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Nineteen genetic therapies have been approved by the U.S. Food and Drug Administration (FDA) to date, a number that now includes the first CRISPR genome editing therapy for sickle cell disease, CASGEVY (exagamglogene autotemcel). This extraordinary milestone is widely celebrated because of the promise for future genome editing treatments of previously intractable genetic disorders and cancers. At the same time, such genetic therapies are the most expensive drugs on the market, with list prices exceeding $4 million per patient. Although all approved cell and gene therapies trace their origins to academic or government research institutions, reliance on for-profit pharmaceutical companies for subsequent development and commercialization results in prices that prioritize recouping investments, paying for candidate product failures, and meeting investor and shareholder expectations. To increase affordability and access, sustainable discovery-to-market alternatives are needed that address system-wide deficiencies. Here, we present recommendations of a multi-disciplinary task force assembled to chart such a path. We describe a pricing structure that, once implemented, could reduce per-patient cost tenfold and propose a business model that distributes responsibilities while leveraging diverse funding sources. We also outline how academic licensing provisions, manufacturing innovation and supportive regulations can reduce cost and enable broader patient treatment.

A major limitation of gene therapy for sickle cell disease (SCD) is the availability and access to a potentially curative one-time treatment, due to high treatment costs. We have developed a high-titer bifunctional lentiviral vector (LVV) in a vector backbone that has reduced size, high vector yields, and efficient gene transfer to human CD34+ hematopoietic stem and progenitor cells (HSPCs). This LVV contains locus control region cores expressing an anti-sickling βAS3-globin gene and two microRNA-adapted short hairpin RNA simultaneously targeting BCL11A and ZNF410 transcripts to maximally induce fetal hemoglobin (HbF) expression. This LVV induces high levels of anti-sickling hemoglobins (HbAAS3 + HbF), while concurrently decreasing sickle hemoglobin (HbS). The decrease in HbS and increased anti-sickling hemoglobin impedes deoxygenated HbS polymerization and red blood cell sickling at low vector copy per cell in transduced SCD patient CD34+ cells differentiated into erythrocytes. The dual alterations in red cell hemoglobins ameliorated the SCD phenotype in the SCD Berkeley mouse model in vivo. With high titer and enhanced transduction of HSPC at a low multiplicity of infection, this LVV will increase the number of patient doses of vector from production lots to decrease costs and help improve accessibility to gene therapy for SCD.

The cause of death in people affected by sickle cell disease (SCD) is often challenging to define as prior studies have used retrospective or administrative data for analysis. We used a prospective longitudinal registry to assess mortality and clinical co-morbidities among subjects enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry. At enrollment, we collected the following data: patient-reported demographics, SCD phenotype, baseline laboratory values, comorbidities, and current medications. Subjects were followed for a median of 4.7 years before the present analysis. The relationship of clinical co-morbidities (at time of enrollment) to mortality was determined using survival analysis, adjusting for SCD phenotype and gender. There was a total of 2439 people with SCD enrolled in the SCDIC registry. One hundred and twenty-eight participants (5%) died during the observation period (2017-2022). Six people died from trauma and were excluded from further analysis. Proximate cause of death was unwitnessed in 17% of the deaths, but commonest causes of death include cardiac (18%), acute chest or respiratory failure (11%), sudden unexplained death (8%). Enrollment characteristics of the individuals who died (n = 122) were compared to those of survivors (n = 2317). Several co-morbidities at enrollment increased the odds of death on univariate analysis. All co-morbidities were included in a multivariable model. After backward elimination, iron overload, pulmonary hypertension, and depression, remained statistically significant predictors of the risk of death. SCD reduces life expectancy. Improved comprehensive and supportive care to prevent end-organ damage and address comorbidities is needed for this population.

AbstractSickle cell disease (SCD) is a genetic disorder affecting 100 000 people with an estimated annual medical cost of $3 billion in the United States; however, the economic impact on patients is not well described. We aimed to examine the indirect economic burden and test the hypothesis that socioeconomic status and greater social vulnerability risks are associated with increased absenteeism and employment loss. We surveyed adults and caregivers of children with SCD at 5 US centers from 2014 to 2021. Logistic regression models were used to examine the associations of employment loss and missed days of work with demographics and social determinants. Indirect costs were estimated by multiplying the self-reported missed days of work and job loss by 2022 average wages by the state of the participating institution. Of the 244 participants, 10.3% reported employment loss in the last 5 years, and 17.5% reported missing 10 or more days of work. Adults had 3 times more employment loss compared with caregivers of children with SCD (OR, 3.18; 95% CI, 1.12-9.01) but fewer missed days of work (OR, 0.24; 95% CI, 0.11-0.0.51). Participants who did not live with a partner reported increased employment loss (OR, 4.70; 95% CI, 1.04-21.17) and more missed days of work (OR, 4.58; 95% CI, 1.04-20.15). The estimated annual indirect economic burden was $2 266 873 ($9290 per participant). Adults with SCD and caregivers of children with SCD commonly report employment loss and missed days of work as important risk factors. The high indirect economic burden suggests that future economic evaluations of SCD should include SCD-related indirect economic burden.

Sickle cell disease (SCD) is a single gene blood disorder characterised by frequent episodes of pain, chronic anaemic, acute chest syndrome, severe disease complications and lifelong debilitating multi-system organ damage. Genetic testing and screening programs for SCD and the sickle cell trait (SCT) are valuable for early diagnosis and management of children living with SCD, and in the identification of carriers of SCT. People with SCT are for the most part asymptomatic and mainly identified as through genetic testing or when they have a child with SCD. This qualitative study explored perceptions towards genetic testing for SCD and SCT in Cameroon, Ghana, and Tanzania. The results show a general preference for newborn screening for SCD over prenatal and premarital/preconception testing, primarily due to its simpler decision-making process and lower risk for stigmatization. Premarital testing for SCT was perceived to be of low public health value, as couples are unlikely to alter their marriage plans despite being aware of their risk of having a child with SCD. Adolescents were identified as a more suitable population for SCT testing. In the case of prenatal testing, major concerns were centred on cultural, religious, and personal values on pregnancy termination. The study revealed a gender dimension to SCD/SCT testing. Participants mentionned that women bear a heightened burden of decision making in SCD/SCT testing, face a higher risk of rejection by potential in-laws/partners if the carriers of SCT, as well as the possibility of  divorce if they have a child with SCD. The study highlights the complex cultural, ethical, religious and social dynamics surrounding genetic testing for SCD and emphasises the need for public education on SCD and the necessity of incorporating genetic and psychosocial counselling into SCD/SCT testing programs.

Objective Methods Results Conclusion The study presents the risk of the maternal‐fetal morbidity and mortality among one of the largest cohort of sickle cell disease (SCD) pregnancies in India and reports the epidemiology of the maternal morbidity.This was a retrospective cohort study conducted at Kasturba Maternity Hospital, SEWA Rural, in the tribal area of Gujarat, India. All pregnant women admitted to the Hospital between 2016 and 2021 were screened for SCD, and their maternal‐fetal morbidities were recorded throughout the pregnancy. We quantified risk of maternal‐fetal morbidity and mortality among SCD, trait and normal pregnancies after adjusting for potential confounders using Poisson and logistic regression.A total of 24 256 delivered during the study period, with 354 (1.5%) and 4216 (17.4%) suffering from SCD and trait, respectively. After adjusting for potential confounders, the women with SCD pregnancy had higher risk of maternal death (adjusted‐odds‐ratio [AOR] 13.7, 95% CI: 4.5–42.7), anemia (AOR 6.8, 95% CI: 4.5–10.2), severe anemia (AOR 4.3, 95% CI: 3.3–5.6), preterm delivery (AOR 4.5, 95% CI: 3.6–5.7), cesarean section (AOR 5.5, 95% CI: 4.7–7.0), stillbirth (AOR 3.4, 95% CI: 2.3–5.3), and low birth weight (AOR 3.1, 95% CI: 2.4–39) compared to normal pregnancies. Maternal morbidities occurred throughout the pregnancy; however, the risk was highest during the last month of pregnancy. Pregnant women who had severe manifestation of SCD before the pregnancy were at higher risk of developing maternal morbidities.We concluded that SCD might be an independent risk‐factor for developing maternal‐fetal morbidities. The SCD pregnancies with prior severe manifestations must be carefully managed during the last month of pregnancy when the risk is highest. [ABSTRACT FROM AUTHOR]

Background Study Design and Methods Results Discussion Many children with sickle cell disease (SCD) who suffer a stroke receive chronic transfusion therapy (CTT) indefinitely; however, their adulthood neurologic outcomes have not been reported. Understanding these outcomes is critical to inform decisions regarding curative therapy in childhood.In this retrospective study, we described a cohort of adults with SCD and a history of childhood stroke who received care at a single center and compared their outcomes with matched subjects without childhood stroke using chi2 and Mann–Whitney U tests.Of 42 subjects with childhood stroke, all received CTT for secondary stroke prophylaxis. Five (11%) developed recurrent stroke. The rate of stroke was similar in subjects with and without childhood stroke (0.7 vs. 1.1 per 100 person·years, p = .63). Both cohorts exhibited evidence of iron overload (median ferritin 2227 vs. 1409 ng/dL, p = .10) and alloimmunization (45% vs. 45%, p = 1.0), despite receiving care in a comprehensive SCD program.For adults with SCD who had a childhood stroke, our results suggest CTT returns the risk of stroke to that of age‐matched stroke naïve patients with SCD. [ABSTRACT FROM AUTHOR]

AbstractSickle cell disease (SCD) is a prevalent inherited blood disorder arising from a single point mutation that results in substitution of valine with glutamic acid in the Beta hemoglobin chain, making red blood cells assume a banana shape under low oxygen state. It is most prevalent in sub-Saharan Africa, affecting approximately 2% of the population in Mali. This study aimed to evaluate the iron status and associated hematological parameters in SCD patients at steady state in an environment with a high prevalence of iron deficiency. A cross-sectional study was conducted at the Center de Recherche et de Lutte contre la Drépanocytose (CRLD) in Bamako, Mali, involving 757 SCD patients aged 10 to 29 years. Iron deficiency was defined as serum ferritin < 20 ng/mL, while iron overload was associated with serum ferritin > 500 ng/mL. The study population consisted of 171 (22.6%) hemolytic phenotypes (SS and Sβ0) and 586 (77.4%) viscous phenotypes (SC and Sβ+). Iron deficiency was found in 19 SCD patients (2.5%), with a higher prevalence in the SC phenotype (68.4%). All iron-deficient subjects exhibited microcytosis (MCV < 80 fL) and hypochromia (MCH < 26 pg). Hemoglobin levels < 12 g/dL were observed only in homozygous SCD patients. Low reticulocyte counts were noted in iron-deficient subjects with SC and Sβ+ phenotypes, but not in iron-deficient SS subjects. Serum C-reactive protein (CRP) was normal (< 10 mg/L) in all iron-deficient subjects, excluding iron deficiency due to chronic inflammation. Iron deficiency was observed among 2.5% of the study population, with a predominant occurrence among those with SC phenotype. All iron deficient subjects had microcytosis and hypochromia. Hemoglobin levels below 12 g/dL were only found in homozygous SCD patients. Additionally, low reticulocyte counts were noted in iron deficient patients with SC and Sβ+ phenotypes, though not in those with the SS phenotype. These findings contribute to the understanding of iron status in SCD patients in an African context and highlights the importance of monitoring iron levels in these population to prevent complications associated with iron deficiency or overload. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions Acute Chest Syndrome (ACS) is the leading cause of death in children with sickle cell disease (SCD) in the US—about half of the children who develop ACS present initially with pain.Here, we studied biomarkers to differentiate ACS from vaso‐occlusive crises (VOC) in children with SCD who presented with pain to the emergency department (ED). We conducted a prospective cohort study of consecutive patients who presented to the ED with pain and were discharged with ACS or VOC between March, 2017 and February, 2020.We identified 7 patients with ACS and 19 patients with VOC. The two groups were comparable in age and sex. All patients with ACS had asthma versus 42% of the VOC group. The ACS group had lower weight and BMI z‐scores. Patients with ACS compared to VOC had significantly higher respiratory rates, lower O2 saturation, and longer hospital stays. They also had higher white blood cell count, glucose level (> 99 mg/dL), anion gap (> 9 mEq/L), sPLA2 (> 7 pg/mL), IFN‐γ (> 17.8 pg/mL), IL‐10 (1.54 pg/mL), and IL‐12 (> 0.5 pg/mL) levels.We identified biomarkers associated with ACS development in children with SCD presenting with pain that allow for earlier ACS interventions to reduce mortality and morbidity. [ABSTRACT FROM AUTHOR]

Summary This study evaluates the neurocognitive and electrophysiological effects of 1‐year memantine treatment in 14 adolescents and young adults (mean age 24 years) with sickle cell disease (SCD, incluing sickle cell anaemia and sickle cell β‐thalassemia), hypothesizing improvements in cognitive functions and neural processing. Participants underwent assessments using subtests from the Wechsler Intelligence Scale and a computerized task‐switching paradigm with concurrent event‐related potential (ERP) recordings, both before and after the treatment period. Assessments focused on processing speed, working memory, attention and executive function. ERP measurements targeted brain response changes during task switching. Memantine treatment enhanced cognitive test performance, especially in processing speed as shown by the Digit–Symbol Coding and Symbol‐Search tests. Results indicated improved visuospatial and graphomotor speed, working memory and attention. The task‐switching test revealed reduced error rates, suggesting decreased cognitive load and enhanced executive control. Electrophysiological changes in P1 and P3 amplitudes at frontal and parietal locations post‐treatment pointed to more efficient neural processing in tasks requiring cognitive flexibility. These preliminary findings from a Phase II clinical study serve as a ‘proof of concept’, exploring the feasibility and potential effectiveness of memantine treatment in SCD—a previously uninvestigated context. They support the rationale for more extensive investigations to confirm these results and assess memantine's broader effectiveness. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is one of the most devastating inherited haemoglobinopathy that affects mostly children. Its prevalence can reach up to 13 % in the south-eastern part of Madagascar. For socio-cultural and economic reasons, the majority of patients use plants to manage the symptoms of this genetic disease. This work aims to inventory these plants and collect all information on their use, their therapeutic effects, and their eventual side effects in order to compile a database. These plants will be the subject of future chemical, pharmacological and toxicological investigations in the laboratory. Semi-directive interviews were led among 208 respondents from January 2018 to January 2020 in the eastern part of Madagascar. After obtaining the informed consent of the interviewees, collected data on the used medicinal plants were analyzed for various ethnomedicinal parameters including frequency of citation (FC), use value (UV), relative frequency of citation (RFC), fidelity level (FL), family use value (FUV) and informant consensus factor (ICF) related to the SCD management and the other mentioned diseases. Among the 208 respondents, 30.29 % were male; 73.39 % received formal education; 53.37 % were farmers, 8.17 % were traditional healers and 6.73 % were herbal sellers. Most of them (94.23 %) have a good knowledge of SCD and 91.83 % of them use herbal medicine to manage SCD. They recommended 123 plant species belonging to 111 genera and 62 families. Asteraceae (14.50 %) was the most cited family however Blechnaceae was the most valued family (FUV = 0.356). The majority of the cited species (70.73 %) were wild plants. Herbs (42.28 %) were the most used plant life form and the most used common parts were leaves (44.68 %). They usually prepare tea by infusion of plant material (71.83 %). Ficus polita was the most important species with the highest FC (10.93 %), UV (0.393), RFC (75.92 %) and FL (94.94 %). ICF of SCD and its symptoms value was 0.50 showing the homogeneity, and the consensus among the informants in the use of medicinal plants for managing this disease. Some species (08) have been reported for their anti-sickling properties and some of the other species have been reported for their pharmacological properties related to SCD symptoms management. These results confirmed the importance of investigating the use of plant species to manage SCD and its symptoms in the eastern part of Madagascar, suggesting the fundamental role of ethnomedicinal studies for the sustainable use of plant species for future scientific investigations on phyto-drugs for SCD management. [Display omitted] • 123 plant species were cited in the management of SCD and/or its symptoms. • The majority (70.73 %) of them were wild plants. • Herbs (42.28 %) was the most used plant life form and the most used common parts were leaves (44.68 %) and aerial parts (25.53 %). • The majority of the herbal preparation was infusion (71.83 %) and the administration is only by oral route. • The knowledge of medicinal plants depends on the age and the occupation of the informants. • Ficus polita and Stenochlaena tenuifolia were the most important species according to their use value. • Among the 123 species, 8 species have been reported for their anti-sickling properties. [ABSTRACT FROM AUTHOR]

Objective To compare the risk of severe maternal morbidity (SMM) from the delivery admission to 42 days' postdischarge among persons with sickle cell disease (SCD) to those without SCD. Study Design This retrospective cohort study included deliveries ≥20 weeks' gestation at an urban safety net hospital in Atlanta, GA from 2011 to 2019. The exposure was SCD diagnosis. The outcome was a composite of SMM from the delivery admission to 42 days' postdischarge. SMM indicators as defined by the Centers for Disease Control and Prevention were identified using the International Classification of Diseases, Ninth and Tenth Revisions (ICD-9/10) codes; transfusion of blood products and sickle cell crisis were excluded. Results Of N = 17,354 delivery admissions, n = 92 (0.53%) had SCD. Persons with SCD versus without SCD had an increased risk of composite SMM (15.22 vs. 2.29%, p < 0.001), acute renal failure (6.52 vs. 0.71%, p < 0.001), acute respiratory distress syndrome (4.35 vs. 0.17%, p < 0.001), puerperal cerebrovascular disorders (3.26 vs. 0.10%, p < 0.001), sepsis (4.35 vs. 0.42%, p < 0.01), air and thrombotic embolism (5.43 vs. 0.10%, p < 0.001), and ventilation (2.17 vs. 0.09%, p < 0.01). Ultimately, those with SCD had an approximately 6-fold higher incidence risk ratio of SMM, which remained after adjustment for confounders (adjusted incidence risk ratio [aIRR]: 5.96, 95% confidence interval [CI]: 3.4–9.19, p < 0.001). Persons with SCD in active vaso-occlusive crisis at the delivery admission had an approximately 9-fold higher risk of SMM up to 42 days' postdischarge compared with those with SCD not in crisis at the delivery admission (incidence: 25.71 vs. 8.77%, p < 0.05; aIRR: 8.92, 95% CI: 4.5–10.04, p < 0.05). Among those with SCD, SMM at the delivery admission was primarily related to renal and cerebrovascular events, whereas most postpartum SMM was related to respiratory events or sepsis. Conclusion SCD is significantly associated with an increased risk of SMM during the delivery admission and through 42 days' postdischarge. Active crisis at delivery further increases the risk of SMM. Key Points Sickle cell disease was associated with an approximately 6-fold increased risk of SMM. Active vaso-occlusive crisis at delivery was associated with an approximately 9-fold increased risk of SMM. 48% of SMM events in persons with SCD occurred postpartum and were respiratory- or sepsis-related. [ABSTRACT FROM AUTHOR]

Genetic manipulation of hematopoietic stem cells (HSCs) is being developed as a therapeutic strategy for several inherited disorders. This field is rapidly evolving with several novel tools and techniques being employed to achieve desired genetic changes. While commercial products are now available for sickle cell disease, transfusion-dependent β-thalassemia, metachromatic leukodystrophy and adrenoleukodystrophy, several challenges remain in patient selection, HSC mobilization and collection, genetic manipulation of stem cells, conditioning, hematologic recovery and post-transplant complications, financial issues, equity of access and institutional and global preparedness. In this report, we explore the current state of development of these therapies and provide a comprehensive assessment of the challenges these therapies face as well as potential solutions. [ABSTRACT FROM AUTHOR]

Background: Ultrasonography is an established and reliable method for assessing the spleen. Because of variation due to genetic and other environmental factors including malaria endemicity, interpretation of spleen sizes requires a knowledge of the normal reference range for a given population. This study aimed to identify spleen size reference ranges across age groups of healthy controls to serve as a baseline to assess changes in spleen size in patients with sickle cell disease. Methods: Using a cross-sectional study design, spleen size was measured in healthy people of different age groups and steady-state sickle cell disease patients (children and adults) using abdominal ultrasonography. Using the age-group-specific reference values obtained from the controls, spleens were classified into small, normal size or enlarged among the sickle cell disease patients. Results: The study consisted of 109 (34.8%) healthy controls and 204 (65.2%) steady-state sickle cell disease patients. The spleen was visualised in all the controls (n = 109) and in 107 (52.4%) sickle cell disease patients. Using cut-off values for spleen length among the controls across age groups (< 5 years (5.0–7.0 cm); 5–9 years (5.5–8.5 cm); 10–14 years (6.0–11.0 cm) and ⩾ 15 years (7.0–12.5 cm)), spleen size was classified as small (n = 18/204; 8.87%), normal (n = 68/204; 33.3%) and enlarged (n = 21/204; 10.3%) among the sickle cell disease patients. Conclusion: Model-based age-group reference ranges and percentile curves for splenic dimensions based on ultrasonography among normal controls in North-Eastern Nigeria were established and may be of value in assessing spleen sizes among sickle cell disease patients living in malaria-endemic regions of Africa. [ABSTRACT FROM AUTHOR]

Objectives: High rate of alloimmunization in sickle cell disease (SCD) patients poses a significant challenge in finding compatible blood unit. Accurate determination of the blood group genotype of them can help reduce the alloimmunization risk. Tetra ARMS PCR is a novel method that has been utilized recently to investigate SNPs in diseases in a fast and reliable way. Methods: Our study included 104 SCD and sickle thalassemia (Sβ) patients referred to Baghaei-2-Hospital of Ahvaz in 2019 using a nonrandom sampling method. Blood samples were collected for serological and molecular tests. Rh genotyping was performed using Tetra ARMS PCR and compared with the serological results. Results: Based on the Tetra ARMS PCR method, out of 104 patients, 7 (6.7%) were d/d, 40 (38.5%) were D/d, 57 (54.8%) were D/D, 25 (24%) were C/C, 59 (56.7%) were C/c, 20 (19.3%) were c/c, 4 (3.8%) were E/E, 25 (24%) were E/e, and patients 75 (72.2%) were e/e. There were discrepancies in the serological and molecular results for 11 patients. Conclusion: Use of Tetra ARMS PCR in combination with serological methods for determining the Rh blood group system in donors and transfusion-dependent patients represents a remarkable transformation in the field of immunohematology. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Methods Results Conclusions Access to crizanlizumab, a disease‐modifying therapy for sickle cell disease (SCD), was provided through a managed access program (MAP, NCT03720626). The present analysis evaluated the impact of 12 months of crizanlizumab treatment on vaso‐occlusive crises (VOCs), and on the use of opioids for VOC‐related pain relief, in patients with SCD from the MAP.From June 2018 to January 2023, 112 patients with a history of recurrent VOCs completed 12 months of crizanlizumab (5 mg/kg) treatment and were monitored for adverse events (AEs).Crizanlizumab led to reductions of 18.0% and 36.2% in the proportions of patients having ≥ 1 home‐ and ≥ 1 healthcare‐managed VOCs. Median absolute changes (interquartile range) from baseline in the rates of home‐ and healthcare‐managed VOCs were −3.0 (−6.0, −1.0) and −2.0 (−4.0, 0), respectively. Data stratified by genotype and prior hydroxyurea use showed similar reductions in VOC rates. A 35.5% reduction in the proportion of patients requiring opioids was noted. AEs were consistent with earlier reports, and no new safety concerns were identified.Crizanlizumab demonstrated potential benefits in attenuating VOC episodes, irrespective of SCD genotype and prior hydroxyurea use, and in lowering opioid usage. The safety of crizanlizumab was consistent with earlier reports.Trial Registration: The MAP has been registered at ClinicalTrials.gov with the ID, NCT03720626 [ABSTRACT FROM AUTHOR]

Summary Sickle cell disease (SCD) with vaso‐occlusive pain crisis (VOC) significantly impacts patient well‐being and often results in extensive healthcare resource utilization. This study assessed the VOC burden, its management and its impact on patients' quality of life (QoL). A cross‐sectional observational study was conducted between November 2021 and June 2022, including 1000 SCD patients from high‐prevalence states in India. Data on demographics, clinical characteristics, VOC severity, management and QoL were collected. The study revealed that 33.5% of patients reported at least one VOC episode during the study period. In the year prior to their enrolment, 836 (83.60%) patients reported at least one VOC episode, with an equal proportion of 407/487 (83.6%) adults and 429/513 (83.6%) paediatric patients, reducing their QoL across all domains compared to patients without VOC. Of these, 469/1000 patients (46.9%) experienced ≥3 VOC episodes. Additionally, 764/1000 (76.40%) patients managed their VOCs at healthcare facilities, with 501/1000 (50.1%) requiring inpatient admissions. Further, 71.80% of patients received Hydroxyurea (HU) therapy. The study depicts the severity of the Arab–Indian haplotype in Indian SCD patients visiting healthcare settings based on high VOC burden. This highlights the urgent need for better management strategies and resource allocation for these patients. [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodsResultsConclusionsThis retrospective, real-world claims database analysis described the clinical burden and healthcare resource utilization (HCRU) among patients with sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs) in France.The French National Health Data System database (système national des données de santé) was used to identify eligible patients from January 1, 2012, to March 1, 2019. Inclusion criteria were a SCD diagnosis, ≥2 VOCs/year for ≥2 consecutive years following the diagnosis, and ≥1 year of follow-up data to March 1, 2020. Patients with hereditary persistence of fetal hemoglobin or hematopoietic stem cell transplant in their medical records were excluded. Clinical complications, mortality, treatment use, and HCRU were evaluated during follow-up.Overall, 4602 patients with SCD with recurrent VOCs were eligible; their mean (standard deviation [SD]) age was 19.8 (13.5) years, and 51.8% were female. Patients experienced a mean (SD) of 3.82 (3.57) VOCs per patient per year (PPPY). Prevalent complications were anemia or leukocytosis (44.1%), infections (42.0%), and organ failure (38.2%). In total, 101 (2.2%) patients died during follow-up (mean age of death [SD]: 39.3 [17.5] years; mortality rate: 0.64 deaths per 100 person-years). Most patients received opioids (89.1%) and hydroxycarbamide (72.8%). Patients had a mean of 5.7 inpatient hospitalizations, 6.0 emergency room visits, 6.6 outpatient visits, and 13.4 outpatient prescriptions PPPY.Patients with SCD with recurrent VOCs in France have substantial clinical complications, mortality, and HCRU despite currently available treatment options. Innovative treatments that reduce frequency of or eliminate VOCs are needed to alleviate the burden associated with SCD. [ABSTRACT FROM AUTHOR]

Importance: While the prevalence and impact of depression have been widely described in sickle cell disease, its relationship with precariousness has never been studied. Objective: This study aimed to describe the prevalence of depression and its relationship with clinical and demographic factors including social precariousness in children with sickle cell disease in French Guiana. Methods: We included children aged 12–18 years with sickle cell disease from the Sickle Cell Reference Center in French Guiana. A simple depression questionnaire "Child depression inventory 2" was proposed and completed by a clinical examination and consultation by a psychologist. Using the known assessment of health inequalities and poverty in health screening centres (EPICES) score, we developed a composite precariousness score that uses five items (each item is scored from 0 to 2). According to the chosen items, precariousness was defined as a score ≥5. Results: The prevalence of depression was 42.5% [95% CI: 31.5–54]. The median age was 15 years [95% CI: 13–17]. The age distribution peaked at 14 years in patients with depression. There were 76% of precarious patients in the depressed group and 18% in the control group (p < 0.0001). In multivariate analysis, genotype SC (OR = 7.66, [1.17; 50.13], p = 0.0338) and precariousness (OR = 15.68, [4.73; 51.94], p < 0.0001) were associated with higher rates of depression. Baseline hemoglobin levels (OR = 0.48, [0.27; 0.88], p = 0.0173) were also associated with lower rates of depression. Conclusions and Relevance: Despite free healthcare, precariousness is an independent risk factor for depression. [ABSTRACT FROM AUTHOR]

Background and Objectives Materials and Methods Results Conclusion This review aims to explore the impact of sickle cell disease (SCD) on patients' quality of life (QoL) and the effectiveness of different transfusion modalities, particularly automated red blood cell exchange (aRBCX), in managing the factors that impact QoL.A systematic search was performed in PubMed to retrieve articles with data on QoL in SCD patients treated with aRBCX during the last 20 years. A targeted search for medical guidelines and a free search were added.When assessing the impact of the transfusion modality on the QoL of patients with SCD, some studies indicated an improvement in health‐related QoL when using aRBCX while others reported no differences. The benefits of aRBCX include a decrease in length of hospital stay, pain‐related hospitalizations and procedure time. The drawbacks of aRBCX were also identified, including an increased number of procedure‐related complications (despite the overall number of complications showing no significant differences) and a more complex vascular access. Chronic red blood cell exchange favours psychosocial factors such as anxiety and social functioning, but the impact of using aRBCX in these parameters is not determined yet.aRBCX, known to be an efficient procedure to manage SCD, appears to be promising in improving patients' QoL. However, more comprehensive studies incorporating patient‐reported outcomes are needed to fully understand the impact of different transfusion modalities on QoL in SCD patients. An integrated care approach, including psychological support and pain management, may further enhance QoL. [ABSTRACT FROM AUTHOR]

Summary Allogeneic haematopoietic cell transplantation (HCT) with HLA‐matched sibling donor remains the most established curative therapeutic option for patients with sickle cell disease (SCD). However, it is not without risks, highlighting the need for a risk stratification system. Utilizing a machine learning (ML) approach that combines clinical and imaging variables, we identified red cell distribution width and renal organ damage as important risk factors for patients undergoing HCT. This ML‐based algorithm, similar to an approach previously reported for predicting mortality in patients with SCD, should be applicable to risk factor discovery in similar studies. [ABSTRACT FROM AUTHOR]

Background and Objectives: Hydroxyurea (HU) is an effective medication used to reduce the frequency of painful crises associated with sickle cell disease (SCD). However, data describing its prevalence among SCD patients in the Eastern Region of Saudi Arabia are scarce. This is a multi-center, retrospective, cross-sectional study that aims to investigate the pattern of prescribing HU in SCD patients and to determine the association between prescribing HU and other co-prescribed medications used to manage SCD complications. Methods: Data were collected from patients who visited the hematology clinics of Al-Qatif Central Hospital (QCH) and King Fahad Hospital in Hofuf (KFHH) between June 2021 to May 2023. The data included demographics, prescribed medications, and recent laboratory test results, all of which were collected from patients' medical records. Descriptive statistics were utilized to assess the difference between HU users vs. non-users. A binary logistic regression model was used to determine the association between prescribing HU and co-prescribed medications used to manage SCD complications. The results are presented as the odds ratio (OR) and 95% confidence interval (95% CI). Results: This study included 2816 SCD patients with a 56% prevalence of HU prescription. HU was prescribed for young age groups more often compared to old age group patients. Young males were more likely to be prescribed with HU compared to females, and it becomes dominant in females after the age of 36. HU users were more likely to have paracetamol (69% vs. 53%, OR = 1.9, 95% CI 1.6–2.2), NSAIDs (50% vs. 35%, OR = 1.7, 95% CI 1.5–2), and opioids (41% vs. 37%, OR = 1.3, 95% CI 1.1–1.6) co-prescribed, and less often to have laxatives (8% vs. 5%, OR = 0.66, 95% CI 0.48–0.9) and anticoagulants (22% vs. 15%, OR = 0.56, 95% CI 0.46–0.68) co-prescribed compared to non-users. Conclusions: The pattern of prescribing HU, supported by the association findings, raises concerns about patients' compliance and adherence to HU therapy. Early health education, specifically to young female SCD patients, is warranted to increase the success rate of HU therapy. [ABSTRACT FROM AUTHOR]

Background: Sickle cell hepatopathy (SCH) is a relatively uncommon complication of sickle cell disease (SCD), yet it does not accommodate variations in presentation, outcome, or severity according to age. Aim: To present SCH characteristics and assess the effect of implementation of a high-suspicion systematic diagnostic approach and early intervention plan of management. Methods: This case series presented the characteristics of five children with SCD with variable hepatic manifestation and implemented a diagnostic approach that included testing the transaminases and bilirubin in any patient with any suspicion of liver affection. Results: The five patients had a complicated SCD history. They all presented with fever, abdominal pain, and deepening of jaundice. The final diagnosis was reached with a more individualized approach; two had significant coagulopathy and were diagnosed with sickle cell intrahepatic cholestasis, while one had normal synthetic functions of the liver with rising transaminases and bilirubin levels, as well as high titer of Epstein–Barr virus diagnosed as acute viral hepatitis complicated with sickle cell hepatic crisis. One other patient had markedly elevated bilirubin with mild elevation of transaminases, and magnetic resonance cholangiopancreatography showed acute extrahepatic biliary dilatation treated by endoscopic removal of the stone. The fifth patient proved to have portal vein thrombosis by portal duplex causing portal hypertension and decompensated liver. The management plan included early exchange transfusion to keep their hemoglobin S (HbS) below 15% which was performed in three of the patients, in addition to aggressive supportive measures for correction of coagulopathy with full recovery and normalization of their liver functions. Conclusion: Despite the diagnostic challenges, the lack of standard diagnostic criteria, and the overlapping clinical presentation of SCH, the management and outcomes improved by following a systematic diagnostic approach. [ABSTRACT FROM AUTHOR]

Background Study Design and Methods Results Discussion With chronic transfusion in sickle cell disease (SCD), equipoise exists regarding whether increasing the post‐procedure hematocrit (Hct) suppresses endogenous erythropoiesis. Reticulocytosis predicts SCD morbidity and mortality, so this study's objective was to clarify the role of the post‐procedure Hct in suppressing reticulocytosis and to identify other potential red cell exchange (RCE) parameters predictive of reticulocytosis.This retrospective analysis of 17 patients who underwent chronic RCE at a single institution between 2014 and 2022 examined both standard red cell exchanges (SRCE) and exchanges preceded by isovolemic hemodilution (IVH‐RCE). Post‐procedure parameters with biologic plausibility to influence the subsequent procedure's absolute reticulocyte count (sPre‐ARC) were examined using regression modeling.Neither post‐hematocrit, nor post‐hemoglobin (Hb), nor ΔHb/day was associated with sPre‐ARC or the change in HbS% per day (ΔHbS%/day). Concurrent Hb was predictive for SRCE but not IVH‐RCE, where ARC trended lower than with SRCE. Male gender and post‐procedure neutrophil and white cell counts were predictors of sPre‐ARC, consistent with their associations with SCD morbidity and mortality. IVH‐RCE had a stronger correlation than standard RCE between pre‐Hct and neutrophil or white cell depletion.Although targeting a post‐procedure Hct maintains a higher subsequent pre‐procedure Hb and a lower sPre‐HbS%, it does not lead to sustained suppression of reticulocytosis as measured by the sPre‐ARC or the ΔHbS%/day. IVH‐RCE or the addition of hydroxyurea could be considered in those patients with high reticulocyte, white blood cell, or neutrophil counts. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease (SCD) is the most common hemoglobinopathy worldwide, characterized by vaso-occlusive crises and ischemia that affects patients on a multi-system level. Despite being a genetically simple disease due to a single base mutation, SCD poses many therapeutic challenges. Additionally, its impact on patients' life remains significant. This narrative review aims to provide a snapshot of recent highlights of the significant progress in SCD therapy, and the impact of SCD on patients' life, including the complications, morbidity, and mortality factors of the disease. Methodology: Google Scholar and PubMed were searched for "sickle cell disease". Only full-text English language original research articles were included in this review. In total, 600 articles were screened, 300 from each database, which were published from 2020 to 2024-06-01. A total of 139 studies were included in this review, after screening for inclusion. Conclusions: The increasing global incidence of sickle cell disease underscores the urgency for healthcare interventions to address the health challenges of an aging population living with this chronic condition. While treatment options for sickle cell disease have broadened, their availability is still limited. Among these options, stem cell transplant stands out as the definitive treatment, with ongoing efforts to enhance the donor pool. The disease significantly affects patients' quality of life and overall health, with emerging neurological and psychiatric issues. Additionally, the impact of sickle cell disease on reproductive health in both men and women presents a pressing need for further research to meet reproductive challenges. [ABSTRACT FROM AUTHOR]

Acute and chronic pain are the most frequent complications of sickle cell disease (SCD), often severely reducing quality of life and requiring management with long-term pharmacological interventions. A biopsychosocial approach conceptualizing pain in SCD as the result of complex biological, psychological, and social factors could facilitate targeted behavioral interventions. Mindfulness is one procedure for management of pain in individuals with chronic pain/illness. The goal of the current project was to design and implement a bedside mindfulness intervention to help patients with SCD enhance self-efficacy of pain management and reduce distress. As part of a quality improvement project in SCD clinics in a large health system, we developed a bedside mindfulness intervention to be provided during infusion sessions for patients presenting for acute vaso-occlusive episodes (VOE). The approach to development and implementation involved engagement of professionals working directly with patients. Concept planning meetings with these professionals along with qualitative patient and provider feedback informed feasibility, design, and intervention application. During a quantitative phase, patients completed validated surveys items on acceptability. Interview data (N = 11) supported patient interest in mindfulness skills and highlighted a need for tailored, person-centered interventions and non-pharmacological treatment strategies. On quantitative items, participants (N = 14) liked the intervention and agreed mindfulness skills would help manage disease-related distress. Following the interventions, participants reported increased mindfulness (p = .005). While preliminary, these results provide support for the continued development of evidence-based, mindfulness-oriented services to help individuals with SCD manage pain and other psychological difficulties. [ABSTRACT FROM AUTHOR]

Background Study Design and Methods Results Discussion Acute chest syndrome (ACS) is the leading cause of mortality, accounting for 25% of all deaths among individuals with sickle cell disease (SCD). There is a lack of evidence‐based laboratory and clinical risk stratification guidelines for the diagnosis and management of ACS.To better understand physician practices for the management of ACS in the United States, we created an ACS Working Group including hematology and transfusion medicine physicians from four different SCD treatment centers in the United States. The working group created a physician survey that included physician demographics and ACS diagnostic criteria that they had to rate. The survey also included three case scenarios to assess physician attitudes about the management of ACS. Management options included supportive and preventive strategies in addition to transfusion therapy options.Out of 455 physicians who received the survey, 195 responded (response rate = 43%). The respondents were primarily hematology/oncology physicians. The responses showed wide variability among physicians in how diagnostic criteria for ACS are used and how physicians risk‐stratify ACS patients in their practice. The responses also reflected variability in the use of transfusions for ACS.Based on our results, we conclude that ACS is diagnosed and managed inconsistently among expert physicians, especially in their transfusion practices due to a lack of consensus on risk stratification criteria. Our data suggest an urgent need for well‐designed prospective studies to provide evidence‐based guidelines and minimize management variability among physicians who care for individuals with SCD and ACS. [ABSTRACT FROM AUTHOR]

Summary: Sickle cell disease (SCD) is a complex genetic blood disorder characterized by abnormal haemoglobin, resulting in sickle‐shaped red blood cells. While extensive research has concentrated on the genetic and physiological aspects of SCD, recent studies suggest a potential role of the human microbiome in SCD pathophysiology, adding new dimensions to its understanding. This review synthesizes current knowledge on the microbiome's involvement in SCD, focusing on alterations in the gut microbiome composition and diversity compared to healthy individuals, and their implications for disease pathogenesis. We explore how microbiome changes may contribute to vaso‐occlusive crises and other complications, along with the possible associations of specific microbial taxa or markers with disease crises and clinical outcomes. Additionally, we discuss the potential of microbiome‐targeted interventions, including probiotics, dietary modifications, and faecal microbiota transplantation, in managing SCD complications and improving patient outcomes. Understanding the intricate relationship between the microbiome and SCD could lead to innovative therapeutic strategies and personalized interventions for better managing the disease. This review underscores the importance of further microbiome research and its integration into holistic SCD care. [ABSTRACT FROM AUTHOR]

Summary: Optimal targets for red blood cell exchange (RCE) are not well defined in the chronic management of sickle cell disease. We analysed transfusion requirements and iron‐related outcomes in 101 patients on chronic RCE with a post‐procedure haematocrit (Ht) targeted at 34%, which is higher than typically used. A majority were of HbSS/HbSβ0 genotype (n = 72) and enrolled for neurological complications (n = 53). Fifty patients had a positive Ht balance with RCE (>2% mean increase from pre‐procedure level), while 43 patients maintained a neutral balance. The first group required fewer red blood cell units/year (65 vs. 80, p < 0.001), but a significant proportion were iron overloaded based on R2* with liver MRI (32% vs. none performed) and prescription of iron chelation (52% vs. 0%, p < 0.001, after a median of 19 months). The second group was more likely to receive iron supplementation (6% vs. 56%, p < 0.001). Chronic automated RCE with a post‐procedure Ht targeted at 34% is not iron‐neutral, and personalized Ht goals may be more appropriate in certain settings. This higher target should be compared with a lower Ht strategy in individuals with similar baseline red cell volumes to assess iron homeostasis and blood product requirements. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

The present study compares postoperative outcomes between patients with and without sickle cell disease (SCD) undergoing 1-to 3-level lumbar spinal fusion for degenerative pathologies. Patients who underwent 1-to 3-level lumbar spinal fusion for degenerative pathologies from 2010 to 2021 were identified using the PearlDiver database. Patients were separated into 1) SCD and 2) non-SCD groups and were propensity-matched 1:1 for age, sex, Elixhauser Comorbidity Index, surgical approach, and various comorbidities. Complications were separately analyzed by single- and multilevel procedures using chi-squared and Mann–Whitney U testing. Propensity-score matching identified 1934 SCD and non-SCD patients who underwent single-level fusion and 2094 SCD and non-SCD patients who underwent multilevel fusion. Across single-level fusions, those with SCD had a significantly higher risk of neurovascular compromise (P < 0.001), venous thromboembolism (P = 0.004), pneumonia (P = 0.032), urinary tract infections (P = 0.001), and greater postoperative opioid usage out to 12 months (P = 0.018). Across multilevel fusions, SCD carried higher risk for neurovascular compromise (P < 0.001), pneumonia (P = 0.010), and urinary tract infections (P < 0.001). All SCD patients had significantly higher opioid use at 1 month (P = 0.001) and at 6 months (P = 0.009) postoperatively. Patients with SCD undergoing lumbar spinal fusion demonstrate higher risks for coagulopathic, ischemic, and infectious-related complications, as well as long-term postoperative opioid use. Awareness of the unique complication profile in SCD patients may help guide surgeons in refining perioperative management strategies to optimize outcomes in patients with SCD. [ABSTRACT FROM AUTHOR]

Introduction: Skull infarction is an uncommonly reported complication of sickle cell disease. We aimed to characterize the clinical and imaging features of skull infarction in pediatric patients with sickle cell disease. Methods: We searched the PubMed database for case reports on skull bone infarction in pediatric patients with sickle cell disease. Out of 67 records retrieved, 15 met inclusion criteria, and a 16th case reported by the senior author was included. We extracted and analyzed clinical and imaging data. Results: The most common symptom at onset was headache (88%). Bilateral skull infarction (50%) and parietal bone involvement (82%) were frequent imaging findings. Epidural hematoma developed in 65% of the cases, 30% of patients required drainage, and exchange infusion was reported in 18%. No fatal outcomes were reported. Conclusions: Skull infarction is a potentially severe complication of sickle cell disease presenting unique clinical challenges. Acute headaches should raise suspicion for this condition and may require additional investigation. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Sickle cell disease (SCD) is a global hemoglobinopathy; approximately 300 000 individuals are diagnosed annually. Acute chest syndrome (ACS), a common complication, leads to significant hospitalization and mortality, particularly in cases of severe respiratory distress. ECMO outcomes in this specific population are poorly described.This retrospective observational study, utilizing data from the Extracorporeal Life Support Organization (ELSO) registry, focuses on children and young adults (<40 years) with SCD undergoing ECMO from 1998 to 2022.We observed a growing trend in ECMO cases over the last 15 years, with 210 SCD patients identified in the registry (five neonates, 95 children, 110 adults). ECMO was predominantly initiated for pulmonary support (62%), and most of the primary diagnoses were related to SCD (reported as “SCD” or “acute chest syndrome”). The global survival rate was 55.8% (59% for children and 52.7% for adults). None of the children supported for extracorporeal cardiopulmonary resuscitation survived, and only 2/18 (11%) of adults cannulated for ECPR survived. Complication rates, including acute renal failure (33.8%) neurological events (13%), thrombotic (23.3%), or bleeding events (22.9%) were not noticeably different from reported outcomes in the ELSO registry.Our findings suggest that ECMO outcomes in SCD patients align with general ECMO trends and may not be limited by suspected unfavorable results in children and young adults. Despite limitations, our study contributes valuable insights into using ECMO in SCD, emphasizing the need for further research and understanding in this underexplored domain. [ABSTRACT FROM AUTHOR]

Objective: Sickle cell disease (SCD), the most common inherited blood disorder in the United States, is associated with severe psychoneurological symptoms. While epigenetic age acceleration has been linked to psychoneurological symptom burden in other diseases, this connection is unexplored in SCD. This study aimed to assess the association between epigenetic age acceleration and psychoneurological symptom burden in SCD. Methods: In this cross-sectional study, emotional impact, pain impact, sleep impact, social functioning, and cognitive function were assessed in 87 adults living with SCD. DNA methylation data were generated from blood specimens and used to calculate epigenetic age using five clocks (Horvath, Hannum, PhenoAge, GrimAge, & DunedinPACE). Associations between epigenetic age acceleration and symptoms were assessed. Results: The sample (N = 87) had a mean (SD) chronologic age was 30.6 (8.1) years. Epigenetic age acceleration was associated with several symptom outcomes. GrimAge age acceleration (β = −0.49, p =.03) and increased DunedinPACE (β = −2.23, p =.004) were associated with worse emotional impact scores. PhenoAge (β = −0.32, p =.04) and the GrimAge (β = −0.48, p =.05) age acceleration were associated with worse pain impact scores. Increased DunedinPACE (β = −2.07 p =.04) were associated with worse sleep impact scores. Increased DunedinPACE (β = −2.87, p =.005) was associated with worse social functioning scores. We did not find associations between epigenetic age acceleration and cognitive function in this sample. Conclusion: Epigenetic age acceleration was associated with worse symptom experiences, suggesting the potential for epigenetic age acceleration as a biomarker to aid in risk stratification or targets for intervention to mitigate symptom burden in SCD. [ABSTRACT FROM AUTHOR]

In patients with sickle cell disease (SCD) and beta-thalassemia major (TM), allogeneic hematopoietic stem cell transplantation (HSCT) was considered the only curative treatment option with a good survival rate. However, with the recent approval of gene therapies, more information is needed to understand the benefits and risks of these interventions. We performed a retrospective analysis of the Kids Inpatient Database to describe demographic features, short-term complications, and hospital charges of patients with SCD and TM treated with HSCT during 2006–2019 in the United States. The database was filtered using the International Classification of Diseases, 9th and 10th edition codes to identify children under 20 years of age with SCD or TM who underwent HSCT. A total of 513 children with SCD or TM who received HSCT were analyzed. The prevalence of HSCT per 1000,000 U.S. population increased from 0.31 in 2006 to 1.99 in 2019 (p < 0.001). The median age of children with SCD who underwent HSCT was 10 (6–15) years, and that for TM was 6 (3–11.5) years (p < 0.001). The combined mortality rate was 4% (2.4%–6.6%) but higher in the TM group. The length-of-stay and total charges were higher in the TM population (p < 0.01). This study provides national data on HSCT among hospitalized children with SCD and TM in the United States, demonstrating an increasing use of HSCT between 2006 and 2019. Although hospital mortality of HSCT in these conditions is low, it still represents a challenge, especially in TM patients. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is well recognized as a hypercoagulablestate, however, it remains unclear whether a subgroup of children with SCD at higher risk of venous thromboembolic event (VTE) during hospitalization may benefit from thromboprophylaxis. Our objectives were to describe the clinical characteristics, outcomes and recurrence of hospital acquired VTE in patients with SCD younger than 21 years. This was a single center retrospective study. Data regarding demographics, reason for admission, location of VTE, risk factors like central venous catheter (CVC), intensive care unit (ICU) admission among others were extracted from electronic medical records over a 10-year study period (2011–2021). Recurrence of VTE at 1 and 5 years was assessed. Descriptive statistics were used as indicated. We identified a total of 20 VTE events over the 10-year study period. Six of these events occurred in those younger than 12 years of age. Fourteen (70%) VTE events occurred in the HbSS or HbSβThal0 genotypes compared to 6 (30%) in HbSC. Most common VTE was isolated pulmonary embolism (PE) (n = 10, 50%). VTE were most often associated with acute chest syndrome (ACS) (n = 14, 70%), ICU admissions (n = 10, 50%) and CVC (n = 5/9, 55%). One patient died from the VTE event. One patient with additional underlying risk factors had a recurrent VTE at 13 months. Our study suggests that ICU admission, ACS and presence of CVC increases the risk of VTE in children and young adults with SCD, but larger studies are indicated to validate our findings. [ABSTRACT FROM AUTHOR]

Background and Objectives: In sickle cell disease (SCD), hepatopathy is a cumulative consequence of ischemia/reperfusion (I/R) injury from a vaso-occlusive crisis, tissue inflammation, and iron overload due to blood transfusion. Hepatopathy is a major contributing factor of shortened life span in SCD patients. We hypothesized that the voxelotor, a hemoglobin allosteric modifier, ameliorates sickle hepatopathy. Materials and Methods: Townes SCD mice and their controls were treated with either chow containing GBT1118, a voxelotor analog, or normal chow. We evaluated inflammation, fibrosis, apoptosis and ferroptosis in their livers using qPCR, ELISA, histology, and immunohistochemistry. Results: GBT1118 treatment resulted in reduced hemolysis, iron overload and inflammation in the liver of SCD mice. There were significant reductions in the liver enzyme levels and bile acids. Furthermore, GBT1118-treated mice exhibited reduced apoptosis, necrosis, and fibrosis. Increased ferroptosis as evident from elevated 4-hydroxynonenal (4-HNE) staining, malondialdehyde (MDA) levels, and expression of Ptgs2 and Slc7a11 mRNAs, were also significantly reduced after GBT1118 treatment. To explain the increased ferroptosis, we evaluated iron homeostasis markers in livers. SCD mice showed decreased expression of heme oxygenase-1, ferritin, hepcidin, and ferroportin mRNA levels. GBT1118 treatment significantly increased expressions of these genes. Conclusions: Our results suggest GBT1118 treatment in SCD confers the amelioration of sickle hepatopathy by reducing inflammation, fibrosis, apoptosis, iron overload and ferroptosis. [ABSTRACT FROM AUTHOR]

Background: Endothelial dysfunction is an integral pathophysiologic mechanism in sickle cell disease (SCD), and can lead to many complications. Sleep-disordered breathing (SDB) is a SCD complication with diverse incidence and pathophysiology. This study aimed to determine the prevalence of SDB in children with SCD and to assess its relation to endothelial dysfunction. Methods: Sixty children with SCD and 60 healthy controls were enrolled. The levels of TNF-α, IL-6, and IL-17A were evaluated in the entire cohort using enzyme-linked immunosorbent assay (ELISA) kits. Polysomnography (PSG) was performed for all SCD patients after completion of the Pediatric Sleep Questionnaire (PSQ). Results: TNF-α, IL-6, and IL-17A levels were significantly greater in children with SCD than in controls (p-values < 0.001, < 0.001, and 0.006, respectively). The PSQ revealed symptoms suggestive of SDB in 50 children with SCD (83.3%), and PSG revealed obstructive sleep apnea (OSA) in 44 children with SCD (73.3%); 22 patients had mild OSA, and 22 had moderate-to-severe OSA according to the apnea–hypopnea index (AHI). TNF-α was significantly greater in SCD children who reported heavy or loud breathing, trouble breathing or struggle to breathe, and difficulty waking up in the morning (p-values = 0.002, 0.002, and 0.031, respectively). The IL-6 levels were significantly greater in SCD children who stopped growing normally (p-value = 0.002). The levels of IL-6 and IL-17A were significantly greater in SCD children with morning headaches (p-values = 0.007 and 0.004, respectively). Conclusion: Children with SCD showed a high prevalence of SDB with significantly elevated levels of markers of endothelial function, highlighting the interplay of SDB and endothelial dysfunction in SCD. [ABSTRACT FROM AUTHOR]

Rationale: Sickle cell disease (SCD) is a monogenetic condition with recurring vasoocclusive events causing lifelong pulmonary morbidity and mortality. There is increasing access to curative therapies, such as hematopoietic cell transplant (HCT), for people living with SCD. However, more information on pulmonary function in adults with SCD after HCT is needed to best guide decisions for HCT and post-HCT care. Objectives: To test the hypothesis that forced expiratory volume in 1 second (FEV1) and other pulmonary function testing (PFT) parameters remain stable 3 years after HCT. Methods: People living with SCD undergoing nonmyeloablative HCT in a prospective cohort at the NIH Clinical Center from 2004 to 2019 were evaluated for enrollment. Global Lung Function Initiative reference equations and descriptive statistics were calculated before HCT and annually for 3 years. Six-minute-walk distance (6MWD) testing was performed. Generalized estimating equations were employed to evaluate interindividual changes in PFT parameters and 6MWD. Results: Of 97 patients with SCD undergoing HCT, 41 (42%) were female with median (25th, 75th percentile) age 31.8 (24.8, 38.0) years. Each year of measurement included the following numbers of subjects available for analysis with PFTs: baseline (n = 97), Year 1 (n = 91), Year 2 (n = 72), and Year 3 (n = 55); and the following numbers of subjects available for analysis with 6MWD: baseline (n = 79), Year 1 (n = 73), Year 2 (n = 57), and Year 3 (n = 41). Pre-HCT FEV1 was median (25th, 75th percentile) 68.3% (61.3%, 80.3%) and 69.2% (60.8%, 77.7%) 3 years after HCT, and pre-HCT diffusing capacity of the lung for carbon monoxide (DlCO) was 60.5% (53.0%, 66.3%) and 64.6% (55.1%, 73.4%) 3 years after HCT. Generalized estimating equations estimated that DlCO percent predicted increased significantly by 3.7% (95% confidence interval, 1.0%, 6.3%), and the 6MWD significantly increased by 25.9 (6.6, 45.2) meters 3 years after HCT, whereas there was no significant change in percent predicted FEV1 or FVC compared with before HCT. Conclusions: Overall, PFT results remained stable and there was an improvement in DlCO and 6MWD in this predominantly adult cohort undergoing nonmyeloablative HCT for SCD. Allogeneic HCT for SCD may cease the cycle of vasoocclusive pulmonary injury and prevent continued damage. Multicenter studies are needed to evaluate the long-term lung health effects of HCT for SCD in adults and children. [ABSTRACT FROM AUTHOR]

Folic acid (FA) supplementation in sickle cell disease (SCD) patients lead to accumulation of unmetabolized folic acid (UMFA) which might influence the level of cytokines and NK cell activity and thus trigger the crisis event. The aim of the study was to investigate the effect of UMFA levels on immuno-inflammatory markers in SCD patients taking FA supplementation. The cross-sectional study was conducted on 60 HbSS confirmed SCD cases with 22 crisis and 38 cases at steady state of 15–40 years age group. Serum FA, 5-Methyl Tetrahydrofolate (5-MTHF), Dihydrofolate reductase, Interleukin-6 (IL-6), Highly sensitive C-Reactive Protein (HsCRP), and natural killer (NK) cell activity were estimated. More than 50% of the study population depicted presence of UMFA. The median UMFA level was significantly elevated in crisis group (131.8 ng/mL) as compared to the steady state group (36.31 ng/mL) (p = 0.041). The median value of HsCRP was significantly higher in the crisis group (18.41 mg/L) than the steady state group (2.04 mg/L) (p = 0.003). Similarly, IL-6 was higher in crisis group (13.29 pg/mL) than steady state group (5 pg/mL) (p = 0.060). The median NK cell activity was 39.28 nmol/L in crisis group and 35.31 nmol/L in steady state groups (p = 0.889). In bivariate correlation analysis, UMFA showed a significant negative correlation with NK cell activity (r = − 0.638; p = < 0.001) and a positive correlation with IL-6 (r = 0.571; p = 0.001) and HsCRP (r = 0.237; p = 0.200). Accumulation of UMFA affect NK cell activity, thus influence the vulnerability for crisis state. Therefore, dosage modification for FA supplementation in SCD patients is suggested. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is a genetic disorder predominantly affecting individuals of African descent, with a significant global health burden. SCD is characterized by intravascular hemolysis, driven by the polymerization of mutated hemoglobin within red blood cells (RBCs), leading to vascular inflammation, organ damage, and heme toxicity. Clinical manifestations include acute pain crises, hemolytic anemia, and multi-organ dysfunction, imposing substantial morbidity and mortality challenges. Current therapeutic strategies mitigate these complications by increasing the concentration of RBCs with normal hemoglobin via transfusion, inducing fetal hemoglobin, restoring nitric oxide signaling, inhibiting platelet-endothelium interaction, and stabilizing hemoglobin in its oxygenated state. While hydroxyurea and gene therapies show promise, each faces distinct challenges. Hydroxyurea's efficacy varies among patients, and gene therapies, though effective, are limited by issues of accessibility and affordability. An emerging frontier in SCD management involves harnessing endogenous clearance mechanisms for hemolysis products. A recent work by Heggland et al. showed that CD-36-like proteins mediate heme absorption in hematophagous ectoparasite, a type of parasite that feeds on the blood of its host. This discovery underscores the need for further investigation into scavenger receptors (e.g., CD36, SR-BI, SR-BII) for their possible role in heme uptake and detoxification in mammalian species. In this review, we discussed current SCD therapeutics and the specific stages of pathophysiology they target. We identified the limitations of existing treatments and explored potential future developments for novel SCD therapies. Novel therapeutic targets, including heme scavenging pathways, hold the potential for improving outcomes and reducing the global burden of SCD. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease (SCD), a genetic blood disorder that affects red blood cells and oxygen delivery to body tissues, is characterized by haemolytic anaemia, pain episodes, fatigue, and end-organ damage with acute and chronic dimensions. Caring for patients with SCD imposes a high burden on informal caregivers. This study aims to capture the impact on health-related quality of life (HRQoL) and economic burden of caregiving for patients with SCD. Methods: Validated instruments of HRQoL (EQ-5D-5L, Carer Quality of Life-7 dimensions [CarerQol-7D]) and productivity (Work Productivity and Activity Impairment Questionnaire: Specific Health Problem [WPAI: SHP]) were administered via a cross-sectional online survey to caregivers in the United Kingdom (UK) and France. Demographics, HRQoL, and economic burden data were analyzed using descriptive statistics. Economic burden was determined using country-specific minimum and average wage values. Subgroup analysis examined caregivers with and without SCD. Results: Sixty-nine caregivers were recruited (UK, 43; France, 26), 83% were female, and 22% had SCD themselves. The mean (SD) caregiver EQ-5D-5L score was 0.66 (0.28) (UK, 0.62; France, 0.73), and the mean CarerQol-7D score was 80.69 (24.40) (UK, 78.72 [25.79]; France, 83.97 [22.01]). Mental health problems were reported in 72% and 70% of caregivers measured using the EQ-5D-5L and CarerQol-7D, respectively. Financial problems were reported by 68% of caregivers, with mean annual minimum wage productivity losses of £4209 and €3485, increasing to £5391 and €9319 for average wages. Sensitivity analysis determined additional HRQoL decrements for caregivers with and without, SCD. Conclusion: Caring for patients with SCD impacts the HRQoL and economic burden of caregivers. Further research to support the complex needs of SCD caregivers is required. Plain English summary: Caregivers play an important role in the lives of the people with sickle cell disease that they care for; however, their mental and physical health and their finances can be affected, particularly if their ability to work is impacted. The extent to which caring for a person with sickle cell disease impacts caregivers is not fully understood. In this study, 69 caregivers of a family member, partner, or friend with sickle cell disease in the United Kingdom or France completed an online survey to share their experiences about how caring for someone with sickle cell disease can impact a caregiver's quality of life and financial well-being. Caregiving negatively affected the quality of life of caregivers compared with people in the general population and caused a large financial and social burden. Around 70% of caregivers reported having mental health problems, 68% reported financial problems, and lost work hours and lost income were not uncommon. More research is needed to understand the specific needs of caregivers of people with sickle cell disease and how best to support them. [ABSTRACT FROM AUTHOR]

Summary Leg Ulcer (LU) pathophysiology is still not well understood in sickle cell anaemia (SCA). We hypothesised that SCA patients with LU would be characterised by lower microvascular reactivity. The aim of the present study was to compare the microcirculatory function (transcutaneous oxygen pressure (TcPO2) on the foot and laser Doppler flowmetry on the arm) and several blood biological parameters between nine SCA patients with active LU (LU+) and 56 SCA patients with no positive history of LU (LU−). We also tested the effects of plasma from LU+ and LU− patients on endothelial cell activation. We observed a reduction of the TcPO2 in LU+ compared to LU− patients. In addition, LU+ patients exhibited lower cutaneous microvascular vasodilatory capacity in response to acetylcholine, current and local heating compared to LU− patients. Inflammation and endothelial cell activation in response to plasma did not differ between the two groups. Among the nine patients from the LU+ group, eight were followed and six achieved healing in 4.4 ± 2.5 months. Among thus achieving healing, microvascular vasodilatory capacity in response to acetylcholine, current and local heating and TcPO2 improved after healing. In conclusion, microcirculatory function is impaired in patients with LU, and improves with healing. [ABSTRACT FROM AUTHOR]

Over the last few years, several mechanisms that are involved in congenital diseases characterized by ineffective erythropoiesis have been described. Therefore, multiple new target drugs are being developed in preclinical models against the main regulators of normal erythropoiesis. Above all, the key mechanism that regulates systemic iron homeostasis, represented by the hepcidin–ferroportin axis, is considered to be the target for new therapies. The main hypothesis is that iron restriction, through blocking ferroportin (the unique iron transporter in mammals) in such diseases, ameliorates erythropoiesis. The action of vamifeport is different from the currently approved drugs in this setting since it acts straight on the ferroportin–hepcidin axis. The data presented in the sickle cell disease (SCD) Townes mouse model showed a preclinical proof-of-concept for the efficacy of oral ferroportin inhibitor. Vamifeport reduced hemoglobin concentration in red blood cells (RBCs) and diminished intravascular hemolysis and inflammation, improving hemodynamics and preventing vascular occlusive crises. On this basis, clinical trials were commenced in patients with SCD, non-transfusion-dependent (NTD) thalassemia and transfusion-dependent (TD) thalassemia. Preliminary data in NTD thalassemic patients also confirm the safety and efficacy in decreasing iron level. In conclusion, vamifeport represents a new option in the panorama of drugs targeting the hepcidin–ferroportin axis, but its efficacy is still under investigation as a single agent. [ABSTRACT FROM AUTHOR]

Summary Background Methods Results Conclusion 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. [ABSTRACT FROM AUTHOR]

Background and purpose of the study: Sickle cell disease (SCD) patients are at a high risk of chronic liver disease (CLD) due to chronic viral hepatitis infection such as hepatitis C virus (HCV) infection, iron overload, and sickle cell hepatopathy. Nowadays, several oral direct-acting antiviral drugs (DAAs) have been developed and approved by the FDA for hepatitis C treatment. However, the safety and efficacy of DAAs in SCD patients remain insufficiently explored. Purpose of the study: To evaluate the efficacy and safety of administration of generic sofosbuvir (SOF) and daclatasvir (DCV) for 12 weeks in SCD patients infected with HCV. Methods: A retrospective study included 38 SCD patients infected with HCV treated with generic SOF (400 mg) and DCV (60 mg) for 12 weeks without ribavirin. The effectiveness of the HCV treatment was assessed by the sustained virologic response (SVR) at 24 weeks after the end of the treatment (SVR24). Results: The SVR24 rate was 100% (38/38).There were insignificant alterations in hemoglobin and total bilirubin levels during HCV treatment or at end of treatment (EOT). The number of anemic patients who needed blood transfusion two weeks before HCV treatment, at week 4 of treatment, and at EOT was 11 (28.9%), 3 (8%), and 1 (3%) respectively. Moreover, the reductions in serum transaminase levels from baseline were statistically significant compared to the EOT. Conclusion: Generic SOF and DCV regimens appear to be safe and effective in the treatment of chronic HCV in patients with SCD. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease (SCD) is among the most frequent hereditary disorders globally and its prevalence in Europe is increasing due to migration movements. Summary: The basic pathophysiological event of SCD is polymerization of deoxygenated sickle hemoglobin, resulting in hemolysis, vasoocclusion, and multiorgan damage. While the pathophysiological cascade offers numerous targets for treatment, currently only two disease-modifying drugs have been approved in Europe and transfusion remains a mainstay of both preventing and treating severe complications of SCD. Allogeneic stem cell transplantation and gene therapy offer a curative option but are restricted to few patients due to costs and limited availability of donors. Key Message: Further efforts are needed to grant patients access to approved treatments, to explore drug combinations and to establish new treatment options. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is the most common hereditary hemoglobinopathy worldwide. It results in characteristic acute and chronic findings on postmortem computed tomography (PMCT), macroscopic and microscopic examinations. While the diagnostic imaging and macroscopic features are not specific for SCD on their own, when coupled with microscopic features such as sickled erythrocytes and evidence of chronic venous congestion (i.e., Gamna-Gandy bodies), these clues can help alert forensic pathologists to the presence of SCD. Despite the prevalence of the disease and the constellation of findings alluded to above, SCD is not often explored in forensic pathology literature. This case demonstrates classic acute and chronic features of SCD on PMCT, macroscopic and microscopic examinations. It explores the pathophysiology leading to sudden and unexpected death in a person with SCD and possible pitfalls in attribution of cause of death. [ABSTRACT FROM AUTHOR]

Background/aim: The evolution of sickle cell disease (SCD) is marked by the occurrence of painful episodes linked to the obstruction of microvessels by sickle cells, known as vaso-occlusive crisis (VOC). The aim of this work was to report the practical aspects of the management of acute pain in adults with SCD. Recommendations based on these practices are also provided. Materials and methods: This prospective, cross-sectional, descriptive, and analytical study was conducted over a four-month period of all sickle cell patients admitted to emergency departments for VOC. The parameters studied were sociodemographic, clinicobiological, therapeutic, and evolutionary. Results: There were 118 cases of VOC identified, representing a prevalence of 78.14% of sickle cell emergencies. The mean age of the patients was 28.41 years. The SS sickle cell phenotype accounted for 86.61% of the cases. Osteoarticular pain was the reason for admission for 88.39% of the patients; it was located in the lower limbs in 39.08% and in the spine in 27.1%. Pain intensity was moderate in 6.25% of the patients, intense in 31.25%, and unbearable in 55.55%. Multimodal analgesia was the most commonly used treatment method, combining those of levels one and two (74.31%) and levels one and three (8.25%). The mean dose of morphine administered was 17.14 mg when morphine alone was prescribed for titration, 13.57 mg when paracetamol and morphine were combined, and 15.83 mg when nefopam and morphine were combined. Clinical outcome was favorable in 68.87% of the cases. Conclusion: Wide variability was observed in the modalities of analgesic treatment of sickle cell VOC. These variations reflect different views on the appropriateness of opioids. This study highlights the efficacy of multimodal analgesia in the management of acute pain in patients with SCD, particularly in regard to morphine sparing. Context-specific recommendations will be needed to harmonize practices. [ABSTRACT FROM AUTHOR]