Sickle Cell Disease Participants Research Articles

Metabolic syndrome among adults living with sickle cell disease

Metabolic syndrome (MetS) is a key risk factor for cardiovascular disease (CVD) incidence and all-cause mortality. MetS prevalence among adults with sickle cell disease (SCD) is not well known. We report initial findings from a cross-sectional study that examined MetS risk factors within a cohort of adults living with SCD.50 adult SCD participants (ages 21–66 years; 72% female) completed demographic and health behavior surveys, health-related family and personal histories, and anthropometric and laboratory measurements. Descriptive and inferential statistics were used to summarize and compare CVD risk factors, stratified in separate analyses by SCD genotype and sex.Triglyceride, blood pressure, and fasting glucose levels were within normal limits. 78% of the cohort reported moderate to high physical activity. However, 46% of this cohort was overweight and dietary saturated fat intake exceeded both the national average (11%) and US Dietary Guidelines (<10%). 14.3% of the cohort fulfilled criteria for MetS with large waist circumference and reduced HDL levels prominently accounting for this status.We evaluated the prevalence of MetS in a cohort of adults living with SCD. Our findings suggest that increased attention to eating habits and physical activity may generate new approaches for decreasing cardiovascular morbidity in SCD.

Exploring putative genetic determinants of inter-individual phenotypic heterogeneity in sickle cell disease: A cross-sectional Jamaican cohort-based study

Patients with sickle cell disease (SCD) display puzzling inter-individual phenotypic heterogeneity, conceivably related to inherent differences in antioxidant protection, hemoglobin binding, bilirubin catabolism and methyl group handling. Therefore, we explored putative associations between clinically important phenotypic measures and functional polymorphisms within specific candidate genes encoding glutathione S-transferase, haptoglobin, uridine 5′-diphospho-glucuronosyltransferase 1A1, methyl tetrahydrofolate reductase, 5-methyltetrahydrofolate-homocysteine methyltransferase, and cystathionine beta-synthase. Two-hundred and thirty SCD participants (mean age 25.1 ± 2.8) were recruited from Jamaica's Annual Sickle Cell Unit Cohort Review – two-hundred and five had homozygous hemoglobin SS (HbSS) disease, twenty-five had hemoglobin SC (HbSC) disease. Regression analyses revealed some novel genotype-phenotype associations. HbSC participants had significantly lower mean lactate dehydrogenase (p = 0.01) and glutathione (p < 0.001) values than HbSS participants. Glutathione S-transferase P1 (GSTP1) was significantly associated with mean corpuscular hemoglobin concentration using univariate (p = 0.044) and multivariable regression (p = 0.012). 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) was significantly associated with hemoglobin F % using univariate (p = 0.010) and multivariable regression (p = 0.009). In conclusion, this exploratory cross-sectional study generated novel, useable, and informative genotype-phenotype estimates of association, but larger studies are needed to determine whether these specific variants are related to inter-individual phenotypic variability in SCD.

Increased prevalence of renal cysts in patients with sickle cell disease

BackgroundEarly detection and interventions have enabled patients with sickle cell disease (SCD) to live well into adulthood. Consequently, the chronicity of SCD allows for the insidious manifestation of multisystem complications, including renal damage. Cystic renal lesions are commonly incidentally discovered on ultrasound and computerised tomography (CT) imaging of the abdomen. Most are benign simple cysts, however, difficulties may be encountered if infection, rupture, haemorrhage or cancerous changes develop. We aimed to determine whether patients with SCD have a higher prevalence of simple renal cysts compared to non-SCD individuals.MethodsData for a group of 223 patients with SCD who had undergone an ultrasound and/or CT imaging of the abdomen were extracted for comparison with 180 control patients (haemoglobin genotype unknown), matched for age and ethnicity. Scans were evaluated for 198 SCD patients and 180 controls.ResultsRenal cysts were found in 58% of the SCD group and 20% of the controls (OR 5.4 (CI 2.6–11.0), RR 2.8 (CI 1.9–4.2)). Bilateral renal cysts were found in 28% of the SCD participants in comparison with 5% of the control group. In those who had one or more cysts identified, the average number of cysts was 3.76 for the SCD group and 1.94 for the controls. Men with SCD were more likely to develop cysts than women (66% vs 53%), as were men without SCD (22% vs 17%).ConclusionsSimple renal cysts occur more frequently, are more abundant and develop at a younger age in patients with SCD than ethnically-matched controls. Further study of the mechanism underlying cyst formation may shed light on both sickle cell nephropathy and other cystic renal diseases.

Suppression of the Hemodynamic Response Function Demonstrates Altered Cerebral Vasoreactivity in Sickle Cell Disease

Introduction: Children with sickle cell disease (SCD) face progressive cognitive decline compared to their unaffected siblings, even prior to the occurrence of stroke, suggesting damage to the underlying functional brain organization. Hence, functional MRI (fMRI) studies are needed to help characterize the pathophysiological basis of cognitive decline in SCD.Functional MRI techniques measure the blood oxygenation level dependent (BOLD) signal, which is sensitive to changes in the ratio of oxy- to deoxy-hemoglobin driven by local changes in neural activity. Regional brain activity raises local oxygen consumption that is overly compensated for by increases in local blood flow, bringing an excess of oxygenated blood and elevating the ratio of oxy- to deoxy-hemoglobin in the active brain regions. This stereotyped neurovascular coupling sequence unfolds over 20 seconds and gives rise to the canonical hemodynamic response function (HRF). Given the severe chronic anemia with attendant hypoxia, alterations in oxygen binding, increased cerebral blood flow (CBF), and prevalence of vasculopathy associated with SCD, careful comparison of the HRF between children with SCD and controls must occur prior to pursuing fMRI analyses.Children with SCD have increased CBF and oxygen extraction fraction at baseline when compared to controls, suggesting that they require these compensatory mechanisms to meet the brain's metabolic demands at rest, which could affect their ability to further increase blood flow in response to local neural activity. Thus, we hypothesized that children with SCD would have a blunted HRF with lower peak amplitudes when compared to sibling controls. To test our hypothesis, we conducted the gold-standard visual task-driven fMRI paradigm for measuring HRF in children with SCD and their siblings.Methods: Children with HbSS or HbS beta thalassemia null disease and healthy, sibling controls between the ages of 5 and 21 years were recruited from St. Louis Children's Hospital. Participants were excluded for history of overt stroke, vasculopathy, stem cell transplant or chronic exchange transfusion therapy. Participants completed a fMRI task that required them to press a button with their right index fingers at the onset of a 30 Hz counterphase-flickering checkerboard and to press a button with their left index finger at its offset. Nine time points (TR = 2.2 s) were included in the general linear model used to describe the HRF in response to each stimulus. No assumptions were made regarding the shape of the HRF. A peak-finding algorithm extracted regions of interest (ROI) from the group fMRI activation map. Activations were averaged across all voxels within each ROI to generate region-wise time courses for each participant. Results are reported as median [interquartile range], and comparisons are made using a Mann Whitney U test or Pearson chi-square test.Results: Fourteen children with SCD and 13 healthy sibling controls were included in the analysis. There was not a statistically significant difference in age (10.0 [9.8-15.5] years vs. 13.0 years [11.0-14.5]; p = 0.66) or gender (p = 0.31) between the SCD and control cohorts. Eighty-six percent of SCD participants were treated with hydroxyurea at a dose of 30.3 [28.6-33.1] mg/kg/day. The baseline hemoglobin of the SCD cohort was 8.8 [8.3-10.1] g/dL. Two children with SCD had a history of silent cerebral infarcts.The peak amplitude of the HRF in the primary visual cortex (V1) was significantly reduced in children with SCD (right: 0.29 [0.23-0.50]% and left: 0.29 [0.20-0.53]%) when compared to sibling controls (right: 0.56 [0.53-0.95]%, p < 0.001 and left: 0.52 [0.38-0.90]%, p = 0.01). While the HRF amplitude was reduced by almost 50%, there was no difference in the timing of the BOLD response (i.e. lag) between groups, both demonstrating a time-to-peak of 8.8 seconds (Figure).Conclusion: The striking decrease in HRF amplitude suggests that patients with SCD have altered cerebral vasoreactivity to neural stimuli. Further investigation into the pathophysiology behind and clinical implications of the blunted hemodynamic response in SCD is warranted. We are currently investigating the relationship between HRF suppression, cognitive outcomes and stroke risk in SCD, and the effects of HRF suppression on functional connectivity networks using resting-state functional connectivity MRI collected simultaneously in the same cohorts. [Display omitted] DisclosuresFields:NeuroPhage Pharmaceuticals: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. King:NIH - BMTCTN: Research Funding; NIH - NHLBI: Research Funding; HRSA: Research Funding. Dosenbach:NeuroPhage Pharmaceuticals: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Elevations in MR Measurements of Whole Brain and Regional Cerebral Blood Flow and Oxygen Extraction Fraction Suggest Cerebral Metabolic Stress in Children with Sickle Cell Disease Unaffected By Overt Stroke

Positron emission tomography (PET) studies have shown that the brain increases cerebral blood flow (CBF) and oxygen extraction fraction (OEF, the fraction of oxygen brain tissue extracts from blood) when oxygen delivery is compromised in adult ischemic stroke. Children with sickle cell disease (SCD) have higher CBF compared to healthy children, suggesting that autoregulatory mechanisms, compensating for compromised oxygen delivery, may underlie the pathophysiology of ischemic stroke in SCD. Until now, evaluation of cerebral oxygen metabolism in children with SCD has been limited to measurement of CBF due to the radiation risks of PET. We used a MR sequence that measures voxel-wise OEF to test our hypothesis that children with sickle cell disease will have elevated whole brain and regional OEF when compared to typically developing, sibling controls without SCD.Thirty-six participants, 8 controls and 28 with SCD (26 HbSS and 2 HbSB0), ages 5-21 years, were recruited from St. Louis Children's Hospital. Participants underwent brain MRI with measurement of CBF via pseudo-continuous arterial spin labeling and OEF via a novel processing of asymmetric spin echo sequence that measures tissue deoxyhemoglobin. CBF and OEF maps were individually co-registered to corresponding T1 images with FMRIB's Linear Image Registration Tool, and gray and white matter were segmented with FMRIB's Automated Segmentation Tool. Visual inspection identified a region of high OEF within the deep white matter of the frontal and parietal lobes in the majority of subjects (figure 1 a,b). OEF maps from control and SCD participants were coregistered and averaged into a single map, and then an OEF threshold of 47.5% was applied to demarcate this "high OEF region" (figure 1c). Hemoglobin (Hb) and hematocrit were obtained in SCD participants, while these values were assumed for the controls. Arterial oxygen content (CaO2) was calculated as 1.36 x Hb x SpO2. Comparisons were made with a Mann-Whitney U test or Student's t-test. Bivariate correlations were tested with Kendall's tau b. Bonferroni correction was used in determining significance. Multivariate linear regression modeling with block entry described covariates associated with CBF.The control and SCD cohorts did not differ in age, gender or SpO2. SCD participants demonstrated higher whole brain, gray matter and white matter CBF and OEF when compared to controls (table 1, figure 1a-b), but there was no difference in whole brain or segmented measures of CBF and OEF between SCD participants with structurally normal brain MRIs (n=16) and silent infarcts (n=12). SCD participants' OEF was higher within the "high OEF region" when compared to controls (table 1), but the regional OEF did not differ between SCD participants with structurally normal brain MRIs versus silent infarcts. Whole brain CBF negatively correlated with age (b = -0.554, p < 0.001), while whole brain OEF did not (b= 0.014, p = 0.921). Lower CaO2 correlated with higher whole brain CBF (b = -0.329, p < 0.016) and higher whole brain OEF (b = -0.587, p < 0.001). CaO2 remained a predictor (β = -0.38, p = 0.009) of CBF when controlling for age (β = -0.63, p < 0.001).We report the first whole brain, segmented and regional analysis of oxygen metabolism, including CBF and OEF, in a pediatric SCD cohort unaffected by overt stroke. Elevation in both CBF and OEF in response to low arterial oxygen content suggests children with SCD are chronically compensating to meet the brain's metabolic demands. OEF is more elevated in children with SCD when compared to healthy controls within the "high OEF region," which coincides with previously reported locations of silent infarcts. We propose that the "high OEF region" provides a tissue signature of vulnerable, metabolically stressed brain that is at risk for future stroke. [Display omitted] [Display omitted] DisclosuresFields:Neurophage: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Retrospective Survey of Sickle Cell Disease in Pregnancy in a Niger-Delta Nigerian Tertiary Health Center

Background: The number of sickle cell disease (SCD) females with pregnancy is increasing worldwide today because of better care for sickle cell patients and an increase in life expectancy for these people. This however poses obstetric complications if pregnancy progresses without adequate care and follow-up. This study aimed at determining the prevalence and challenges of SCD among pregnant women seen in ante-natal clinic in a Niger-delta Nigerian tertiary health center.Methodology: This was a-ten-year retrospective study of thirty five thousand, nine hundred and seventy six pregnant women seen at the antenatal clinic of Braithwaite Memorial Specialist Hospital (BMSH) (2003-2013). Biomedical data and hemoglobin (Hb) electrophoresis were obtained using hypothesis generation questionnaires and conventional hemoglobin electrophoretic machines respectively. Data analysis was obtained using SPSS version 16.Result: A total of 35,976 pregnant women registered in the ante-natal clinic within the study period out of which 28,815 (80.09%) were Hb AA, 7,109 (19.77%) were Hb AS, and 52 were Hb SS (prevalence of 1.4 per 1000 pregnant women). The average booking gestational ages of 22.6 and 29.1 weeks were recorded for SCD and non-SCD participants respectively. The higher level of education (Post-secondary and post-graduate) recorded was relatively higher among the SCD (60%) compared to non-SCD (58.05%) population, although this was not statistically significant (Table 1). Hemoglobin concentration below 11 g/dl were recorded by 39.4 % and 80.8% of non-SCD and SCD participants respectively (P=0.001) (Table 2a). The study population recorded 20.8% as Hb AS (Table 2b).Conclusion: The prevalence of sickle cell disease in pregnancy is on the increase in this region. Anemia, late ante-natal booking, and poor educational empowerment rank among the greatest challenges confronting management of sickle cell disease in pregnancy in Nigeria. Therefore, awareness creation and national policies that will scale up the care of sickle cell disease in pregnancy should be topmost priorities in improving their life expectancies in Nigeria.Table 1Levels of Education: SCD Pregnant women compared to Non-SCD PregnantLevels of EducationFrequency n (%)Total n (%)p-valueNon HbSSHbSSPrimary (1-6)71 (0.2)- (0)71 (0.2)<0.05JSS (1-3)810 (2.4)1 (2)811 (2.4)>0.05SS (1-3)13,308 (39.4)19 (38)13,417 (39.7)>0.05Post-Secondary (Tertiary)19,419 (57.5)28 (56)19,447 (57.2)>0.05Post-graduate (Masters, Ph.D.)188 (0.55)2 (4%)190 (0.5)<0.05Total33,756 (100)50 (100)33,806 (100)Table 2(a) Pattern of Hemoglobin Concentration in HbSS and Non-HbSS Pregnant womenHb Conc. (g/dl)Frequency n (%)Total n (%)p-valueNon-HbSSHbSS<1113,276 (39.2)42 (80.8)13,318 (39.3)<0.05≥1120,554 (60.8)10 (19.2)20,564 (60.7)<0.05Total33,830 (100)52 (100.0)33,882 (100)Chi-square: 188.78, p-value = 0.001Note: Hb Concentration <11.0 g/dl is termed "Anemia in pregnancy" [1],[2]. 34,020 of the registered women had their Hemoglobin concentration documented.

Sickle Cell Disease Patients Show Sensitization of Myelinated Sensory Nerve Fibers

There is increasing evidence that many patients with sickle cell disease (SCD) develop chronic pain in addition to experiencing acute pain secondary to vaso-occlusive episodes (VOE). Those patients who develop chronic pain often exhibit features suggestive of neuropathic processes such as allodynia and pain "shooting" or "tingling" in character. Using electrophysiologic techniques in ex-vivo nerve-skin preparations and nocifensive behavior studies in sickle cell mouse models, we and others have shown that SCD is associated with sensitization of light touch cutaneous sensory fibers, and decreased threshold in response to 2000Hz and 250 Hz electrical sine wave stimulation. These findings are indicative of Aβ and Ad fibers sensitization and in turn compatible with neuropathic process.We hypothesized that the same phenomena of nerve fiber sensitization in the mouse model would be observed in SCD patients. This hypothesis was tested using an experimental paradigm with sine-wave electrical stimulation delivered at three different frequencies: 2000, 250, and 5 Hz, which preferentially stimulate Aβ, Ad, and C fibers, respectively. Thermal and mechanical sensory testing was also performed. After IRB approval, SCD subjects with high (≥ than 3 ER visits or admissions for VOEs per year) or low (< 2 ER visits or admissions per year) pain frequency, and age- and sex-matched African-American healthy controls were recruited at baseline states during routine clinic visits. After informed consent (and/or assent) was obtained, patients underwent quantitative sensory testing (QST) that included heat and cold perception and tolerance (with a TSA II-Sensory Analyzer), mechanical (using a Wagner FDIX Force One) and current perception and pain tolerance thresholds (using the Neurometer).We enrolled 19 SCD subjects with high and 4 with low pain frequency (total 23 SCD participants), and 11 African-American non-SCD subjects who tolerated and completed all QSTs. As there was no difference between QST responses in patients with high and low pain frequency, these two groups were combined as the SCD group. We found that SCD subjects had significantly decreased cold tolerance threshold (p=0.034) and a trend towards lower thresholds for cold perception and heat tolerance, which is in concert with previously reported findings. Expanding upon these findings, SCD patients had a significantly reduced pain tolerance threshold in response to 2000 Hz stimulation (p=0.005), which preferentially stimulates Aβ fibers (see figure). These results suggest that adolescents with SCD have sensitization of myelinated Aβ fibers. Interrogation of the Ad and C fibers with 250 and 5 Hz stimulation, respectively, revealed no significant differences in tolerance thresholds among the groups, however SCD patients showed a trend toward lower thresholds in both frequencies (see figure). Combined, these findings support the use of sine-wave stimulation on the evaluation of pain phenotype in SCD and the notion that SCD subjects may have neuropathic processes contributing to their pain phenotype. TableDemographics, thermal and mechanical sensory testing in SCD and control subjects.VariableSCD (n=23)Control (n=11)Age (years)16 (15-18.8)19 (14-21)Male (%)3 (30%)11 (48%)Cold Perception (°C)29.8 (28.5-30.5)30.4 (29.9-30.9)Cold Tolerance (°C)8.5 (2.0-17.0) *0.9 (0.0-6.9)Heat Perception (°C)34.4 (33.5-35.2) *33.6 (33.2-34.1)Heat Tolerance (°C)48.9 (47.5-49.8)50.0 (45.3-50.1)Mechanical Tolerance (lbF)7.7 (5.9-9.7)9.5 (7.7-10.8)*p < 0.05. Values are shown as median and interquartile range. SCD subjects reached cold tolerance and heat perception at significantly higher temperatures as compared to controls; p=0.034 and p= 0.035, respectively. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Chronobiology of Hypertension in Sickle Cell Disease

Introduction: Adult patients with Sickle Cell Disease (SCD): 1) develop renal failure at an earlier age than non-SCD black patients with end stage renal disease and 2) renal transplant outcomes in patients with SCD are so inferior that many transplant programs will not consider patients with SCD as candidates. More research is needed to understand the development of renal disease in patients with SCD; particularly in the earlier stages in which interventions might be most successful. In non-SCD pediatric populations, 24 hour Ambulatory Blood Pressure Monitoring (ABPM) is the gold standard method to document hypertension as it has been shown to be a better surrogate outcome for end organ damage from hypertension. The association between hypertension (as defined by ABPM) and progressive kidney disease needs to be assessed in SCD.Objective: To identify baseline blood pressure (BP) abnormalities as measured by ABPM and conventional clinic measurement and to characterize factors associated with ABPM abnormalities among a cohort of sickle cell participants enrolled in a 5 year prospective study of hypertension and progressive kidney injury.Methods: Participants ages 5-21 yrs with HbSS or SB0 thalassemia were enrolled in a five year IRB approved prospective cohort study; participants 11-20 yrs were also eligible to undergo 24 hr ABPM. Demographics, therapies,and laboratory data (CBC, CMP, uric acid, LDH, cystatin c, and urine microalbumin/creatinine) were recorded. The pre-transfusion CBC was used for patients on chronic transfusion therapy. Clinic BP and 24 hr ABPM (using SpaceLabs 90217 monitors which records BP every 20 minutes while awake and 30 minutes while asleep for at least 24 hours) were measured. BP level norms were determined by pediatric BP tables created by the NHLBI (clinic BP) and American Heart Association (ABPM) for age and height. Abnormal nocturnal dipping is defined as <10% BP dip (daytime-nighttime BP)/daytime BP x 100). Abnormal BP load is defined as > 25% of blood pressure recordings exceeding the 95th percentile BP for normative data.Results: At the time of this abstract, 29/108 (27%) of participants were hypertensive at their baseline clinic visit and 24-hr ABPM has been conducted in 27 participants (7 were normotensive in clinic; 20 were normotensive during clinic visit). Twenty two of the 27 (81%) participants were identified with abnormal systolic nocturnal BP dipping and 15/27 (56%) had abnormal diastolic nocturnal BP dipping. Of concern, 10/27 (37%) participants had an increase in SBP while sleeping and 7/27 (26%) had an increase in DBP while sleeping. Among the seven participants with hypertension in clinic, all had abnormal nocturnal BP dipping. In those participants with normal clinic BP, 15/20 (75%) had abnormal systolic BP dipping. Nine (33%) participants had an abnormal nocturnal systolic BP load and 7 (26%) participants had abnormal nocturnal diastolic BP load. Eight of 10 participants with an increase in systolic BP while sleeping were on chronic transfusion therapy (p=0.06). Variables that may be associated with an increase in systolic BP while sleeping were: lower GFR (p=0.06), higher BMI (p=0.02), and higher hemoglobin (p=0.08). Participants on chronic transfusion had a higher mean nocturnal systolic BP load than participants on no chronic therapy or hydroxyurea therapy (p=0.04). Variables that may be associated with an abnormal nocturnal systolic BP load were: lower GFR (p<0.001), higher BMI (p=0.01), and higher Hb (p=0.01). Transfusion volume (mL) was not associated with abnormal dipping (p=0.72) or BP load (p=0.52).Conclusion: Abnormal nocturnal BP is highly prevalent among SCD participants with and without hypertension in clinic. Blood therapy or need for blood therapy may be associated with abnormal nocturnal BP. Participants with abnormal nocturnal BP may have a lower GFR. Over time, this cohort will determine if abnormal nocturnal BP predicts a progressive decline in GFR in SCD as it does in non-SCD populations. DisclosuresNo relevant conflicts of interest to declare.

Experimental pain and depression: differences between Sickle Cell Disease patients, other chronic pain populations and healthy controls

Sickle Cell Disease (SCD) affects approximately 100,000 Americans, decreases life expectancy by 2 to 3 decades, causes chronic pain, and reduces quality of life. The underlying mechanisms involved in this population's experience of pain are still largely unknown. The present study sought to compare depressive symptomatology and experimental pain sensitivity in SCD patients to patients with Temporomandibular Joint Disorder (TMD), Arthritis and healthy controls. Forty-four SCD participants (62.2% female; age x=37.2, SD=11.7), forty-nine TMD participants (41.6% female; age x=33.9, SD=12.02), forty-two Arthritis participants (25.7% female, age x=54.57, SD=9.72), and eighty-five healthy controls (25.7%; age x=34.00, SD=14.59) completed quantitative sensory testing.