Hemoglobin SS Sickle Cell Disease Research Articles

Detection of Subclinical Cardiac Dysfunction in Patients With Sickle Cell Disease Using Speckle-Tracking Echocardiography

Sickle cell disease (SCD) is characterized by chronic anemia and recurrent ischemia-reperfusion episodes, which can lead to high-output heart failure. The impact of SCD on cardiac structure and function remains underinvestigated. We conducted a single-institution retrospective analysis of clinical and echocardiographic data from patients with hemoglobin SS SCD (SCD-SS) between January 2016 and June 2022. Patients with known heart failure, left ventricular (LV) ejection fraction <50%, moderate or severe valvular heart disease, congenital heart disease, established coronary artery disease, diabetes mellitus, hypertension, or coexistent lung disease were excluded. Compared with healthy controls (n = 28), patients with SCD-SS (n = 66) had a significantly higher left atrial (LA) volume index (35.7 vs 23.9 ml/m², p <0.001) and average E/e' (7.4 vs 6.5, p = 0.003) but lower average e' (12.3 vs 13.6 cm/s, p = 0.047) and LA reservoir strain (32.9% vs 42.4%, p <0.001). Patients with SCD-SS had higher LV end-diastolic (132.5 vs 104.1 ml, p <0.001) and LV end-systolic volumes (51.0 vs 43.8 ml, p = 0.017) with reduced LV global longitudinal strain (17.6% vs 20.0%, p <0.001). In addition, patients with SCD-SS showed reduced right ventricular (RV) global longitudinal strain (19.7% vs 22.8%, p <0.001) in the setting of normal RV tricuspid annular plane systolic excursion. Maximal systolic tricuspid regurgitation velocity (231 vs 202 cm/s, p <0.001) and right atrial area (16.6 vs 12.8 cm², p <0.001) were statistically greater in SCD-SS. Hemoglobin and hematocrit negatively correlated with LA volume index, average E/e', LV end-diastolic and LV end-systolic volumes. In conclusion, patients with SCD-SS had notable differences in cardiac chamber size and impaired LV, RV, and LA strain compared with healthy controls. Further investigations are needed to assess the impact of these variables on SCD clinical course and prognosis.

Neuropsychological, behavioral, and quality‐of‐life outcomes in children and adolescents with sickle cell disease treated with nonmyeloablative matched sibling donor hematopoietic cell transplantation: A case series

Despite advances in the treatment of sickle cell disease (SCD), cerebrovascular and cognitive insults can have lifelong consequences. Hematopoietic cell transplantation (HCT) is an established curative therapy, and recent studies have demonstrated efficacy with reduced toxicity nonmyeloablative (NMA) regimens, but little is known about neuropsychological outcomes. The objective of this study was to describe neuropsychological, behavioral, and quality-of-life outcomes with medical correlates in children with SCD who received an NMA matched sibling donor (MSD) HCT. Retrospective cohort analysis of nine recipients with hemoglobin SS SCD who underwent MSD HCT using the National Institutes of Health (NIH) NMA protocol. Mean full-scale intellectual functioning (FSIQ) was average pre-HCT (FSIQ= 92.1, SD 9.0; n = 8) and 2years post-HCT (mean FSIQ= 96.6; SD 11.1; N = 9). Neuropsychological functioning was largely average across all cognitive domains, and no pre/post-HCT differences were found to be statistically significant given the small sample size. However, effect sizes revealed moderate improvements in processing speed (Cohen's d = .72) and verbal memory (Cohen's d = .60) post-HCT, and declines in measures of attention (Cohen's d = -.54) and fine motor speed and dexterity (Cohen's d = -.94). Parents endorsed better quality of life (Cohen's d = .91), less impact of SCD on their family, and less worry about their child's future (Cohen's d = 1.44). Neuropsychological functioning in a sample of children and adolescents treated uniformly with NMA MSD HCT remained stable or improved in most cognitive domains, and improvements in quality of life and family functioning were observed.

The Prevalence of Uterine Fibroids in African American Women with Hemoglobin SS Sickle Cell Disease as Determined by Pelvic Magnetic Resonance Imaging

This study explores the relationship between the development of uterine fibroids and hemoglobin SS sickle cell disease (SCD) by examining the prevalence of uterine fibroids as detected by pelvic magnetic resonance imaging (MRI) in African American (AA) women with and without SCD. A single-center, retrospective review was performed of all adult AA women at a large, academic medical center who received pelvic MRI from January 1, 2007 to December 31, 2018. Propensity score matching conditional on age and ZIP code evaluated the differences in fibroid prevalence between the two groups. Subanalyses by age in 10-year intervals were also performed. Twenty-one (23.9%) of 88 patients with SCD had fibroids on pelvic MRI versus 1493 (52.1%) of 2868 patients without SCD (p value <0.001). After propensity score matching, 21 (24.7%) of 85 patients with SCD compared to 52 (61.2%) of 85 patients without SCD had fibroids (p value <0.001). Subanalyses in 10-year age intervals showed significance for patients between 30 and 39 years old in which 4 (13.8%) of 29 SCD patients versus 374 (65.3%) of 573 no SCD patients had fibroids (p value <0.001), and for patients between 40 and 49 years old in which 9 (42.9%) of 21 SCD patients versus 667 (73.8%) of 904 no SCD patients had fibroids (p value = 0.002). These findings indicate an overall significantly lower prevalence of uterine fibroids in AA women with SCD, suggesting that SCD may be protective against the development of uterine fibroids in these patients.

A Multidimensional Electronic Hydroxyurea Adherence Intervention for Children With Sickle Cell Disease: Single-Arm Before-After Study.

BackgroundHydroxyurea is a disease-modifying medication for patients with sickle cell disease (SCD). Despite demonstrated efficacy, hydroxyurea nonadherence in clinical practice is common and results in worse health outcomes for nonadherent patients. Mobile Directly Observed Therapy (Mobile DOT) is a pilot-tested, electronic, multidimensional hydroxyurea adherence intervention for children with SCD. Mobile DOT includes sending daily text message reminders to patients to take hydroxyurea, patients recording and sending daily videos that capture their hydroxyurea administrations for the research team to review and track adherence, providing personalized feedback to patients about their adherence, and providing small monetary incentives to patients if they achieve high hydroxyurea adherence.ObjectiveThis study aimed to determine if Mobile DOT increases hydroxyurea adherence in children with SCD and to explore its impact on hematologic and clinical outcomes.MethodsThis was a single-arm, 6-month intervention study of patients with SCD on hydroxyurea who were aged ≤19 years and reported having access to an electronic device. Participants’ hydroxyurea adherence when they received Mobile DOT was compared with their adherence 6 months before and after receiving Mobile DOT. Participants’ medication possession ratio (MPR) was calculated from their pharmacy dispensing records and was used to measure adherence. Laboratory and clinical outcomes were abstracted from participants’ electronic medical records. Infrequently hospitalized patients who received at least 160 days of the intervention were considered to be engaged participants.ResultsOf 91 patients who were approached, 55 enrolled and 34 engaged with Mobile DOT. The median age of the engaged participants was 10 years (range 2-18.8 years), and 21 (62%, 21/34) participants were male, 28 (82%, 21/34) had hemoglobin SS SCD, and 19 (56%, 19/34) were prescribed hydroxyurea for at least a year before enrollment. With Mobile DOT, engaged participants’ median MPR increased from 61.7% to 84.4% (P<.001) and significantly more (67% vs 30%; P=.002) achieved ≥80% hydroxyurea adherence compared with baseline values. Engaged participants’ mean fetal hemoglobin (HgbF) levels and mean corpuscular volumes (MCV) improved significantly after 6 months of Mobile DOT (P=.04 and P=.001, respectively), but their adherence, HgbF levels, and MCV returned to baseline values during the 6 months after the intervention. Hospitalizations and the clinical outcomes that were measured occurred infrequently during the study. Nonengagement was associated with being female and having a recent SCD complication. In addition, having insufficient electronic data, being unable to quickly complete Mobile DOT each day, and not perceiving that Mobile DOT was beneficial may have further decreased engagement.ConclusionsMobile DOT shows promise as an effective intervention for some children with SCD. Modifications that may improve recruitment, reduce attrition, and increase engagement were identified and could increase the impact that Mobile DOT has on children with SCD.Trial RegistrationClinicalTrials.gov NCT02578017; https://clinicaltrials.gov/ct2/show/NCT02578017

Intracranial Aneurysms in Sickle-Cell Disease Are Associated With the Hemoglobin SS Genotype But Not With Moyamoya Syndrome.

Intracranial aneurysms and aneurysmal subarachnoid hemorrhage may occur more frequently in sickle-cell disease (SCD), and this could be related to the sickle genotype and moyamoya syndrome seen in SCD. Records from a total of 1002 patients with SCD attending 2 specialized adult hematologic services were retrospectively reviewed. We analyzed data of a cohort of 767 patients attending 1 SCD clinic between 2002 and 2013 and of 235 patients from the other clinic who have had neurovascular imaging between 2007 and 2014. We identified 4 patients in the cohort who had an aneurysmal subarachnoid hemorrhage during 9063 patient-years. The highest incidence rate was seen among women in the age group 30 to 39 years with the hemoglobin SS (HbSS) genotype (440 per 100 000 patient-years). Unruptured intracranial aneurysms were found in 20 of the 324 patients, who had imaging data; the prevalence was significantly higher in patients with HbSS genotype compared with other sickle genotypes with the highest prevalence (15%) observed in women in the age group 30 to 39 years. Fifty-one HbSS patients had a moyamoya vasculopathy, but only 3 of these had concomitant intracranial aneurysms. Intracranial aneurysms are common in HbSS SCD. There was also a trend toward more common occurrence of aneurysmal subarachnoid hemorrhage in HbSS; women in the age group 30 to 39 years were most at risk. There was no correlation between the occurrence of intracranial aneurysms and moyamoya syndrome.

Correction of Murine Sickle Cell Disease Using γ-Globin Lentiviral Vectors to Mediate High-level Expression of Fetal Hemoglobin

Increased levels of red cell fetal hemogloblin, whether due to hereditary persistence of expression or from induction with hydroxyurea therapy, effectively ameliorate sickle cell disease (SCD). Therefore, we developed erythroid-specific, gamma-globin lentiviral vectors for hematopoietic stem cell (HSC)-targeted gene therapy with the goal of permanently increasing fetal hemoglobin (HbF) production in sickle red cells. We evaluated two different gamma-globin lentiviral vectors for therapeutic efficacy in the BERK sickle cell mouse model. The first vector, V5, contained the gamma-globin gene driven by 3.1 kb of beta-globin regulatory sequences and a 130-bp beta-globin promoter. The second vector, V5m3, was identical except that the gamma-globin 3'-untranslated region (3'-UTR) was replaced with the beta-globin 3'-UTR. Adult erythroid cells have beta-globin mRNA 3'-UTR-binding proteins that enhance beta-globin mRNA stability and we postulated this design might enhance gamma-globin expression. Stem cell gene transfer was efficient and nearly all red cells in transplanted mice expressed human gamma-globin. Both vectors demonstrated efficacy in disease correction, with the V5m3 vector producing a higher level of gamma-globin mRNA which was associated with high-level correction of anemia and secondary organ pathology. These data support the rationale for a gene therapy approach to SCD by permanently enhancing HbF using a gamma-globin lentiviral vector.

Lung function and somatic growth in patients with hemoglobin SC sickle cell disease

To investigate the changes in lung function and somatic growth that occur over time in children with hemoglobin SC (Hb-SC) sickle cell disease (SCD). Measurements of lung function and somatic growth were performed in patients with Hb-SC twice with an interval of 50.2 +/- 26.0 months. Comparisons were made with a group of patients with hemoglobin SS (Hb-SS) SCD, matched by age, race, and gender who underwent similar testing and served as controls. Indices of lung function in patients with Hb-SC were and remained within the normal range in the two testing periods and they were significantly higher than those measured among patients with Hb-SS. However, there was significant and similar decline (as percentage from baseline) over time in both groups (forced vital capacity, FVC: -3.7 +/- 9.4 vs. -3.8 +/- 14.2; forced expiratory volume in the first second, FEV1: -7.4 +/- 9.3 vs. -6.8 +/- 15.2; forced expiratory flow at 25-75% of FVC, FEF(25-75): -13.7 +/- 20.6 vs. -12.1 +/- 24.7 for Hb-SC and Hb-SS respectively). The body mass index (BMI, percentile) was significantly (P < 0.05) higher among patients with Hb-SC (49 +/- 36 vs. 26 +/- 18) and increased over time in both groups (50 +/- 33 vs. 32 +/- 31). Lung function is generally normal among children with Hb-SC, but it declines over time in a fashion similar to that observed among patients with Hb-SS SCD. The decline is slow and it is not associated with changes in somatic growth. Our findings suggest that patients with Hb-SC should probably have the same close follow-up as patients with Hb-SS.

Bilateral simultaneous retinal arteriolar obstruction in a child with hemoglobin SS sickle cell disease

J AAPOS 2001;5:126-8.

Prevalence and reversibility of lower airway obstruction in children with sickle cell disease

Objective: To determine the prevalence and reversibility of lower airway obstruction (LAO) in children and adolescents with hemoglobin SS sickle cell disease (HbSS SCD). Study Design: Retrospective evaluation of lung function in a cross-section of 35 African American and 28 Hispanic children and adolescents with HbSS SCD. Lung function was evaluated with maximal respiratory flow-volume curves and body plethysmography. Each patient was assigned to 1 of 3 patterns of lung function (normal, obstructive, or restrictive). Airway hyperresponsiveness was assessed by means of a trial with bronchodilator. Results: Normal pattern was detected in 57% of the patients, LAO in 35%, and restrictive lung disease in 8%. Positive response to bronchodilator was documented in 30% of those with normal pattern of lung function, 78% in those with LAO, and 67% of those with restrictive lung disease. The pattern of lung function was not associated with race or with history of vaso-occlusive crises, acute chest syndrome, reactive airways disease/asthma, or long-term transfusion therapy. Conclusion: Obstructive lung disease possibly precedes the development of restrictive lung disease, and airway reactivity may be part of the pathogenic mechanism. (J Pediatr 2001;138:188-92)

Bone Marrow Uptake Complicating Radionuclide Venography in a Patient With Sickle Cell Anemia

A 49-year-old black woman with hemoglobin SS sickle cell disease presented with right calf pain and swelling. She had a history of deep venous thrombophlebitis of the left calf. Because of the risks of iodinated contrast in patients with sickle cell disease, a radionuclicle venogram was performed with Tc-99m labeled red blood cells. This revealed intense uptake in the bone marrow, which significantly interfered with visualization of the deep venous structures in the patient's lower legs. Assessment of venous patency in this area could not be made. Hyperemia of the bone marrow secondary to the patient's sickle cell disease is felt to be responsible for the unusual pattern of uptake. This case demonstrates a potential limitation of labeled red blood cell radionuclide venography in patients with hyperemic bone marrow

Relationship between peripheral vascular closure and proliferative retinopathy in sickle cell disease

In a study involving 97 patients with hemoglobin SC sickle cell disease (Hb SC) and 87 subjects with hemoglobin SS sickle cell disease (Hb SS) on the island of Curaçao, we found a higher incidence of peripheral retinal vascular closure and proliferative retinopathy in the former as compared with the latter. Examination of composite fluorescein angiograms obtained from 15 Hb SS and 36 Hb SC patients, whose mean and median age were the same and in whom more advanced stages of sickle retinopathy were equally represented, revealed statistically significantly smaller measurements of perfused retina (indicative of larger areas of non-perfusion) in Hb SC patients as compared with Hb SS patients (P = 0.002, P = 0.014) as well as in subjects exhibiting neovascularization as compared with those who did not (P = 0.022, P = 0.004). This suggests that a vaso-occlusive tendency in the retina is greater in individuals with Hb SC than in those with Hb SS; the more extensive ischemic areas provide a stimulus for neovascularization, explaining the higher prevalence of proliferative retinopathy in the former patients as compared with the latter.