We sought to determine whether transamniotic stem cell therapy (TRASCET) could be a viable alternative for the fetal administration of genetically modified hematopoietic stem cells (HSCs) carrying a human hemoglobin subunit beta gene (hHBB) in a healthy syngeneic rat model.

Time-dated pregnant Lewis dams underwent volume-matched intra-amniotic injections in all their fetuses (n = 61) of a suspension of donor HSCs genetically modified with either both a hHBB gene and a firefly luciferase reporter gene (n = 42) or the firefly luciferase reporter gene alone to control for HBB-derived protein interspecies homology (n = 19) on gestational day 17 (E17; term = E21). Donor HSCs consisted of syngeneic cells phenotyped by flow cytometry with successful hHBB transduction confirmed by ELISA prior to administration in vivo. At term, fetal samples from five anatomical sites relevant to hematopoiesis were screened for the presence of human hemoglobin subunit beta by ELISA and by digital droplet PCR (ddPCR).

When controlled by HSCs without hHBB injections, human hemoglobin subunit beta production was documented at term in the fetal bone marrow and spleen (p < 0.001 and p = 0.028 respectively). Positive hHBB expression by ddPCR was detected in the spleen (54 %), bone marrow (46 %), blood (46 %), liver (23 %), and thymus (15 %).

Genetically modified hematopoietic stem cells carrying a human hemoglobin subunit beta gene can reach fetal hematopoietic sites after simple intra-amniotic injection in a healthy syngeneic rat model. Transamniotic hematopoietic stem cell-based gene therapy could become a novel strategy for the perinatal management of select hemoglobinopathies.

N/A (animal and laboratory study).

animal and laboratory study.

Sickle cell disease (SCD) is a genetic condition affecting approximately 5 % of the global population, with significant prevalence in sub-Saharan Africa and an estimated 89,079 cases in the United States. Osteonecrosis, particularly of the femoral head (ONFH), is a common orthopaedic complication in SCD, often requiring total hip arthroplasty (THA) when conservative treatments fail. While THA can improve pain and function, it carries significant perioperative risks, with complication rates in patients with SCD as high as 67 %. This study aims to compare postoperative outcomes, medical costs, and the impact of different THA implant designs in patients with SCD versus a matched non-SCD cohort.

The study utilized the National Inpatient Sample (NIS) database. Postoperative outcomes in patients with and without SCD undergoing total hip arthroplasty between the fourth quarter of 2015 and 2020 were analyzed using propensity score matching and multivariable logistic regression modeling. Additionally, a subgroup analysis examined outcomes based on the use of cemented versus non-cemented implants.

The study analyzed 2,830,040 hip arthroplasty patients, including 2535 with sickle cell disease (SCD), and after propensity score matching, found that patients with SCD had significantly higher rates of postoperative complications such as periprosthetic fractures, dislocations, infections, and acute kidney injury. Multivariate analysis confirmed SCD as an independent risk factor for these complications, along with increased hospital stays and higher charges. Additionally, patients with SCD receiving cemented implants experienced worse outcomes, including higher risks of periprosthetic fractures and infections, compared to those with non-cemented implants.

This study found that patients with sickle cell disease (SCD) undergoing total hip arthroplasty had significantly higher complication rates, increased healthcare costs, and longer hospital stays, with cemented implants posing greater risks compared to press-fit implants.

Patients with sickle cell disease (SCD) experience painful vaso-occlusive episodes that increase with age; a subset develops chronic pain (CP). CP is usually managed with acute pain management guidelines despite evidence of ineffectiveness. Buprenorphine (BUP), a partial opioid agonist, is a potent analgesic with less euphoric effect and a respiratory "ceiling effect." BUP therefore provides an alternative "harm reduction" approach for CP management in pediatric SCD patients.

This single urban center retrospective study assessed the feasibility of inpatient transition to BUP-containing analgesics in adolescents with SCD and CP. Patients aged 12-20 years who transitioned from full opioid agonists (FOA) to BUP between December 2020 and September 2022 were included. Acute care utilization, hospital length of stay, and FOA use in both inpatient and outpatient settings were compared pre- and post-BUP induction for up to a year.

Fourteen adolescents with SCD underwent inpatient BUP induction and maintenance therapy. Inpatient transition using a micro-induction approach was feasible and well tolerated in this population. There were low rates of adverse events, such as opioid withdrawal signs. Maintenance on BUP products was sustainable over the 1-year post-induction period. Three patients (21%) discontinued BUP during maintenance therapy. There was a significant reduction (p < 0.05) in acute care utilization, length of stay, and FOA use (both inpatient and outpatient).

Inpatient micro-induction to BUP from FOA in adolescent SCD patients with CP is feasible with minimal signs of opioid withdrawal. This study suggests decreased acute care utilization with BUP.

Sickle cell disease (SCD) is a genetic disorder characterized by sickle red blood cells (RBCs). Sickle RBCs cause cerebral vasculopathies including vaso-occlusive events, leading to ischemia-reperfusion injury and hypoxic tissue environment. To date, the physiological blood flow velocities in cerebral vessels of preclinical SCD models has not been evaluated under hypoxic-reoxygenation. In our study, we used transcranial ultrasound techniques to measure abnormal blood flow velocities in the internal carotid (ICA) and middle cerebral arteries (MCA) of transgenic sickle cell mice (SS) challenged with hypoxia-reoxygenation. Our study showed that SS mice that underwent hypoxic stress exhibited lower relative mean velocities in the MCA compared to wildtype mice (AA) (0.67 ± 0.18 vs. 0.95 ± 0.15; p < 0.05). Comparison of the Lindegaard ratio between normoxia and hypoxia in SS mice suggested that the MCA underwent vasodilation (0.67 ± 0.18 vs. 0.95 ± 0.15; p < 0.05). Bilirubin, a potential biomarker for cerebral vasculopathies in SCD, was higher in SS than AA mice (0.56  ±   0.28 vs. 0.05  ±   0.07 mg/dL; p < 0.05). Correlation analyses revealed a significant association between bilirubin levels and blood velocities of MCA (r = -0.9377, p = 0.0002) and ICA (r = 0.8203, p = 0.0068), especially in hypoxic conditions of SS mice. We propose that the reactivity of cerebral vessels in SS mice is correlated with the elevated plasma bilirubin level.

Sickle cell disease (SCD) is one of the most prevalent hereditary blood disorders characterized by aberrant hemoglobin synthesis that causes red blood cells (RBCs) to sickle and result in vaso-occlusion. The complex pathophysiological mechanisms that underlie SCD are explored in this study, including hemoglobin polymerization, the formation of fetal hemoglobin (HbF), and hemoglobin switching regulation. Notably, pharmaceutical approaches like hydroxyurea, l-glutamine, voxelotor, and crizanlizumab, in addition to therapeutic techniques like gene therapies like Casgevy and Lyfgenia, signify noteworthy advancements in the management of issues connected to SCD. Furthermore, the deciphering of the molecular mechanisms that dictate hemoglobin switching has revealed several potentially therapeutic targets, including key transcriptional repressors such as β-cell lymphoma/leukemia 11A (BCL11A), Zinc finger and BTB domain-containing 7A (ZBTB7A), Nuclear Factor IX (NFIX), and Nuclear Factor IA (NFIA), which play crucial roles in γ-globin silencing. Additionally, transcriptional activators such as Nuclear Factor Y (NF-Y), and Hypoxia-inducible factor 1α (HIF1α) have emerged as promising regulators that can disrupt repression and enhance HbF synthesis. Other epigenetic regulators, such as lysine-specific histone demethylase 1 (LSD1), euchromatic histone methyltransferases 1/2 (EHMT1/2), histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and protein arginine methyltransferases (PRMTs). It has been demonstrated that inhibiting these targets can prevent the silencing of the gene encoding for the formation of γ-chains and, in turn, increase the synthesis of HbF, providing a possible treatment option for SCD symptoms. These approaches could pave the way for innovative, mechanism-driven therapies that address the unmet medical needs of SCD patients.

The most common hemoglobin disorder worldwide is sickle cell disease (SCD) caused by a point mutation in the adult β-globin gene. As a result, hemoglobin S production occurs leading to clinical symptoms including vaso-occlusive pain, organ damage, and a shortened lifespan. Hydroxyurea is the only FDA-approved fetal hemoglobin (HbF) inducer in the United States that ameliorates the clinical severity of SCD. Due to challenges with hydroxyurea, our study aimed to address the unmet need for the development of non-chemotherapeutic HbF inducers. We investigated the ability of CT-101, a Class 1 histone deacetylase inhibitor, to flip the γ-globin to β-globin switch in a humanized SCD mouse model. Pharmacokinetic parameters were assessed in CD-1 and Townes SCD mice after a single intraperitoneal drug dose. Similar drug uptake and half-life were observed in both animals. Subsequent studies in β-YAC mice expressing human γ-globin and β-globin genes established the optimal dose of CT-101 that induces HbF without peripheral blood toxicity. Subsequent confirmatory studies were conducted in the SCD mouse treated with intraperitoneal CT-101, demonstrating increases in F-cells, HbF, and γ-globin gene mRNA levels. Hydroxyurea combined with CT-101 significantly decreased spleen size and hemorrhagic infarcts and improved splenic extramedullary hematopoiesis. Our novel agent, CT-101, flipped the switch by activating γ-globin gene transcription and HbF protein synthesis in the preclinical SCD mouse model without significant toxicity in the peripheral blood. These findings support the development of an oral CT-101 formulation for clinical testing in SCD.

Babesiosis in sickle cell disease (SCD) is marked by severe anemia but the underlying red blood cell (RBC) rheologic parameters remain largely undefined. Here, we describe altered RBC deformability from both primary (host RBC sickle hemoglobin mediated) and secondary changes (Babesia parasite infection mediated) to the RBC membrane using wild-type AA, sickle trait AS, and sickle SS RBCs. Our ektacytometry analysis demonstrates that the changes in the host RBC biomechanical properties, before and after Babesia infection, reside on a spectrum of severity, with wild-type infected AA cells, despite showing a significant reduction of deformability under both shear and osmolarity gradients, exhibiting only a mild phenotype, compared with infected AS RBCs that show median changes in deformability and infected SS RBCs that exhibit the most dramatic impact of infection on cellular rheology, including an increase in point of sickling values. Furthermore, using ImageStream cytometric technology to quantify changes in cellular shape and area along with a tunable resistive pulse sensor to measure release of extracellular vesicles from these host RBCs, before and after infection, we offer a potential mechanistic basis for this extreme SS RBC rheologic profile, which include enhanced sickling rates and altered osmotic fragility, loss of RBC surface area, and hypervesiculation in infected SS host RBCs. These results underline the importance of understanding the impact of intraerythrocytic parasitic infections of SCD RBCs, especially on their cellular membranes and studying the mechanisms that lead to hyperhemolysis and extreme anemia in patients with SCD.

This study aimed to estimate the proportion of pediatric emergency admissions related to sickle cell disease.

This is a cross-sectional study. The data were collected over a period of 9 years, from 1 January 2014 to 31 December 2022.

We recorded 858 emergency department visits related to sickle cell disease out of a total of 135,000 pediatric emergency department visits, giving a prevalence of 6.4 per 1000 children aged up to 18 years. The median age was 12 years (8-16) years. The average waiting time in the emergency department for children with sickle cell disease was 2 h (±1) in 2014 and 45 min (±15) in 2022. Children with sickle cell anemia were more likely than others to have been seen by a consultant in an emergency department. The most commonly associated pathology was asthma, with a frequency of 17%. The risk factors for hospitalization were an age between 5 and 10 years and a severe form of sickle cell disease.

The treatment of pain and fever were often delayed. This leads us to suggest that systematic prior communication between the pediatric hematologist and the emergency physician is crucial. However, there is a need to define best practices for the management of children with sickle cell disease presenting to the emergency department with a fever.

Aim: To evaluate healthcare resource utilization (HCRU) and costs for US commercially insured adult and pediatric patients with sickle cell disease (SCD) and matched non-SCD cohorts. Materials & methods: Patients with ≥3 SCD diagnosis codes (D57.0-D57.219; D57.4-D57.819) from July 2016 to December 2020 were identified from the IBM® MarketScan® Commercial database. The earliest SCD diagnosis was defined as the index date. Non-SCD control patients were matched 1:1 on age, gender and region. Continuous 6-month baseline and ≥12-month follow-up coverage was required. Follow-up HCRU and costs (2020 USD) were calculated per patient per year. Pediatric (<18 years) and adult (≥18 years) patients were analyzed separately. Results: For 1299 pediatric patients with SCD and matched controls, mean (SD) age was 10.0 (4.8) years and 51% were female; mean (SD) follow-up was 34.3 (14.4) months. In the first 12 months, pediatric patients with SCD had higher HCRU (hospitalizations: 0.6 vs 0.01; hospital length of stay: 2.4 vs 0.05 days; outpatient visits: 13.4 vs 6.0; office visits: 6.9 vs 4.7; prescriptions: 12.8 vs 3.8) and mean total costs ($31,445 vs $2844), mainly due to hospitalizations ($15,195 vs $477) and outpatient visits ($12,746 vs $1758), versus controls (all p < 0.0001). For 2792 adults with SCD and matched controls, mean (SD) age was 38.0 (13.2) years and 62% were female; mean (SD) follow-up was 31.8 (13.7) months. Adults with SCD had higher per-patient per-year HCRU (hospitalizations: 0.8 vs 0.06; hospital length of stay: 4.3 vs 0.2 days; outpatient visits: 20.9 vs 9.3; office visits: 10.4 vs 6.9; prescriptions: 20.5 vs 11.7) and mean total costs ($42,550 vs $7522), also due to hospitalizations ($20,056 vs $1326) and outpatient visits ($17,508 vs $4301), versus controls (all p < 0.0001). Conclusion: The economic burden of SCD among pediatric and adult patients is substantial with increased HCRU and costs compared with matched controls. Better treatments for SCD could reduce the economic burden for patients, as well as payers.

Sickle Cell Disease is a chronic inflammatory disease that could be aggravated by exposure to variable factors such as infections, hemolysis, oxidative stress and so forth. that could preciptate variable acute or end-organ manifestation. However, the degree of inflammation could vary in individuals. Thus this study evaluates the inflammatory state (hs-CRP, IL6, ferritin) of children living with SCD and the associated factors.

We conducted an analytical cross-sectional study for 03 months. The patients included were those from the Central Hospital of Yaounde and the Regional Hospital of Bafoussam in which they are regularly monitored and/or interned in the Hematology department. The exploration of inflammation was made by determining hs-CRP, IL6, and ferritin concentrations. The hematological parameters and iron profile were evaluated using standard methods. Statistical analyses of the data were carried out using the statistical software R version 4.1.1. from which logistic regression analyses according to univariate and multivariate models made it possible to identify factors associated with inflammation in patients.

Hundred and forty-nine SCD patients were included in the study. The frequency of inflammation in the population was 42.3%. Hyperferritinemia was significantly greater (p < 0.001) in patients with inflammation compared to the noninflammatory patients (96.8% and 76.7% respectively). Patients with inflammation showed a significant elevation of iron parameters (p < 0.05). In addition, ferritin and IL6 elevation were associated with inflammation during sickle cell disease, respectively (OR = 4.96; 95% CI [1.15-36.42]; p = 0.056) and (OR = 6.23; 95% CI [1.43-45.96]; p = 0.030).

The elevated iron in plasma is an effect of inflammation in sickle cell patients. Thus, inflammation constitutes a significant and significant factor in worsening the pathophysiology of sickle cell disease. Hence the need of controlling inflammation and iron in the latter is necessary.

Sickle cell disease (SCD) is frequently associated with cardiovascular complications, with cardiac involvement being evident in the electrocardiogram (ECG). This study aimed to systematically research the literature to investigate factors associated with ECG abnormalities in SCD patients.

Five online databases of PubMed, Scopus, Web of Science, Embase, and Google Scholar were reviewed using a broad search strategy to identify original studies reporting factors associated with abnormal ECG findings among patients with SCD. Using Comprehensive Meta-Analysis software, various effect sizes-odds ratios (ORs), mean differences, and correlation coefficients-were analyzed, pooled with a random effects model, and visualized through forest plots.

Data analysis from 23 studies covering 2943 SCD patients revealed increased odds of prolonged QTc interval (2.54, 95% CI = 1.34-4.83), ST segment elevation (9.23, 95% CI = 3.15-27.07), and ST segment depression (3.82, 95% CI = 1.99-7.33) during crises. Patients with moderate SCD severity had higher odds of having any ECG abnormalities compared to those with mild severity (2.80, 95% CI = 1.47-5.33). No significant associations were observed between moderate and mild severity for left ventricular hypertrophy, sinus arrhythmia, and sinus tachycardia, or between male and female for having any ECG abnormalities, left ventricular hypertrophy, and prolonged QTc interval. Additionally, mean hemoglobin level was 0.60 mg/dL lower (95% CI = -0.91 to 0.28) in those with prolonged QTc interval.

This study highlights the link between SCD status and severity, and hemoglobin, and ECG abnormalities. It emphasizes the need for cardiac monitoring, caution with QTc-prolonging medications, and routine ECG assessments to prevent cardiovascular complications in these high-risk patients.

Patients with sickle cell disease (SCD) experience recurrent, severe pain events due to vaso-occlusion. Eliminating these acute pain events is a key outcome in SCD clinical trials; however, the definition of a vaso-occlusive crisis (VOC) or a vaso-occlusive event (VOE) has not been consistently applied, hampering comparisons of treatment efficacy between different therapeutic approaches. We have examined the degree to which differing definitions of vaso-occlusion in clinical trial endpoints impact efficacy outcomes.

Descriptions of clinical endpoints related to vaso-occlusion and pain events were reviewed from trials of exagamglogene autotemcel (exa-cel), lovotibeglogene autotemcel (lovo-cel), renizgamglogene autogedtemcel (reni-cel), hydroxyurea, L-glutamine, voxelotor, and crizanlizumab. Patient-level data from the published exa-cel Phase 3 pivotal trial (CLIMB SCD-121; data cut 14 Jun 2023) was used to evaluate efficacy outcomes based on differing endpoint definitions of vaso-occlusion.

In the seven clinical trials reviewed, definitions of vaso-occlusion and/or pain events varied by care setting, duration of care, treatments used, and associated complications, with the frequency and duration of medical facility visits for acute pain events being most dissimilar between trials. Definitions of severe VOCs (exa-cel), VOC (voxelotor), and sickle cell-related pain crises (SCPCs; crizanlizumab and L-glutamine) included pain events requiring a medical facility visit of any duration, whereas the definition of painful crises (hydroxyurea) required a medical facility visit of > 4 h and the definition of severe vaso-occlusive events (VOEs; lovo-cel and reni-cel) required a hospital or emergency room (ER) observation unit visit lasting ≥ 24 h or ≥ 2 visits to a day unit or ER over a 72-h period. Based on the definition of severe VOCs, 29/30 patients [96.7%; 95% confidence interval (CI): 82.8, 99.9] in the CLIMB SCD-121 trial were considered free from severe VOCs for ≥ 12 consecutive months, whereas when the severe VOEs definition was applied to the same data, all patients (30/30; 100.0%; 95% CI: 88.4, 100.0) were considered free from severe VOEs for ≥ 12 consecutive months.

Differences exist in definitions of vaso-occlusion and pain events used in SCD clinical trials. Severe VOCs (exa-cel), VOC (voxelotor), and SCPCs (crizanlizumab and L-glutamine) were more broadly inclusive than severe VOEs (lovo-cel and reni-cel) or painful crisis (hydroxyurea). Clinically, these differences resulted in differing numbers of patients being considered free from vaso-occlusion pain events, underscoring the challenge in comparing frequencies of pain events across SCD clinical trials.

A case of a patient in her 30s with sickle cell anaemia who developed multiorgan failure and Acute Respiratory Distress Syndrome(ARDS) from acute chest syndrome (ACS) despite a simple red blood cell transfusion is presented in this report. She was treated with plasma exchange (PLEX) due to a history of severe delayed haemolytic transfusion reaction and a lack of available compatible units of packed red blood cells. Following one session of PLEX with half plasma/half albumin, she had rapid clinical improvement from mechanical ventilation to room air in 5 days. This finding is consistent with existing case reports of rapid improvement in pain, oxygenation and organ function following PLEX. Proposed mechanisms include the modulation of rheological properties of red blood cells by plasma, as well as the removal of the cytotoxic effects of haptoglobin and haemopexin. This case demonstrates the effectiveness and safety of an alternative upfront approach to managing complications related to ACS in those who are heavily alloimmunised.

Acute chest syndrome (ACS) is among the most serious complications of sickle cell disease (SCD). While the pathogenesis of ACS is incompletely understood, endothelial damage and microvascular occlusion are critical components. Our previous studies have implicated small extracellular vesicles in the plasma of subjects with SCD in causing endothelial dysfunction. This suggested that microRNAs within these small EVs might be responsible for endothelial damage. The sequencing of microRNAs in small EVs from the plasma of subjects with SCD revealed that several miRNAs were differentially expressed between subjects with and without ACS history, including let-7c-5p. In a replication cohort, plasma let-7c-5p levels were quantified via RT-qPCR. The baseline plasma let-7c-5p level was twofold higher in patients without previous ACS. Furthermore, we observed a positive correlation between let-7c-5p levels and time to subsequent ACS events. These findings suggest a role for let-7c-5p in endothelial disruption underlying ACS pathogenesis. It may also serve as a novel biomarker for ACS detection and the prediction of disease progression.

The canonical complement-mediated lysis of mature red blood cells (RBCs) leads to severe pathogenesis. However, inhibition strategies targeting complement are not always as efficient as expected, indicating that unknown mechanisms are awaiting elucidation. In this study, we investigate the intracellular events in mature RBCs following complement activation. The collected evidence demonstrates that complement-induced hemolysis is a caspase-8-dependent programmed RBC death. Furthermore, short NLRP3 (miniNLRP3) fragments in RBCs are identified to engage in the assembly of NLRP3-apoptosis-associated speck-like protein containing a CARD (ASC)-caspase-8 complex. Activated caspase-8 directly induces the proteolysis of β-spectrin, thereby disrupting the skeletal network of the RBC membrane, a process we refer to as spectosis. Spectosis signaling is also activated in autoimmune hemolytic anemia or paroxysmal nocturnal hemoglobinuria, and the inhibition of spectosis significantly reduced complement-induced hemolysis. These findings reveal a programmed death cascade in mature RBCs, which may have important implications for the treatment of hemolytic disorders.

Priapism is a major clinical complication of sickle cell disease (SCD), with severe sexual, reproductive, and mental health impact. There are currently no consensus diagnostic biomarkers for identifying individuals with SCD at risk of priapism before its occurrence.

To systematically review the biochemical, hematological, imaging, genetic, and rheological parameters associated with priapism occurrence among individuals with SCD.

A systematic literature search for studies investigating the association of biochemical, hematological, rheological, imaging, rheological, and genetic parameters with the occurrence of priapism in individuals with SCD was performed in the MEDLINE, Embase, and Cochrane databases, using the following terms: "priapism," "sickle cell," "biomarker," "marker," "laboratory," "radiographic," "diagnostic," and "predictive." A systematic review of the identified studies was conducted to describe the landscape of priapism-related biomarkers in individuals with SCD.

A total of 358 studies were identified, of which 14 studies were eventually selected for evidence synthesis. The selected studies were published between 2005 and 2023, with authorship spanning five continents. We identified multiple clinical parameters investigated as potential biomarker candidates for their association with priapism occurrence in patients with SCD. We classified these into biochemical (lactate dehydrogenase, bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, nitric oxide metabolites, interleukin 6), hematological (hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, reticulocyte count, leukocyte count), genetic (Klotho, TGFBR3, QAP1, ITGAV, LNC02537, NAALADL2), rheological (red blood cell deformability, aggregation index, augmentation index), and imaging parameters. However, the results were often contradictory and do not support the clinical application of any of the investigated parameters.

Several clinical and laboratory parameters have been associated with priapism occurrence in SCD; however, contradictory findings across geographical locations paint an unreliable picture of their clinical utility. Additional studies are needed to generate enough level 1 evidence in support of any of the current candidates.

Sickle cell disease (SCD) is an inherited hemoglobin disorder that is widespread across the globe. It is characterized by a very complex pathogenesis, but at the basis of the disease is the mutation of the HBB gene, which determines the production of a mutated hemoglobin: sickle cell hemoglobin (HbS). The polymerization of HbS, which occurs when the protein is in a deoxygenated state, and the greater fragility of sickle cell red blood cells (sRBCs) determine the release of iron, free heme, and HbS in the blood, favoring oxidative stress and the production of reactive oxygen species (ROS). These features are common to the features of a new model of cell death known as ferroptosis, which is characterized by the increase of iron and ROS concentrations and by the inhibition of glutathione peroxidase 4 (GPx4) and the System Xc-. In this context, this review aims to discuss the potential molecular and biochemical pathways of ferroptosis involved in SCD, aiming to highlight possible tags involved in treating the disease and inhibiting ferroptosis.

Extramedullary hematopoiesis (EMH) is very rarely described during sickle cell disease (SCD). Our aim was to describe six cases of EMH occurring in adult SCD patients and to conduct a literature review.

Retrospective, descriptive, and monocentric study, identifying all cases of EMH recorded in our cohort of adult SCD patients, up to April 2024. A literature review via PubMed included thirty-five articles (44 patients).

Six patients (4 men, 83.3% with SS genotype [n=5], 1 SC), with a median age of 22 (range 12-64) years at the time of EMH diagnosis were included. Four patients (66.7%) had an aseptic osteonecrosis of the hip. The localization of EMH varied: paravertebral (n=3), peri-articular in the hip (n=1), adrenal (n=1), hepatic (n=1), splenic (n=1) and was similar to the localizations reported in the literature. EMH was symptomatic at diagnosis in half of the cases. The diagnosis was established by histology (n=3/3) and/or typic magnetic resonance imaging (MRI) (n=4/4). The median baseline hemoglobin was 9.1 (extremes 5.8-10.9) g/dL. A watch-and-wait approach was primarily observed.

EMH in SCD patients appears to be rare, with varied localizations. Its diagnosis is made with MRI and/or biopsy, and its treatment is not consensual.

While asthma is a known risk factor for Acute Chest Syndrome (ACS) and may increase overall mortality in SCD patients, this study specifically focuses on the rate of inpatient mortality, hospital stay, and costs in SCD patients who develop ACS. Our study was conducted using a retrospective cohort from the National Inpatient Sample (NIS), spanning 5 years from 2016 to 2020. Patients were carefully divided into two cohorts for comparison: those admitted with ACS and a history of asthma and those with ACS without a history of asthma. The primary endpoint was all-cause inpatient mortality, and we built a robust multivariate regression model adjusting for confounders. We also thoroughly examined secondary endpoints, including a comparison of length of stay (LOS), hospital, transfusion rates, mechanical ventilation (MV) rates, Continuous Renal Replacement Therapy (CRRT), and rates of hemodialysis (HD) for acute kidney injury (AKI). Our analysis of LOS and total cost was conducted using a multivariate linear regression model adjusted for confounders, ensuring the thoroughness and validity of our results. Additionally, genotypes, demographics, and common comorbidities were described. Categorical variables required Chi-square (X2), and continuous variables required a Student t-test for hypothesis testing. A two-tailed P-value of < 0.05 was considered statistically significant. We utilized the National Inpatient Database (NIS). A total of 26,280 hospitalizations met the inclusion criteria:5,685 had ACS with a history of asthma, and 20,622 without ACS. Patients with ACS and Asthma were younger (mean age, 28 years vs. 32 years; p < 0.001), and females represented a higher proportion (53.03% vs. 47.56%; p = 0.940). Patients admitted with ACS and Asthma did not have higher odds of dying than those admitted with ACS without asthma (p = 0.176). The Charlson Comorbidity Index (CCI) was the only predictor of mortality. (aOR 1.52; p < 0.001). ACS with Asthma was a predictive factor for LOS (coefficient -0.65; p = 0.009). Conversely, female patients had a higher likelihood of experiencing a more extended hospital stay (coefficient, 0.61; p = 0.001). Additionally, ACS with Asthma significantly affected the total cost (coefficient: -15,201; p < 0.001), resulting in a lower cost than ACS patients without asthma. Finally, patients with ACS with Asthma did not have higher rates of transfusions, MV, CRRT, or HD due to AKI than those without asthma. Asthma did not increase the risk of in-hospital mortality in this large retrospective cohort study of patients admitted for Acute Chest Syndrome (ACS). While patients with ACS and a history of asthma were younger and had a lower total cost of care, their length of stay was shorter, and they did not experience higher rates of transfusion, mechanical ventilation, or acute kidney injury requiring dialysis. The primary predictor of mortality was the Charlson Comorbidity Index (CCI), highlighting the importance of overall comorbidity burden. These findings suggest that although asthma is a known risk factor for ACS, it does not independently worsen patient outcomes or survival, underscoring the need for a broader focus on managing comorbid conditions in these patients.

Sickle cell anemia (SCA) presents a complex interplay of factors, with the production of high levels of reactive oxygen species (ROS) and the chronic inflammatory process leading to chronic oxidative stress. In this context, efficient action of antioxidant systems becomes crucial, with particular emphasis on peroxiredoxins (PRDXs) due to their abundance and vital roles. Our primary objective was to establish associations between gene and protein expression of PRDXs 1, 2, and 6, as well as their reducers TRX1, TRXR1, and SRX1, with the characteristic hyperoxidative status observed in SCA patients. Concomitantly, we assessed the production of other essential antioxidant enzymes (SOD1, CAT, and GPX1) in reticulocytes and erythrocytes and explored mRNA levels of the NRF2/KEAP1/PKCδ complex. Our comprehensive analysis revealed a ∼ 3-fold elevation in ROS levels in erythrocytes of patients compared to healthy individuals. However, the NRF2/KEAP1/PKCδ complex exhibited a significant reduction in gene expression, hinting that another transcription factor may regulate the antioxidant response among SCA patients. In addition, the pattern of increased transcript levels of antioxidants in SCA patients was not associated with their protein levels, indicating a possible degradation by proteasome. The protein content of PRDX2 showed a significant reduction, indicating an increased vulnerability of these cells to oxidative damage. Intriguingly, both PRDXs 1 and 2 exhibited significant increases in the plasma of SCA patients, indicating that, besides their well-known intracellular antioxidant role, these enzymes may also play a vital extracellular role in modulating inflammation in these individuals. Our findings unveil novel insights into the redox metabolism adaption of erythroid cells in response to the presence of HbS in homozygosity, thus, into the complex SCA pathophysiology. Moreover, our study reveals the simultaneous presence of both PRDXs 1 and 2 in the plasma of these patients, thereby offering valuable implications for potential prognostic and therapeutic avenues.

To determine the outcomes of patients with sickle cell retinopathy who experienced at least one episode of being lost to follow-up (LTFU) compared with those who attended all appointments.

Adult patients with sickle cell retinopathy who visited Wills Eye Hospital Retina service (January 2012-December 2021) with >2 visits were reviewed for LTFU events, defined as failure to return for a follow-up appointment within 6 months of the scheduled date.

One hundred and eighty-one eyes of 94 patients were included. Fifty-one patients (99 eyes) attended all appointments ("attended group"), whereas 43 patients (82 eyes), or 46%, had at least one LTFU event ("LTFU group"). The mean (SD) LTFU duration was 470 (329) days. In the LTFU group, mean (SD) VA was significantly worse at the final visit (logMAR 0.45 (0.63), Snellen 20/56) and at the post-LTFU visit (0.36 (0.59), 20/46) compared with the pre-LTFU visit (0.3 (0.47), 20/40, P = 0.001). In the attended group, mean (SD) VA was significantly better at the final visit (0.41 (0.63), 20/51) compared with the initial visit (0.52 (0.78), 20/66, P = 0.038).

Patients with sickle cell retinopathy with an LTFU event have worse visual outcomes compared with patients who attend all appointments.

Mannose-binding lectin (MBL) is an important glycoprotein of the human innate immune system. Furthermore, individuals with sickle cell anemia (SCA) and MBL deficiency seem more susceptible to vaso-occlusive crises, suggesting an MBL role on HbSS red blood cells (RBCs). This study investigated the interaction of MBL with HbA (healthy) and HbSS RBCs using optical tweezers (OT) and atomic force microscopy (AFM). OT was employed to measure the RBC overall elasticity, while AFM was applied to assess the local stiffness and roughness of the cell membrane. Osmotic fragility assays were also performed. Additionally, cationic quantum dots (QDs) were applied to evaluate the membrane charges of HbSS RBCs. Results using QDs indicated that HbSS RBCs have a less negatively charged surface than HbA RBCs, potentially due to a reduced sialic acid content. Osmotic fragility assays showed that MBL enhanced the resistance of RBCs to lysis, while OT and AFM indicated a decrease in their elastic capacity following MBL incubation. Moreover, OT and membrane roughness results suggested a greater interaction of MBL with HbSS RBCs. We believe this study provided insights into the MBL interaction with HbSS RBCs, inciting further investigations to better understand its involvement in SCA pathophysiology in vivo.

Fibroblast Growth Factor 23 (FGF23) is increased in serum of humanized Sickle Cell Disease (SCD) mice. Since FGF23 is associated with impaired bone formation, we examined the effect of FGF23-neutralizing antibody (FGF23Ab) on bone loss in SCD mice. Healthy control (Ctrl) and SCD 5-months-old female mice were treated with FGF23Ab or isotype-specific IgG for 6 weeks. Significantly reduced hematocrit in SCD mice was increased by FGF23Ab. MicroCT of SCD femurs revealed no significant reduction in metaphyseal bone volume/total volume vs. Ctrl mice. However, histomorphometry of SCD femur revealed significantly reduced mineral apposition rate, bone formation rate, inter-label thickness, and osteoid surface, which were increased by FGF23Ab. Significantly increased osteoclast number/bone perimeter in SCD mice was reduced by FGF23Ab. Bone marrow stromal cells (BMSC) cultured in osteogenic media revealed significantly reduced mineralized nodules in SCD-IgG-BMSC that was increased in SCD-FGF23Ab-BMSC. FGF23 and αKlotho protein was significantly increased in SCD-IgG-BMSC and was not reduced by FGF23Ab. However, phosphorylated FGF Receptor-1, the receptor through which FGF23 signals, was significantly reduced by FGF23Ab. The mineralization inhibitor osteopontin was significantly increased in SCD-IgG-BMSC cultures and was reduced by FGF23Ab. We conclude that FGF23Ab may be efficacious in improving some parameters of reduced bone formation in female SCD mice.

The purpose of this study is to synthesize evidence on disease-specific outcomes in patients with sickle cell disease (SCD) or transfusion-dependent beta-thalassemia (TDT) following allogeneic hematopoietic stem cell transplant (allo-HSCT).

A systematic literature review (SLR) was conducted in MEDLINE and Embase to identify publications up to May 2023, including patients with SCD or TDT treated with allo-HSCT. Occurrence of vaso-occlusive crises (VOCs) including acute pain, acute chest syndrome, priapism, and splenic sequestration in SCD, and red blood cell transfusion (RBCT) requirements in TDT were the main outcomes of interest. Transplant-related outcomes such as graft-versus-host disease (GVHD) and graft failure/rejection were summarized in the studies that reported main outcomes. Proportion of patients experiencing VOCs or RBCTs, GVHD, and graft failure/rejection after allo-HSCT were aggregated and descriptively reported with range across studies.

Thirty-one SCD studies met inclusion criteria. Twenty-nine studies assessed for VOC and pain crisis events after allo-HSCT; 11 studies reported ≥1 VOCs after allo-HSCT in 6.9% of the 2,760 patients. Graft failure was reported in 14.4% (0.9%-18.8%, 14 studies) of patients, graft rejection in 5.5% (1.6%-100.0%, 12 studies) of patients, acute GVHD in 22.4% (1.6%-50.0%, 19 studies) of patients, and chronic GVHD in 20.4% (3.3%-57.1%, 14 studies) of patients. Seventy-eight TDT studies met inclusion criteria. Fifty-six studies reported that 8.8% of the 3,107 patients required RBCTs after allo-HSCT. Graft failure was reported in 5.4% (1.1%-80.0%, 21 studies) of patients, graft rejection in 7.5% (0.5%-42.9%, 50 studies) of patients, acute GVHD in 28.4% (5.2%-100.0%, 57 studies) and chronic GVHD in 15.2% (1.3%-50.0%, 51 studies) of TDT patients.

Based on this SLR, after allo-HSCT, a portion of patients with SCD continue to experience VOCs and a portion of patients with TDT continue to require RBCTs, in addition to experiencing GVHD and graft failure or rejection.

Sickle cell disease (SCD) is a severe inherited blood disorder characterized by abnormal hemoglobin (HbS) that leads to varying degrees of severity, including chronic hemolysis, episodic vaso-occlusion, and damage to multiple organs, causing significant morbidity and mortality. While SCD is a monogenic disease, its complications are influenced by polygenic factors. SCD prevalence is notably high in regions including the Middle East, with Saudi Arabia reporting significant cases, particularly in the Eastern Province. Most genetic factors associated with SCD outcomes have been identified in populations predominantly from Africa or of African ancestry. This study aims to identify genetic variants that characterize Saudi SCD patients with the potential to influence disease outcomes in this population. A multicenter case-control genome-wide association study (GWAS) was conducted involving 350 adult Saudi SCD patients and 202 healthy controls. Participants were genotyped using the Affymetrix Axiom array, covering 683,030 markers. Rigorous quality control measures were applied to ensure data integrity. Fisher's exact was used to identify genetic variants with a significant difference in allele frequency (p < 5 × 10-8). Functional annotations and regulatory functions of variants were determined using the Ensembl Variant Effect Predictor (VEP) and RegulomeDB databases. The GWAS identified numerous significant genetic variants characterizing SCD cases in the Saudi population. These variants, distributed across multiple chromosomes, were found in genes with known functional consequences. A substantial proportion of the markers were detected in the olfactory receptor cluster, TRIM family, and HBB locus genes. Many of the identified genes were reported in previous studies showing significant associations with various SCD outcomes, including hemoglobin regulation, inflammation, immune response, and vascular function. The findings highlight the genetic complexity underlying SCD and its clinical manifestations. The identified variants suggest potential molecular biomarkers and therapeutic targets, enhancing our understanding of the molecular basis of SCD in the Saudi population. This is the first genetic analysis characterizing SCD patients compared to healthy individuals, uncovering genetic markers that could serve as diagnostic biomarkers and therapeutic targets. Given the known molecular mechanisms of the detected genetic loci, these provide a foundation for precision medicine in SCD management, highlighting the need for further studies to validate these results and explore their clinical implications.

Related human leukocyte antigen (HLA)-haploidentical bone marrow transplantation (BMT) with posttransplant cyclophosphamide may be curative for sickle cell disease. However, graft failure, severe graft-versus-host disease (GVHD), infections, and mortality remain a concern. We evaluated a novel conditioning regimen followed by related HLA-haploidentical BMT in adults with sickle cell disease.

In a phase 2, open-label, single-arm, multicenter study, 54 eligible participants from 19 U.S. centers were enrolled. Of these, 42 (78%) received transplantation with conditioning including antithymocyte globulin, fludarabine, cyclophosphamide, thiotepa, and total body irradiation. GVHD prophylaxis included posttransplant cyclophosphamide, mycophenolate mofetil, and sirolimus. The primary outcome was event-free survival at 2 years, while secondary outcomes included overall survival and other transplant-related end points.

The median age at enrollment was 22.8 years (range, 15.5 to 43.2), and the median follow-up period was 37.2 months (range, 20.4 to 56.4). The 2-year event-free and overall survival rates were 88.0% (95% confidence interval [CI], 73.5 to 94.8%) and 95.0% (95% CI, 81.5 to 98.7%), respectively. Two participants experienced primary and another secondary graft failure. The incidence of grade-3-to-4 acute GVHD at day 100 was 4.8% (95% CI, 0.9 to 14.4%), while the 2-year chronic GVHD rate was 22.4% (95% CI, 10.9 to 36.4%). Two of the four reported deaths were due to early infectious complications.

HLA-haploidentical BMT is an accessible and potentially curative therapy for adults with sickle cell disease. Adverse events were those anticipated from this procedure, including GVHD. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; BMT CTN 1507; ClinicalTrials.gov number, NCT03263559).

In this study, we aimed to explore the inflammatory and angiogenic pathways in sickle cell disease (SCD). We used proximity extension assay technology (Olink) to measure 92 plasma proteins involved in inflammation and angiogenesis. Plasma samples were collected from 57 SCD patients (sickle cell anaemia/HbS-β0 thalassaemia-thalassaemia) in steady-state and 13 healthy ethnicity-matched healthy controls (HCs). From 15 patients, paired samples were collected during both steady-state and vaso-occlusive episodes (VOEs) and from 23 SCD patients longitudinal samples were collected before and after treatment with either voxelotor (n = 10), hydroxyurea (n = 8) or allogeneic haematopoietic stem-cell transplantation (n = 5). Fifty plasma proteins were differentially expressed in steady-state SCD patients as compared to HC. These included proteins involved in angiogenesis (i.e. ANGPT1, ANGPT2 and VEGFA), the IL-18 signalling pathway (i.e. IL-6, IL-10, IL-18), T-cell activation (i.e. LAG3, PDCD1) and natural killer (NK)-cell activation (CD244, NCR1, GZMB). While proteins involved in angiogenesis and the IL-18 signalling pathway were further upregulated during VOE, levels of several proteins involved in the IL-18 pathway, T-cell and NK-cell activation and angiogenesis, restored towards levels detected in HCs after curative or disease-modifying treatment. These findings might contribute to a better understanding of SCD pathophysiology and identifying potential new targets for therapeutic interventions.

Sickle cell disease (SCD) is an inherited blood disorder characterized by the production of abnormal hemoglobin S (HbS), leading to the deformation of red blood cells into a sickle shape under low oxygen conditions. These deformed cells impede blood flow, causing vaso-occlusive crises (VOCs), which result in severe pain, multiorgan damage, and increased mortality. Despite advancements in understanding the pathophysiology and management of VOCs, optimal pain management remains a significant challenge. This review aims to evaluate patient-controlled analgesia compared to standard opioid analgesic therapy in pain management among patients with SCD.

The relevant studies will be searched using a well-formulated search strategy using databases such as PubMed, Embase, Scopus, and Web of Science. It will be screened by two reviewers independently (screening phase), and further, the third reviewer may solve if any discrepancies are noted. The primary outcomes will be pain reduction in intensity and frequency of breakthrough pain reported using a standard pain scale. The secondary outcomes will be adverse reactions, mortality rate, length of hospital stay, and 30-day readmission. Then, the eligible studies are assessed for risk for bias and quality by two review members using the Newcastle-Ottawa Scale for observational studies or Cochrane Risk of Bias assessment tool version 2. Besides, it provides strong evidence in support of patient-controlled analgesia (PCA) as an optimal pain management strategy compared to other pain management strategies. It also explores PCA's safety profiles and common adverse events to provide evidence-based recommendations and establish a standard of care for treating SCD patients.

PRISMA format of reporting systematic review and meta-analysis protocols will be followed while presenting the results of this study.

The findings potentially influence clinical practice, healthcare policy, and future research thereby guiding the development of evidence-based standards for VOC management in SCD patients.

CRD42024573178.

The purpose of this study was to describe clinical complications and healthcare resource utilization (HCRU) among patients with sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs) and patients with transfusion-dependent β-thalassemia (TDT) in Germany.

The Betriebskrankenkasse (BKKs) Database was used to identify patients with SCD or TDT. To be eligible for inclusion, patients with SCD were required to have ≥ 2 VOCs/year in any two consecutive years and ≥ 12 months of available data before and after the index date (second VOC in the second consecutive year). Patients with TDT were required to have ≥ 8 red blood cell transfusions (RBCTs) in any 12-month period and ≥ 12 months of available data after the index date (first RBCT). Clinical and HCRU outcomes were analyzed during follow-up.

Overall, 84 patients with SCD with recurrent VOCs and 68 patients with TDT were identified in the BKKs database. Among patients with SCD with recurrent VOCs, the most prevalent complications were retinopathy (45.2%), multisystem organ disease/failure (40.5%), and mental health complications (31.0%); among patients with TDT, they were endocrine (69.1%) and cardiopulmonary (55.9%) complications and malignancies (44.1%). Patients with SCD experienced a mean of 4.0 (standard deviation [SD] 3.9) VOCs and 1.9 (SD 2.5) hospitalizations per patient per year (PPPY) during follow-up. Patients with TDT had a mean (SD) of 16.4 (11.2) RBCTs and 59.4 (40.8) outpatient visits PPPY.

Patients with SCD with recurrent VOCs or TDT in Germany experience significant clinical complications and HCRU.

Sickle cell disease is a hereditary disorder in which the pathophysiology is driven by the aggregation of a mutant (sickle) hemoglobin (HbS). The self-assembly of deoxygenated sickle hemoglobin molecules into ordered fiber structures has consequences extending to the cellular and rheological levels, stiffening red blood cells and inducing pathological flow behavior. This review explores the current understanding of the molecular processes involved in the polymerization of hemoglobin in sickle cell disease and how the molecular phase transition creates quantifiable changes at the cellular and rheological scale, as well as, identifying knowledge gaps in the field that would improve our understanding of the disease and further improve treatment and management of the disease.

Pediatric patients with sickle cell disease and vitamin D deficiency have worse clinical and laboratory outcomes. This study aims to quantify the prevalence of vitamin D deficiency in this population and identify possible risk factors for hypovitaminosis D by performing a cross-sectional study with children aged 3-18 years old with sickle cell disease. Sixty patients were evaluated, with a mean age of 10.80 + 4.21 years. The prevalence of vitamin D deficiency was 46.7% (21.02 ± 8.47 ng/mL). Patients were clustered into two groups regarding vitamin D deficiency (25-OH-D < 20 ng/mL). When comparing groups with and without vitamin D deficiency, age (p = 0.002) and season of 25-OH-D collection (p = 0.005) were statistically significant. Age presented OR 1.23 (95% CI: 1.07; 1.41/p = 0.004), as well as the season of the 25-OH-D collection with OR 5.21 (95% CI: 1.58; 17.14/p = 0.007) for autumn/winter assessment. After linear regression, an association was noted for age (β = -0.80/95% CI: -1.29; -0.320/p = 0.002), days of sun exposure (β = 0.83/95% CI: 0.07; 1.58/p = 0.032), and autumn/winter vitamin D assessment (β = -7.94/95% CI: -12.02; -3.85/p = 0.032). In conclusion, hypovitaminosis D is highly prevalent in this population; meanwhile, age, season of 25-OH-D collection, and days of sunlight exposure appeared as risk factors for deficiency.

One of the most common presentations of sickle cell disease (SCD) in the emergency department (ED) is acute severe pain episodes due to a vaso-occlusive crisis (VOC). Management of these episodes is primarily through intravenous pain control, but patients often return to the ED with the same complaint a few days after discharge. While some global studies have explored the risk factors for ED revisits due to VOC, the literature is lacking in the adult population, specifically in Saudi Arabia where SCD prevalence is high. The goal of this study is to measure the incidence of ED 72-hour early revisit (ERV) among SCD patients due to a VOC episode and to identify factors that might be associated with an ERV in this population. We conducted a retrospective cohort study using the electronic medical records, retrieving all patients who presented to the ED with a VOC from the period of 2017 to 2022.

This study included 120 VOC visits. The percentage of 72-hour ERV to the ED among VOC patients was 39.2%, in which 91.5% received opioids, and 31.9% were admitted during the return visit. Return visitors' median age was 29, most of them were male. There was no statistically significant correlation found between the patients' 72-hour ERV to the ED and their age, gender, comorbidities, history of exchange transfusion, pain score, or dose of opiates received. Of the variables measured at the index visit only the direct bilirubin level, and time to first opioid dose was associated with 72-hour ERV with an OR of 1.08 (95%CI: 1.0 to 1.16, P = 0.022) and 0.99 (95%CI: 0.99 to 0.99, P = 0.012) respectively.

We found that 39.2% of VOC episodes discharged from the ED had an ERV. This rate is higher than what is reported internationally. Additionally, the lack of clear predictors for revisits raises doubts regarding the efficacy of the ED ''treat and release'' approach in this population.

Not applicable.

National guidelines for the acute management of sickle cell disease vaso-occlusive episodes recommend the use of a patient-specific or a weight-based protocol. The authors compared patient satisfaction with pain management between those randomized to receive either a patient-specific or weight-based pain protocol in the COMPARE-VOE randomized control trial.

Participants with sickle cell disease were pre-enrolled and patient satisfaction with pain management was assessed at the time of discharge from the 6 participating emergency departments. Patients were randomized to receive a patient-specific or weight-based pain protocol. The authors compared continuous variables between the patient-specific and weight-based protocols with the 2-sample t test and categorical variables by the chi-square test.

The authors enrolled 104 participants. Compared with satisfaction with pain management on previous ED visits, more participants in the patient-specific protocol group than the weight-based group (57.1% vs 31.8%; P = .02) were satisfied with pain management. Most who were discharged home (91.2%) felt their pain was sufficiently relieved to be discharged home.

These findings support evidence-based guidelines to manage vaso-occlusive episodes in emergency departments. Patient-specific protocols can be implemented by partnering with local sickle cell disease providers to make protocols available in the emergency department.

Background: Sickle cell anemia (SCA) affects a significant number of children worldwide, for whom the progression of the disease can lead to functional disability-impaired development. Nurses are pivotal in providing holistic care to these children and their families. This review aims to identify recent evidence on the role of nurses in intervening with children with SCA and their families in a hospital setting. Methods: A rapid review reported under the PRISMA methodology was carried out in the CINAHL, MEDLINE, and Scopus databases with the expression (sickle cell anemia OR sickle cell disease) AND (child* OR family OR pediatric*) AND (nurs* OR "nursing interventions" OR "pediatric nursing") AND (hospital*), considering studies between 2019 and 2024, written in English, identifying articles with insights about the role of nurses in this context. Articles other than primary or secondary studies were excluded. Data were analyzed through a rapid qualitative approach. Results: Fifty-two studies were identified and seventeen articles were included. The nurse's role is key and multidisciplinary, focusing on the child and family (care management and therapeutic education), the team (training, and the promotion of safety and quality of care), and the health system (optimizing access to care and promoting adequate resources for its implementation). Such a role is important for short-term clinical problems and to prevent long-term complications. Conclusions: Nurses play a central role in empowering families and coordinating multidisciplinary care. Greater investment is needed at a clinical level, through a more effective response to the needs of these patients, and in research, through experimental studies and other designs focused on multidisciplinary interventions.

Sickle cell trait was once considered to benign hereditary condition, besides the association of renal medullary carcinoma, affecting red blood cells. The inherited disorder creates several health issues under various conditions, such as dehydration, hypoxia, or extreme physical exertion. Healthcare professionals and patients with the disorder should understand the importance of vascular complications in sickle cell traits. This article emphasizes the pathophysiology, epidemiology, and molecular basis of the sickle cell trait, which involves virtually every organ system and involves vascular endothelial dysfunction, cerebral vasculopathy, renal complications, cardiopulmonary manifestations, and splenic issues. Techniques of prevention and management strategies for quality-of-life improvement in the case of sickle cell trait are presented.

Sickle cell disease (SCD) is an inherited hematologic disease caused by sickle hemoglobin as the predominant RBC hemoglobin or by sickle hemoglobin in combination with other abnormal β-hemoglobin variants like HbC, HbD and others. Sickling of erythrocytes under deoxygenated conditions is the basis of inflammatory and thrombotic cascades which result in multiple serious complications, leading to early morbidity and mortality. While HLA-matched allogeneic bone marrow transplantation is potentially curative, it has considerable limitations due to potential severe toxicities. Despite slow progress towards novel therapeutic strategies for SCD and hydroxyurea being the sole medication that is shown to reduce vaso-occlusive events and mortality for almost 20 years, several pharmacological agents targeting different mechanisms have been examined in clinical trials and recently US- US-FDA-approved, including L-glutamine and crizanlizumab. Voxelotor was previously US-FDA-approved but has been voluntarily withdrawn from the market as the overall benefit did not outweigh the risks. Gene therapies based on CRISPR-Cas9 and lentiviral vectors have been very recently approved. However, excessive costs are a barrier to widespread use. Nonetheless, there is still a large area of unmet needs for patients with SCD, and further research towards better care is warranted.

Sickle cell disease (SCD) is characterized by chronic hemolytic anemia and intermittent vasoocclusive crises. To date, 4 disease-modifying drugs have been approved for the treatment of SCD: hydroxyurea (an S-phase inhibitor), L-glutamine (an amino acid), crizanlizumab (a P-selectin inhibitor), and voxelotor (a hemoglobin S polymerization inhibitor). Preclinical studies suggested that voxelotor effectively treats SCD and sickle cell anemia (SCA). In a phase III trial, voxelotor-treated patients showed significantly elevated hemoglobin levels (>1 g/dL from baseline) compared to placebo-treated patients. The group that received voxelotor also showed a greater decrease in hemolytic markers but a comparable incidence of side effects. Six ongoing clinical trials also sought to ascertain the effectiveness and safety of high-dose voxelotor when administered to children younger than 12 years. Studies assessing their long-term efficacy and safety are needed to fully understand the role of voxelotor in treating SCD/SCA. In this review, we discuss the mechanisms, trials to date, and future treatment directions of voxelotor.

Individuals living with sickle cell disease (SCD) commonly report impaired health-related quality of life (HRQoL). However, impacts of SCD on HRQoL and the unmet needs of SCD treatment/management are under-researched. This study characterized the impact of SCD on HRQoL and identified the unmet needs of individuals with SCD.

Adults with SCD (aged ≥ 18 years) and caregivers of adolescents (aged 12‒17) with SCD in the United States (US) and United Kingdom (UK) participated in one-on-one virtual semi-structured interviews and focus group discussions (hereafter referred to as 'interviews'). Interviews were transcribed and thematically analyzed.

Nineteen individuals participated in the study (across five interviews and three focus group discussions), including 18 adults with SCD (United States, n = 11; United Kingdom, n = 7) and one caregiver of an adolescent with SCD (United States). Most participants were female (n = 15). Participants reported negative impacts of SCD on their HRQoL, including the burden of structuring their lives around SCD, due to unpredictable symptoms. They reported negative impacts to psychological health (e.g., depression/low mood and anxiety) and physical health (e.g., chronic pain and fatigue) that affected their social and family life, work, and education, leading to feelings of isolation. Participants expressed concerns about the future, feelings of resentment, and the need for high resilience when facing the barriers/impacts associated with SCD. Many participants reported negative interactions with healthcare professionals, leading to trauma, anxiety, and routine care avoidance. Most participants reported perceived prejudice during routine SCD treatment/management, including being treated as drug-seekers.

Individuals with SCD experience negative HRQoL impacts, including impacts to daily activities, social and family life, work and education, psychological health, and prejudice/stigma. Our findings highlight significant unmet needs of individuals living with SCD, including alternative treatment options to reduce vaso-occlusive crisis (VOC) frequency and treat fatigue.

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.

Sleep-disordered breathing is prevalent in children with sickle cell disease (SCD) and is associated with worse outcomes. This study aimed to compare the outcomes of polysomnography (PSG) performed for pediatric patients with SCD at 3 US centers.

We included patients with SCD aged 0-21 years who underwent PSG at 3 American Academy of Sleep Medicine-accredited centers, the University of Alabama at Birmingham, the University of Florida, and Duke University Hospital, between 2012 and 2022. Descriptive statistics were used as appropriate to compare the baseline characters and PSG outcomes among the different centers.

A total of 210 children with SCD from the 3 centers were included, with comparable sex, SCD genotypes, hemoglobin, hematocrit levels, and chronic transfusion. Children from the different centers exhibited variations in age (P < .001), body mass index (P < .05), mean corpuscular volume (P < .05), and hydroxyurea usage (P < .05) at the time of the PSG. Overall, the 3 centers showed significantly different PSG outcomes. Patients from the University of Florida had worse obstructive sleep apnea, oxygenation, and periodic leg movement events, together with lower hydroxyurea usage, and those from Duke University Hospital showed higher hypoventilation and arousal indices.

This multicenter study underscores variations in PSG outcomes among pediatric SCD patients at different centers in the southeastern United States. These findings emphasize the need for standardized approaches to screen for sleep-disordered breathing, refer to PSG, and interpret the results in children with SCD. These conclusions may apply to other genetic disorders associated with an increased risk of sleep-disordered breathing.

Alishlash AS, Nourani AR, Lebensburger J, Rothman JA, Ali-Dinar T, Ezmigna D. Multicenter comparative study of polysomnography outcomes in children with the monogenic disorder sickle cell disease. J Clin Sleep Med. 2025;21(2):297-304.