrictive LV physiology; and decreased estimated GFR, which may hint at similar etiologies. In summary, ECV is a clinically relevant cardiovascular biomarker and current preventative therapies may ameliorate but not abrogate myocardial fibrosis.

Abdominal ultrasound in adult sickle cell patients

Background: Sickle cell disease (SCD) causes recurring crises that lead to changes in organs such as the spleen, liver, and kidneys, resulting in high morbidity and mortality. Materials and Methods: This study was carried out in the Adult Haematology Clinic and the Radiology Department of Lagos State University Teaching Hospital, Ikeja Nigeria. Consenting SCD participants in a steady state and consenting blood donors with HbAA phenotype, representing controls were subjected to an abdominal ultrasound scan. The sizes of their spleen, liver, and kidneys were measured. Results: There were 82 participants, 41 in each group (SCD and HbAA controls). The mean age for SCD was 25.9 ± 7.49 years and for HbAA was 26.49 ± 4.35 years. In each group, there were 41 participants, comprising 19 males and 22 females. Individuals with HbAA had spleen sizes approximately one and a half times larger than those with SCD (SCD: 6.81 ± 3.83 cm, HbAA: 9.97 ± 1.11 cm, P = 0.01). Conversely, participants with SCD exhibited larger liver, right kidney, and left kidney measurements compared to those with HbAA (Liver SCD: 14.91 ± 1.60 cm, HbAA: 13.32 ± 1.56 cm, P = 1.00), (right kidney SCD: 10.52 ± 1.16 cm, HbAA: 9.92 ± 1.04 cm, P = 0.02), (left kidney SCD: 10.76 ± 1.45 cm, HbAA: 10.58 ± 1.60 cm, P = 0.53). Conclusion: The study found that SCD affects the sizes of abdominal organs, including the spleen, kidneys, and liver, compared to those without the condition.

Silent infarction in sickle cell disease is associated with brain volume loss in excess of infarct volume.

Sickle cell disease (SCD) increases cerebral infarct risk, but reported effects on brain volume have varied. More detailed information using larger cohorts and contemporary methods could motivate the use of longitudinal brain volume assessment in SCD as an automated marker of disease stability or future progression. The purpose of this study was to rigorously evaluate whether children and young adults with SCD have reduced gray matter volume (GMV) and white matter volume (WMV) compared to healthy controls using high-resolution MRI. We tested the hypotheses that (i) elevated CBF, a marker of cerebral hemodynamic compensation in SCD, is associated with global and regional brain atrophy, and (ii) silent cerebral infarct burden is associated with brain atrophy in excess of infarct volume. Healthy controls (n = 49) and SCD participants without overt stroke (n = 88) aged 7-32 years completed 3 T brain MRI; pseudocontinuous arterial spin labeling measured CBF. Multivariable linear regressions assessed associations of independent variables with GMV, WMV, and volumes of cortical/subcortical regions. Reduced hemoglobin was associated with reductions in both GMV (p = 0.032) and WMV (p = 0.005); reduced arterial oxygen content (CaO2) was also associated with reductions in GMV (p = 0.035) and WMV (p = 0.006). Elevated gray matter CBF was associated with reduced WMV (p = 0.018). Infarct burden was associated with reductions in WMV 30-fold greater than the infarct volume itself (p = 0.005). Increased GM CBF correlated with volumetric reductions of the insula and left and right caudate nuclei (p = 0.017, 0.017, 0.036, respectively). Infarct burden was associated with reduced left and right nucleus accumbens, right thalamus, and anterior corpus callosum volumes (p = 0.002, 0.002, 0.009, 0.002, respectively). We demonstrate that anemia and decreased CaO2 are associated with reductions in GMV and WMV in SCD. Increased CBF and infarct burden were also associated with reduced volume in subcortical structures. Global WMV deficits associated with infarct burden far exceed infarct volume itself. Hemodynamic compensation via increased cerebral blood flow in SCD seems inadequate to prevent brain volume loss. Our work highlights that silent cerebral infarcts are just a portion of the brain injury that occurs in SCD; brain volume is another potential biomarker of brain injury in SCD.

Red cell exchange transfusions increase cerebral capillary transit times and may alter oxygen extraction in sickle cell disease.

Persons with sickle cell disease (SCD) suffer from chronic hemolytic anemia, reduced blood oxygen content, and lifelong risk of silent and overt stroke. Major conventional stroke risk factors are absent in most individuals with SCD, yet nearly 50% have evidence of brain infarcts by the age of 30 years, indicating alternative etiologies for ischemia. We investigated whether radiological evidence of accelerated blood water transit through capillaries, visible on arterial spin labeling (ASL) magnetic resonance imaging, reduces following transfusion-induced increases in hemoglobin and relates to oxygen extraction fraction (OEF). Neurological evaluation along with anatomical and hemodynamic imaging with cerebral blood flow (CBF)-weighted pseudocontinuous ASL and OEF imaging with T2 -relaxation-under-spin-tagging were applied in sequence before and after blood transfusion therapy (n = 32) and in a comparator cohort of nontransfused SCD participants on hydroxyurea therapy scanned at two time points to assess stability without interim intervention (n = 13). OEF was calculated separately using models derived from human hemoglobin-F, hemoglobin-A, and hemoglobin-S. Gray matter CBF and dural sinus signal, indicative of rapid blood transit, were evaluated at each time point and compared with OEF using paired statistical tests (significance: two-sided p < 0.05). No significant change in sinus signal was observed in nontransfused participants (p = 0.650), but a reduction was observed in transfused participants (p = 0.034), consistent with slower red cell transit following transfusion. The dural sinus signal intensity was inversely associated with OEF pretransfusion (p = 0.011), but not posttransfusion. Study findings suggest that transfusion-induced increases in total hemoglobin may lengthen blood transit times through cerebral capillaries and alter cerebral OEF in SCD.

Effect of Blood Transfusion on Cerebral Hemodynamics and Vascular Topology Described by Computational Fluid Dynamics in Sickle Cell Disease Patients.

The main objective of this study was to demonstrate that computational fluid dynamics (CFD) modeling can be used to study the contribution of covert and overt vascular architecture to the risk for cerebrovascular disease in sickle cell disease (SCD) and to determine the mechanisms of response to therapy such as chronic red blood cell (cRBC) transfusions. We analyzed baseline (screening), pre-randomization and study exit magnetic resonance angiogram (MRA) images from 10 (5 each from the transfusion and observation arms) pediatric sickle SCD participants in the silent cerebral infarct transfusion (SIT) trial using CFD modeling. We reconstructed the intracranial portion of the internal carotid artery and branches and extracted the geometry using 3D Slicer. We cut specific portions of the large intracranial artery to include segments of the internal carotid, middle, anterior, and posterior cerebral arteries such that the vessel segment analyzed extended from the intracranial beginning of the internal carotid artery up to immediately after (~0.25 inches) the middle cerebral artery branching point. Cut models were imported into Ansys 2021R2/2022R1 and laminar and time-dependent flow simulation was performed. Change in time averaged mean velocity, wall shear stress, and vessel tortuosity were compared between the observation and cRBC arms. We did not observe a correlation between time averaged mean velocity (TAMV) and mean transcranial Doppler (TCD) velocity at study entry. There was also no difference in change in time average mean velocity, wall shear stress (WSS), and vessel tortuosity between the observation and cRBC transfusion arms. WSS and TAMV were abnormal for 2 (developed TIA) out of the 3 participants (one participant had silent cerebral infarctions) that developed neurovascular outcomes. CFD approaches allow for the evaluation of vascular topology and hemodynamics in SCD using MRA images. In this proof of principle study, we show that CFD could be a useful tool and we intend to carry out future studies with a larger sample to enable more robust conclusions.

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease

AbstractChildren with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (−19.4 mL/100 g/min) and OEF (−8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, −0.9 mL/100 g/min; P = .024; OEF, −3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.

Lung function abnormalities in patients with sickle cell disease in a Nigerian tertiary health centre

ABSTRACT Introduction Pulmonary complications with the subsequent lung function abnormalities occur commonly among sickle cell disease (SCD) patients even while at their steady states. This study, therefore, aimed to determine the prevalence and pattern of lung function abnormalities and its associated factors among SCD patients. Methods This was a hospital-based cross-sectional study in a Nigerian tertiary hospital involving 113 SCD participants and age- and gender-matched non-SCD controls. Spirometry, transthoracic echocardiography, oxygen saturation, complete blood count, serum urea and creatinine were done for the participants. Results The forced vital capacity, forced expiratory volume in 1 second and the peak expiratory flow rate of the SCD participants were significantly lower than that of the control group with p-values of 0.004, 0.000 and 0.000 respectively. Of the SCD participants; 40.7% recorded abnormal lung function with the restrictive pattern occurring most commonly with a prevalence of 28.3%. There was a statistically significant relationship between age and lung function of the SCD participants (p = 0.044). Conclusion Lung function abnormalities occur frequently among people with SCD with the restrictive pattern being the most common abnormality and these abnormalities occur more frequently as these patients age.

Exploring the relationship of sleep, cognition, and cortisol in sickle cell disease

BackgroundNeurocognitive impairment is common in people with Sickle Cell Disease (SCD) and evidence is accumulating that sleep disturbances play a role. The interaction between cortisol and sleep in the general population is associated with cognition as well as general wellbeing but there are few data in SCD. We aimed to understand the relationship between cortisol and sleep in individuals with SCD and explored associations with cognition. MethodsForty-five participants of black heritage (SCD: N = 27, 9–29 years, 16 females; Controls: N = 18, 11–25 years, 13 females) were recruited from the community between 2018 - 2020. Participants completed standardized questionnaires about their sleep behaviour and wore actigraphy MotionWatch8 for 7 nights to assess nocturnal sleep patterns. Salivary cortisol samples were taken on wakening and 3 times after 14:00. Cognition was assessed using the Wechsler Intelligence Scales for children and adults. ResultsPeople with SCD took longer to fall asleep and experienced greater wake bouts, mobile minutes and fragmented sleep compared to controls. Although non-significant, people with SCD experienced lower morning cortisol, with a flattened diurnal cortisol ratio compared to controls. Interestingly, SCD participants, but not controls, with low diurnal variation scored lowest on processing speed (PSI) and perceptual reasoning index (PRI). A moderator analysis revealed that the effect of morning cortisol and diurnal cortisol ratio on PRI by group health (i.e., SCD and healthy controls) depended on sleep quality. DiscussionSleep and cortisol may play a crucial role in the expression of cognitive difficulties seen in SCD. This should be considered for the development of interventions to optimise cognitive functioning and sleep. This, in turn, could positively impact on secretion of cortisol and general health in SCD.

Enuresis and Hyperfiltration in Children With Sickle Cell Disease.

Nocturnal enuresis is a common symptom in children with sickle cell disease (SCD). Risk factors for development of enuresis are currently unknown. An early manifestation of SCD-associated kidney damage is glomerular hyperfiltration. We test the hypothesis that in a pediatric SCD cohort, individuals with hyperfiltration are more likely to have nocturnal enuresis when compared to children without hyperfiltration. To assess the relationship between nocturnal enuresis and hyperfiltration, we retrospectively evaluated children with SCD enrolled in the Evaluation of Nocturnal Enuresis and Barriers to Treatment among Pediatric Patients with SCD study and prospectively identified children who reported nocturnal enuresis and were enrolled in the longitudinal cohort study Sickle Cell Clinical Research and Intervention Program. Nocturnal enuresis occurred in 46.5% of Pediatric Patients with Sickle Cell Disease participants and was more frequent in participants with HbSS/HbSβ 0 thalassemia and in male participants. We did not identify an association between hyperfiltration from 3 to 5 years of age with the later development of enuresis. Severe SCD genotypes and male sex were associated with nocturnal enuresis after age 5 years. We could not identify additional renal or hematologic predictors associated with the diagnosis of nocturnal enuresis. Future studies should incorporate nonrenal risk factors into studies that predict development of enuresis.