Controversies in the pathophysiology of leg ulcers in sickle cell disease.

Patients with sickle cell disease (SCD) often experience painful vaso-occlusive crises and chronic haemolytic anaemia, as well as various acute and chronic complications, such as leg ulcers. Leg ulcers are characterized by their unpredictability, debilitating pain and prolonged healing process. The pathophysiology of SCD leg ulcers is not well defined. Known risk factors include male gender, poor social conditions, malnutrition and a lack of compression therapy when oedema occurs. Leg ulcers typically start with spontaneous pain, followed by induration, hyperpigmentation, blister formation and destruction of the epidermis. SCD is characterized by chronic haemolysis, increased oxidative stress and decreased nitric oxide bioavailability, which promote ischaemia and inflammation and consequently impair vascular function in the skin. This cutaneous vasculopathy, coupled with venostasis around the ankle, creates an ideal environment for local vaso-occlusive crises, which can result in the development of leg ulcers that resemble arterial ulcers. Following the development of the ulcer, healing is hindered as a result of factors commonly observed in venous ulceration, including venous insufficiency, oedema and impaired angiogenesis. All of these factors are modulated by genetic factors. However, our current understanding of these genetic factors remains limited and does not yet enable us to accurately predict ulceration susceptibility.

Endothelial dysfunction in Sickle Cell Disease: Strategies for the treatment.

Sickle Cell Anemia (SCA), is an inherited hemoglobinopathy characterized by the presence of an abnormal hemoglobin (HbS), being the most prevalent sickle cell disease (SCD). SCA is characterized by vascular endothelial dysfunction, which contributes significantly to various clinical conditions, including but not limited to pulmonary hypertension, priapism, cutaneous leg ulceration, and stroke. The pathophysiology of endothelial dysfunction (ED) in SCA is a multifaceted process involving a chronic inflammatory and hypercoagulable state. Key factors include hemolysis-associated elements like reduced arginine and nitric oxide (NO) availability, elevated levels of vascular adhesion molecules, the uncoupling effect of NO synthase, heightened arginase activity, an environment characterized by oxidative stress with the production of reactive oxygen and nitrogen species, and occurrences of ischemia-reperfusion injury, along with apolipoprotein A-1 depletion. The urgency for novel interventions addressing ED is evident. Presently, there is a focus on investigating small molecules that disrupt the arginine-nitric oxide pathway, exhibiting anti-inflammatory and antioxidant properties while diminishing levels of cellular and vascular adhesion molecules. In this mini-review article, we delve into the progress made in strategies for treating ED in SCD with the aim of cultivating insights for drug design.

Electrocardiographic abnormalities in patients with sickle cell disease: A systematic review and meta-analysis.

BACKGROUND: Previous studies have documented that electrocardiography (ECG) can reveal a range of abnormalities, offering valuable insights into the cardiac evaluation of patients with sickle cell disease (SCD). The objective of this study is to assess the patterns of ECG abnormalities observed in these patients with SCD, and to determine their prevalence. METHOD: We systematically reviewed the literature using online databases of PubMed, Scopus, Web of Science, Embase, and Google Scholar to identify original studies that reported findings of standard ECG assessments in patients with SCD. Statistical analyses were performed using the random effects model. Additional analyses including sensitivity analysis and subgroup analysis were also conducted. RESULTS: Analysis of data from 59 studies involving 897,920 individuals with SCD revealed that 75% of these patients had abnormal ECG findings (67%-81%), which were predominantly nonspecific ST-T changes, left ventricular hypertrophy, T-wave changes, prolonged corrected QT (QTc) interval, and ischemic changes. Besides, it was shown that these patients had significantly higher odds of having any ECG abnormalities (OR of 17.50, 4.68-65.49), right atrial enlargement (6.09, 1.48-25.09), left ventricular hypertrophy (3.45, 1.73-6.89), right ventricular hypertrophy (7.18, 2.28-22.57), biventricular hypertrophy (10.11, 1.99-51.38), prolonged QTc interval (5.54, 2.44-12.59), ST depression (3.34, 1.87-5.97), and T-wave changes (5.41, 1.43-20.56). Moreover, the mean of QTc interval was significantly higher among those with SCD (23.51 milliseconds, 16.08-30.94). CONCLUSION: Our meta-analysis showed a higher prevalence of abnormal ECG findings among individuals with SCD. A significant proportion of these patients had various ECG abnormalities, suggesting a potential need for regular ECG assessments for patients with SCD.

Association of elevated tricuspid regurgitation velocity with cerebrovascular and kidney disease in children with sickle cell disease.

BACKGROUND: Tricuspid regurgitation velocity (TRV), measured by echocardiography, is a surrogate marker for pulmonary hypertension. Limited pediatric studies have considered the association between TRV and surrogate markers of end-organ disease. METHODS: We conducted a cross-sectional study that evaluated the prevalence of elevated TRV ≥2.5 m/s and its associations with renal and cerebrovascular outcomes in children with sickle cell disease (SCD) 1-21 years of age in two large sickle cell cohorts, the University of Alabama at Birmingham (UAB) sickle cell cohort, and the Sickle Cell Clinical Research and Intervention Program (SCCRIP) cohort at St. Jude Children's Research Hospital. We hypothesized that patients with SCD and elevated TRV would have higher odds of having either persistent albuminuria or cerebrovascular disease. RESULTS: We identified 166 children from the UAB cohort (mean age: 13.49 ± 4.47 years) and 325 children from the SCCRIP cohort (mean age: 13.41 ± 3.99 years) with echocardiograms. The prevalence of an elevated TRV was 21% in both UAB and SCCRIP cohorts. Elevated TRV was significantly associated with cerebrovascular disease (odds ratio [OR] 1.88, 95% confidence interval [CI]: 1.12-3.15; p = .017) and persistent albuminuria (OR 1.81, 95% CI: 1.07-3.06; p = .028) after adjusting for age, sex, treatment, and site. CONCLUSION: This cross-sectional, multicenter study identifies associations between surrogate markers of pulmonary hypertension with kidney disease and cerebrovascular disease. A prospective study should be performed to evaluate the longitudinal outcomes for patients with multiple surrogate markers of end-organ disease.

Prevalence, patterns, and factors associated with abnormal lung function among children with sickle cell disease in Uganda: a cross-sectional study.

BACKGROUND: Pulmonary complications are common among children with sickle cell disease (SCD). However, there is little literature on associated lung function abnormalities in Uganda. We aimed to determine the prevalence, patterns, and factors associated with abnormal lung function among children with SCD in a tertiary care hospital in Uganda. METHOD: A cross-sectional study was conducted among children aged 6 to 18 years at the SCD clinic (SCC) of Mulago National Super-Specialized Hospital between January 2020 and April 2021. Data on sociodemographic and clinical characteristics was collected using a standardized questionnaire. Laboratory investigations, including a complete blood count and serum lactate dehydrogenase (LDH), were done. Spirometry was performed following the ATS/ERS standards. Multivariable modified Poisson regression analysis was performed to determine factors associated with abnormal lung function. RESULTS: A total of 332 participants were enrolled. The mean age was 11.7 ± 3.4 years, and 184 (55.4%) were female. Overall, 126 (37.9%) participants had abnormal lung function: 67/126 (53.2%) restrictive, 57/126 (45.2%) obstructive, and 2/126 (1.6%) mixed-ventilatory patterns. Factors associated with abnormal lung function were; serum LDH level > 600UL (aIRR: 1.89 95% CI: 1.2 - 7.4, p = 0.049), a history of acute chest syndrome (aIRR: 1.55, 95% CI: 1.06-2.25, p = 0.024), wasting (aIRR: 1.33, 95%CI: 1.02 - 1.72, p = 0.032), and use of charcoal for household cooking (aIRR: 1.49, 95% CI: 1.03-2.15, p = 0.035). CONCLUSION: More than one-third of children with SCD in Uganda have lung function abnormalities. Strategies to improve nutrition, reduce exposure to charcoal smoke, and monitoring serum LDH levels may be important in preventing or managing abnormal lung function in this population. The identification of reversible and irreversible airway obstruction in children with sickle cell disease also highlights the need for targeted interventions to address these specific patterns of abnormal lung function.

Prediction of Functional Academic Outcomes by Fine Motor Skills in Individuals With Sickle Cell Disease.

IMPORTANCE: Individuals with sickle cell disease (SCD) are at heightened risk of poor neurocognitive and academic outcomes. The relationship between fine motor skills and academic outcomes is not well understood. OBJECTIVE: To compare the fine motor skills of individuals with SCD with normative expectations, test whether demographic and medical factors are associated with fine motor performance, and determine the impact of fine motor performance on academic performance. DESIGN: Cross-sectional. SETTING: St. Jude Children's Research Hospital. PARTICIPANTS: Individuals with SCD (N = 376; ages 8-24 yr). OUTCOMES AND MEASURES: Fine motor outcomes included visual-motor integration, manual dexterity, and graphomotor speed. Academic outcomes included math fluency and word reading. Demographic and medical variables were obtained via medical records and interviews. RESULTS: Compared with normative expectations, the performance of individuals with SCD on all fine motor measures was lower than expected. Male sex, lower socioeconomic status, and lower oxygen saturation was associated with slower graphomotor speed. Lower socioeconomic status and older age were associated with lower visual-motor integration scores. Performance on all fine motor measures was positively associated with math fluency and word reading. CONCLUSIONS AND RELEVANCE: Individuals with SCD exhibited poorer than expected fine motor skills across multiple motor domains, and these deficits were associated with poorer academic outcomes. Early referral to intervention services for fine motor skills may facilitate improved academic outcomes for individuals with SCD. Plain-Language Summary: This study had three objectives: (1) Compare the fine motor skills of people with sickle cell disease (SCD) with normative expectations, (2) test whether demographic and medical factors are associated with fine motor performance, and (3) determine the impact of fine motor performance on academic performance. We found that SCD is a risk factor for lower than expected fine motor performance across multiple fine motor domains and that these deficits also affect functional academic skills.

Acute chest syndrome in sickle cell disease.

ABSTRACT: Sickle cell disease (SCD) is an autosomal recessive disorder altering the shape of red blood cells, causing harmful obstructions in blood vessels, therefore altering normal blood flow. SCD can escalate quickly into acute chest syndrome (ACS), a life-threatening complication that requires immediate care. This article discusses the pathophysiology, assessment, diagnosis, and treatment of ACS, as well as nursing care and patient education.

P-selectin deficiency promotes liver senescence in sickle cell disease mice.

Sickle cell disease (SCD) is caused by a homozygous mutation in the ß-globin gene, which leads to erythrocyte sickling, vasoocclusion, and intense hemolysis. P-selectin inhibition has been shown to prevent vasoocclusive events in patients with SCD; however, the chronic effect of P-selectin inhibition in SCD remains to be determined. Here, we used quantitative liver intravital microscopy in our recently generated P-selectin-deficient SCD mice to show that chronic P-selectin deficiency attenuates liver ischemia but fails to prevent hepatobiliary injury. Remarkably, we find that this failure in resolution of hepatobiliary injury in P-selectin-deficient SCD mice is associated with the increase in cellular senescence and reduced epithelial cell proliferation in the liver. These findings highlight the importance of investigating the long-term effects of chronic P-selectin inhibition therapy on liver pathophysiology in patients with SCD.

IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias.

Previous reports indicate that IL18 is a novel candidate gene for diastolic dysfunction in sickle cell disease (SCD)-related cardiomyopathy. We hypothesize that interleukin-18 (IL-18) mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared with control mice, a humanized mouse model of SCD exhibited increased cardiac fibrosis, prolonged duration of action potential, higher VT inducibility in vivo, higher cardiac NF-κB phosphorylation, and higher circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, which translates to reduced transient outward potassium current (Ito) in isolated cardiomyocytes. Administering IL-18 to isolated mouse hearts resulted in VT originating from the right ventricle and further reduced Ito in SCD mouse cardiomyocytes. Sustained IL-18 inhibition via IL-18-binding protein resulted in decreased cardiac fibrosis and NF-κB phosphorylation, improved diastolic function, normalized electrical remodeling, and attenuated IL-18-mediated VT in SCD mice. Patients with SCD and either myocardial fibrosis or increased QTc displayed greater IL18 gene expression in peripheral blood mononuclear cells (PBMCs), and QTc was strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in patients who did not survive compared with those who did. IL-18 is a mediator of sickle cell cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for sudden death.

Effect of hydroxyurea exposure before puberty on sperm parameters in males with sickle cell disease.

Sperm parameters are known to be impaired in men with sickle cell disease (SCD). Although treatment with hydroxyurea (HU) has an impact on sperm quality, sperm preservation is impossible before puberty. This study's primary objective was to analyze and compare sperm parameters in male patients with SCD exposed (or not) to HU before puberty. Twenty-six sperm samples from 15 patients (median age, 17 years; range, 16-23) treated with HU during childhood were compared with 46 samples from 23 HU-naïve patients (20 years; 16-24). The median age at HU initiation was 6 years (1-14 years), the median duration of HU treatment was 4 years (0.5-10), and the mean dose of HU was 22.4 ± 3.7 mg/kg per day. Although we observed substantial quantitative and qualitative semen abnormalities in all patients, there were no significant differences in semen volume, sperm concentration, total sperm count, or spermatozoa motility, morphology, and vitality between the HU-exposed and HU-naïve groups. At the time of the semen analysis, 100% of the patients in the HU-exposed group and 52% of the patients in the HU-naïve group received transfusion therapy. The specific effect of HU on spermatogenesis in very young infants and the putative value of transfusion for reversing the toxicity of HU warrant further investigation.

Muscle Properties, Gross Motor Performance, and Quality of Life in Children With Sickle Cell Disease.

PURPOSE: To explore muscle properties, gross motor performance, and quality of life (QoL) in children with sickle cell disease (SCD) compared with controls and to assess relationships among these outcomes. METHODS: A cross-sectional study of 24 children assessed muscle properties including: knee extension strength by dynamometry; vastus lateralis (VL) and rectus femoris (RF) muscle thickness by ultrasonography; and VL and RF neuromuscular activation (rate of muscle activation [RoA]) by electromyography (EMG). Gross motor performance and QoL were assessed by standardized tests and questionnaires. RESULTS: Children with SCD had impaired knee extension strength, VL EMG RoA, gross motor performance, and QoL compared with children without SCD. Relationships among muscle properties, gross motor performance, and QoL were identified. CONCLUSIONS: These findings indicate that comprehensive muscle properties, gross motor performance, and QoL assessments should be considered to support and develop individualized physical therapy plans for children with SCD.

Heart rate variability associated with acute exercise challenge in children with sickle cell anaemia.

We examined heart rate variability (HRV) during exercise testing in 20 children with sickle cell anaemia (SCA) and 12 controls. Subjects achieved lower median HRV at peak exercise [standard deviation of R-wave to R-wave intervals (SDNN), 2·3 vs 2·9 ms, P = 0·027; logarithmic transformation of high frequency power (lnHF), 0·9 vs 1·3 ln(ms2 ), P = 0·047] and had lower post-exercise HRV across minute-by-minute analysis of recovery. After adjustment for haemoglobin, fitness and SCA status, subjects had lower HRV at the end of recovery with differences increasing as baseline HRV increased. Further investigation of HRV and exercise safety in SCA is warranted.

Plasma microparticles of sickle patients during crisis or taking hydroxyurea modify endothelium inflammatory properties.

Microparticles (MPs) are submicron extracellular vesicles exposing phosphatidylserine (PS), detected at high concentration in the circulation of sickle cell anemia (SS) patients. Several groups studied the biological effects of MPs generated ex vivo. Here, we analyzed for the first time the impact of circulating MPs on endothelial cells (ECs) from 60 sickle cell disease (SCD) patients. MPs were collected from SCD patients and compared with MPs isolated from healthy individuals (AA). Other plasma MPs were purified from SS patients before and 2 years after the onset of hydroxyurea (HU) treatment or during a vaso-occlusive crisis and at steady-state. Compared with AA MPs, SS MPs increased EC ICAM-1 messenger RNA and protein levels, as well as neutrophil adhesion. We showed that ICAM-1 overexpression was primarily caused by MPs derived from erythrocytes, rather than from platelets, and that it was abolished by MP PS capping using annexin V. MPs from SS patients treated with HU were less efficient to induce a proinflammatory phenotype in ECs compared with MPs collected before therapy. In contrast, MPs released during crisis increased ICAM-1 and neutrophil adhesion levels, in a PS-dependent manner, compared with MPs collected at steady-state. Furthermore, neutrophil adhesion was abolished by a blocking anti-ICAM-1 antibody. Our study provides evidence that MPs play a key role in SCD pathophysiology by triggering a proinflammatory phenotype of ECs. We also uncover a new mode of action for HU and identify potential therapeutics: annexin V and anti-ICAM-1 antibodies.

Fetal hemoglobin in sickle cell anemia.

Fetal hemoglobin (HbF) can blunt the pathophysiology, temper the clinical course, and offer prospects for curative therapy of sickle cell disease. This review focuses on (1) HbF quantitative trait loci and the geography of ß-globin gene haplotypes, especially those found in the Middle East; (2) how HbF might differentially impact the pathophysiology and many subphenotypes of sickle cell disease; (3) clinical implications of person-to-person variation in the distribution of HbF among HbF-containing erythrocytes; and (4) reactivation of HbF gene expression using both pharmacologic and cell-based therapeutic approaches. A confluence of detailed understanding of the molecular basis of HbF gene expression, coupled with the ability to precisely target by genomic editing most areas of the genome, is producing important preliminary therapeutic results that could provide new options for cell-based therapeutics with curative intent.

Altered cardiac reserve is a determinant of exercise intolerance in sickle cell anaemia patients.

BACKGROUND: The underlying mechanisms of exercise intolerance in sickle cell anaemia (SCA) patients are complex and not yet completely understood. While latent heart failure at rest could be unmasked upon exercise, most previous studies assessed cardiac function at rest. We aimed to investigate exercise cardiovascular reserve as a potential contributor to exercise intolerance in adult SCA patients. METHODS: In this observational prospective study, we compared prospectively 60 SCA patients (median age 31 years, 60% women) to 20 matched controls. All subjects underwent symptom-limited combined exercise echocardiography and oxygen uptake (VO2 ) measurements. Differences between arterial and venous oxygen content (C(a-v)O2 ) were calculated. Cardiac reserve was defined as the absolute change in cardiac index (Ci) from baseline to peak exercise. RESULTS: Compared to controls, SCA patients demonstrated severe exercise intolerance (median peakVO2 , 34.3 vs. 19.7 ml/min/kg, respectively, p < .0001). SCA patients displayed heterogeneously increased Ci from rest to peak exercise (median +5.8, range 2.6 to 10.6 L/min/m²) which correlated with peakVO2 (r = 0.71, p < .0001). In contrast, the C(a-v)O2 exercise reserve was homogenously reduced and did not correlate with peakVO2 (r = 0.18, p = .16). While haemoglobin level and C(a-v)O2 were similar in SCA subgroups, SCA patients in the lower VO2 tertile had chronotropic incompetence and left ventricular diastolic dysfunction (left atrial peak longitudinal strain was reduced, and both E/e' ratio and left atrial volume index were increased) and were characterized by a reduced cardiac reserve, +5.0[4.2-5.5] compared to +6.7[5.5-7.8] L/min/m² for the rest of the patient cohort, p < .0001. CONCLUSIONS: Altered cardiac reserve due to chronotropic incompetence and left ventricular diastolic dysfunction seems to be an important determinant of exercise intolerance in adult SCA patients.

Can subjective pain be inferred from objective physiological data? Evidence from patients with sickle cell disease.

Patients with sickle cell disease (SCD) experience lifelong struggles with both chronic and acute pain, often requiring medical interventMaion. Pain can be managed with medications, but dosages must balance the goal of pain mitigation against the risks of tolerance, addiction and other adverse effects. Setting appropriate dosages requires knowledge of a patient's subjective pain, but collecting pain reports from patients can be difficult for clinicians and disruptive for patients, and is only possible when patients are awake and communicative. Here we investigate methods for estimating SCD patients' pain levels indirectly using vital signs that are routinely collected and documented in medical records. Using machine learning, we develop both sequential and non-sequential probabilistic models that can be used to infer pain levels or changes in pain from sequences of these physiological measures. We demonstrate that these models outperform null models and that objective physiological data can be used to inform estimates for subjective pain.

Xanthine Oxidase Drives Hemolysis and Vascular Malfunction in Sickle Cell Disease.

OBJECTIVE: Chronic hemolysis is a hallmark of sickle cell disease (SCD) and a driver of vasculopathy; however, the mechanisms contributing to hemolysis remain incompletely understood. Although XO (xanthine oxidase) activity has been shown to be elevated in SCD, its role remains unknown. XO binds endothelium and generates oxidants as a byproduct of hypoxanthine and xanthine catabolism. We hypothesized that XO inhibition decreases oxidant production leading to less hemolysis. Approach and Results: Wild-type mice were bone marrow transplanted with control (AA) or sickle (SS) Townes bone marrow. After 12 weeks, mice were treated with 10 mg/kg per day of febuxostat (Uloric), Food and Drug Administration-approved XO inhibitor, for 10 weeks. Hematologic analysis demonstrated increased hematocrit, cellular hemoglobin, and red blood cells, with no change in reticulocyte percentage. Significant decreases in cell-free hemoglobin and increases in haptoglobin suggest XO inhibition decreased hemolysis. Myographic studies demonstrated improved pulmonary vascular dilation and blunted constriction, indicating improved pulmonary vasoreactivity, whereas pulmonary pressure and cardiac function were unaffected. The role of hepatic XO in SCD was evaluated by bone marrow transplanting hepatocyte-specific XO knockout mice with SS Townes bone marrow. However, hepatocyte-specific XO knockout, which results in >50% diminution in circulating XO, did not affect hemolysis levels or vascular function, suggesting hepatocyte-derived elevation of circulating XO is not the driver of hemolysis in SCD. CONCLUSIONS: Ten weeks of febuxostat treatment significantly decreased hemolysis and improved pulmonary vasoreactivity in a mouse model of SCD. Although hepatic XO accounts for >50% of circulating XO, it is not the source of XO driving hemolysis in SCD.

EVALUATION OF MACULAR FLOW VOIDS ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY AS POTENTIAL BIOMARKERS FOR SILENT CEREBRAL INFARCTION IN SICKLE CELL DISEASE.

PURPOSE: To determine the relationship between macular microvascular abnormalities on optical coherence tomography angiography and silent cerebral infarctions (SCIs) on cerebral magnetic resonance imaging in sickle cell disease. METHODS: Patients (age <18 years old) from our previous pediatric sickle cell disease study cohort who had prior optical coherence tomography angiography and brain magnetic resonance imaging were identified. Brain magnetic resonance imaging images were compared with macular optical coherence tomography angiography scans to identify macular vascular density differences between patients with SCI and without SCI. RESULTS: Sixty-eight eyes from 34 patients who underwent optical coherence tomography angiography were evaluated, of whom 28 eyes from 14 patients met the inclusion criteria for this study. Eight patients (57%) with SCI and 6 patients (43%) without SCI were identified. The mean age (17 years in SCI and 16.3 years in non-SCI) was comparable between groups. There was no statistically significant difference in systemic complications. Deep capillary plexus vessel density was lower in the temporal quadrant in patients with SCI (49.3% vs. 53.7%, P = 0.014). CONCLUSION: Patients with SCI were found to have lower vessel density in the deep capillary plexus compared with those without SCI. This finding suggests that deep capillary plexus vessel density may have utility as an imaging biomarker to predict the presence of SCI.

Cerebral Hemodynamics and Executive Function in Sickle Cell Anemia.

BACKGROUND AND PURPOSE: Individuals with sickle cell anemia experience cognitive deficits, even in the absence of cerebral infarcts or strokes. This study tested the hypothesis that elevated cerebral blood flow and oxygen extraction fraction are associated with lower executive function in individuals with sickle cell anemia. METHODS: Three-Tesla brain magnetic resonance imaging was performed, including anatomic, gray matter cerebral blood flow, and global oxygen extraction fraction imaging. Executive function was measured using the working memory index from an age-appropriate Wechsler battery and tasks from the National Institutes of Health Toolbox Cognition Battery. Bivariate and multivariate models were examined (significance: P<0.05). RESULTS: Fifty-four participants (age range=6-31 years) with sickle cell anemia were enrolled. Hematocrit was positively related to fluid cognition, cerebral blood flow was inversely related to working memory and inhibitory control, and oxygen extraction fraction was inversely related to processing speed. Associations remained significant in multivariate analyses controlling for age, income, and infarcts. CONCLUSIONS: Elevated cerebral blood flow and oxygen extraction fraction, markers of hemodynamic impairment, are associated with deficits in executive function in individuals with sickle cell anemia.

Sickle Cell Anemia and Its Phenotypes.

In the 100 years since sickle cell anemia (SCA) was first described in the medical literature, studies of its molecular and pathophysiological basis have been at the vanguard of scientific discovery. By contrast, the translation of such knowledge into treatments that improve the lives of those affected has been much too slow. Recent years, however, have seen major advances on several fronts. A more detailed understanding of the switch from fetal to adult hemoglobin and the identification of regulators such as BCL11A provide hope that these findings will be translated into genomic-based approaches to the therapeutic reactivation of hemoglobin F production in patients with SCA. Meanwhile, an unprecedented number of new drugs aimed at both the treatment and prevention of end-organ damage are now in the pipeline, outcomes from potentially curative treatments such as allogeneic hematopoietic stem cell transplantation are improving, and great strides are being made in gene therapy, where methods employing both antisickling ß-globin lentiviral vectors and gene editing are now entering clinical trials. Encouragingly, after a century of neglect, the profile of the vast majority of those with SCA in Africa and India is also finally improving.