Sickle Cell Research Articles

Sickle cell crisis: inpatient management

Sickle cell anemia is the world's most common monogenic disease, with a steady rise in the number of cases also in Switzerland. It presents as regenerative anemia and recurrent vaso-occlusive episodes, which can impact all organs. Acute and chronic complications increase morbidity and mortality, significantly reducing life expectancy compared to the general population. Optimal and multidisciplinary management of acute events is essential to improve patients' quality of life and overall prognosis. Vaso-occlusive crises and acute chest syndrome are the two most frequent acute complications. Their treatment, described here, is threefold: analgesia, treatment of causative factors and prevention of further complications.

Society for Maternal-Fetal Medicine Consult Series #68: Sickle Cell Disease in Pregnancy

(Am J Obstet Gynecol. 2024;230(2):B17–B40. doi: 10.1016/j.ajog.2023.10.031) The Society for Maternal-Fetal Medicine (SMFM) has published recommendations for managing sickle cell disease (SCD) in pregnancy as part of its Consult Series. The guidance also summarizes what is known about the disease.

A Cross-Sectional Study on the Quality of Life of Adults With Sickle Cell Disease Followed-Up in Outpatient Clinics: A Single-Center Experience

A Cross-Sectional Study on the Quality of Life of Adults With Sickle Cell Disease Followed-Up in Outpatient Clinics: A Single-Center Experience

Minimally invasive treatment with radiofrequency ablation and kyphoplasty for avascular necrosis of the spine in sickle cell disease: illustrative case.

Avascular necrosis (AVN) of the spine is a rare sequela of chronic sickle cell disease (SCD) in which the shape of the sickled red blood cells interfere with the normal vascular supply of vertebral bodies. In this report, the authors describe a case of progressive spinal AVN treated with radiofrequency ablation (RFA) and kyphoplasty for the patient's persistent lower back pain. A 38-year-old male with long-standing spinal AVN due to SCD had been managed conservatively with hydroxyurea and oral opioid analgesics for several years until breakthrough episodes of low-back pain began to occur with an inability to perform activities of daily life. The patient's condition progressed to involve multiple vertebral bodies, leading to a refractory response. Bipedicular RFA directed at L3 and L4 with kyphoplasty was proposed as a novel, minimally invasive approach. The patient was found to have lasting postoperative relief. Patients with pain attributed to a sickle cell crisis can benefit from RFA and kyphoplasty to potentially eliminate or minimize symptoms from spinal AVN due to chronic SCD not responding to conservative management. https://thejns.org/doi/10.3171/CASE24343.

Revealing health and socioeconomic realities among individuals with sickle cell trait through case studies from remote areas of India

There is a widespread misperception that sickle cell trait (SCT) is not a major health issue, since people with SCT do not normally exhibit apparent symptoms like those found with sickle cell disease (SCD). Therefore, SCT individuals are often neglected, as SCT is assumed to be a benign condition. However, in the present study, growing evidence has linked SCT to severe health risks. This study aims to comprehensively examine the clinical and socioeconomic aspects of SCT individuals in Koraput district of Odisha, India. A total of 9 individuals with specific, uncommon comorbidities and social issues were selected for a detailed case study during the SCT screening program, which involved 1132 individuals aged 30 years and above from scheduled tribe (ST) and scheduled caste (SC) categories, unrelated up to the 1st cousin. Physiological measurements such as weight, height, blood pressure, fasting blood sugar, and haemoglobin levels were recorded. Mental health and quality of life (QOL) were assessed using the Beck Depression Inventory (BDI) and WHOQOL-BREF tools. In-depth interviews were conducted to explore socioeconomic factors. Case studies revealed various comorbidities and social issues among SCT individuals. These included priapism, anaemia, hypotension, low blood glucose, decreased BMI, reduced SpO2 levels, retinopathy, paralysis, social barriers affecting marriage prospects, diagnosis stigma and depression, neonatal deaths, clinical negligence, consanguineous marriages leading to offspring with SCD. Additionally, the economic burden associated with healthcare expenditures was evident. The study highlights the need for awareness and comprehensive support systems for individuals with SCT, particularly in marginalized communities.

Management of Spontaneous Epidural Hematoma in the Setting of Vaso-Occlusive Crisis Among Pediatric Patients With Sickle Cell Disease: A Case Series and Scoping Literature Review

Management of Spontaneous Epidural Hematoma in the Setting of Vaso-Occlusive Crisis Among Pediatric Patients With Sickle Cell Disease: A Case Series and Scoping Literature Review

Pericardial effusion, a complication common both to expanded dengue syndrome and to sickle cell disease.

Pericardial effusion, a complication common both to expanded dengue syndrome and to sickle cell disease.

Impact of hydroxycarbamide treatment on the whole‐blood transcriptome in sickle cell disease

SummaryHydroxycarbamide (HC) is the most widely used therapeutic for individuals with sickle cell disease (SCD, including sickle cell anemia and other forms of the disease). HC's clinical benefits are primarily associated with its ability to induce foetal haemoglobin (HbF); this limited view of HC's therapeutic potential may lead to its discontinuation when a modest amount of HbF is induced. A better understanding of the HbF‐independent effects of HC on genes and pathways relevant to SCD pathophysiology is therefore needed. In this study, we performed bulk RNA‐Seq on whole blood samples collected from a cohort of 25 paediatric patients with SCD to identify genes and pathways that are affected by treatment with HC. At the maximum tolerated dose (MTD) of HC, patients showed altered expression levels of several genes and biological pathways. Pathways related to haeme metabolism, interferon‐alpha response, and interferon‐gamma response were significantly downregulated at HC MTD relative to the matched pre‐HC samples. Pathways linked with IL2‐STAT5 signalling and TNFα signalling via NF‐Kβ were observed to be up‐regulated at HC MTD. These results illustrate the range of effects exerted by HC during therapy for SCD and pave the way for an improved understanding of the HbF induction‐independent benefits of HC.

MEGALOBLASTIC CRISIS IN SICKLE CELL DISEASE–A RARE PHENOMENA WITH AVAILABLE REVIEW OF LITERATURE

Sickle cell disease (SCD) is an inherited disease where some red blood cells are shaped like sickles or crescent moons. This condition affects the blood and various organs of the body. These sickle cells also become rigid and sticky, which can slow or block blood flow, resulting in episodes of sickness that produce pain and other crisis. There are different types of crisis. SCD with a megaloblastic crisis is rare. The frequency of the carrier state determines the prevalence of sickle cell anemia. Here we describe a 20 y old female patient with sickle cell disease who experienced a megaloblastic crisis.

Accompanying Hemoglobin Polymerization in Red Blood Cells in Patients with Sickle Cell Disease Using Fluorescence Lifetime Imaging.

In recent studies, it has been shown that fluorescence lifetime imaging (FLIM) may reveal intracellular structural details in unstained cytological preparations that are not revealed by standard staining procedures. The aim of our investigation was to examine whether FLIM images could reveal areas suggestive of polymerization in red blood cells (RBCs) of sickle cell disease (SCD) patients. We examined label-free blood films using auto-fluorescence FLIM images of 45 SCD patients and compared the results with those of 27 control persons without hematological disease. All control RBCs revealed homogeneous cytoplasm without any foci. Rounded non-sickled RBCs in SCD showed between zero and three small intensively fluorescent dots with higher lifetime values. In sickled RBCs, we found additionally larger irregularly shaped intensively fluorescent areas with increased FLIM values. These areas were interpreted as equivalent to polymerized hemoglobin. The rounded, non-sickled RBCs of SCD patients with homogeneous cytoplasm were not different from those of the erythrocytes of control patients in light microscopy. Yet, variables from the local binary pattern-transformed matrix of the FLIM values per pixel showed significant differences between non-sickled RBCs and those of control cells. In a linear discriminant analysis, using local binary pattern-transformed texture features (mean and entropy) of the erythrocyte cytoplasm of normal appearing cells, the final model could distinguish between SCD patients and control persons with an accuracy of 84.7% of the patients. When the classification was based on the examination of a single rounded erythrocyte, an accuracy of 68.5% was achieved. Employing the Linear Discriminant Analysis classifier method for machine learning, the accuracy was 68.1%. We believe that our study shows that FLIM is able to disclose the topography of the intracellular polymerization process of hemoglobin in sickle cell disease and that the images are compatible with the theory of the two-step nucleation. Furthermore, we think that the presented technique may be an interesting tool for the investigation of therapeutic inhibition of polymerization.

Current trends and ethical considerations in gene therapy

Abstract. This paper explores the advancements, applications, and ethical challenges associated with gene therapy, a transformative approach to treating genetic disorders. Gene therapy corrects genetic defects at the molecular level, offering potential cures for diseases previously considered intractable. Techniques like CRISPR-Cas9 have revolutionized this field by enabling precise genetic editing. We discuss both ex vivo and in vivo methods, highlighting their applications in treating diseases such as sickle cell disease and inherited blindness. However, the implementation of gene therapy raises significant ethical and safety concerns, including the risks of germline modifications and the high costs limiting access. Safety concerns associated with viral vectors, such as potential oncogenesis and immune reactions, are also examined. The paper calls for evolved regulatory frameworks to ensure safe, ethical, and equitable access to gene therapy, underscoring the need for ongoing public engagement and education to navigate the complex landscape of genetic medicine. This study concludes that while gene therapy holds great promise, it requires evolved regulatory frameworks to ensure safe, ethical, and equitable access. Ongoing public engagement and education are essential to navigating the complex landscape of genetic medicine.

Adolescents and young adults with sickle cell disease exhibit accelerated aging with elevated T-cell p16INK4a expression.

People living with sickle cell disease (SCD) experience complications indicative of an accelerated aging phenotype typified by early decline in physical function and increased risk for age-related conditions. Cellular senescence, measured by expression of p16INK4a in peripheral T-lymphocytes, is recognized as one of the underlying contributors to organismal aging. To examine if cellular senescence is increased in SCD patients, we cross-sectionally measured and compared expression of p16 mRNA in peripheral blood T lymphocytes in 18 adolescents and young adults with SCD to 27 similarly aged individuals without SCD. Expression of p16 was dramatically higher in individuals with SCD vs. without SCD (10.1 vs. 8.7 log2 p16 units, respectively, p < 0.001) - a gap of 43 years in biological age - consistent with accelerated aging in the SCD population. Race was not associated with the increased p16 expression in the SCD group. These initial results suggest that individuals with SCD have a significantly higher cellular senescence burden which may contribute to premature aging, physiological decline, and excess morbidities. Additional longitudinal assessment and consideration for trials of senolytic therapies among individuals living with SCD and high p16 expression are warranted to improve their health span.

Discovery and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease.

Sickle cell disease (SCD) is a prevalent, life-threatening condition with few treatment options, attributed to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) with small molecules has been pursued as a treatment to ameliorate many disease complications but with limited success. Herein, we report the discovery of 10, a novel, potent, and selective molecular glue degrader of the transcription factor WIZ that robustly induces HbF expression as a potential treatment for SCD. 10 was optimized from a phenotypic screening hit utilizing insights from X-ray crystallography and computational modeling to improve potency, selectivity and in vivo exposure. In an hNBSGW mouse xenograft model, 10 demonstrated robust WIZ degradation and HbF induction. These results highlight the potential of WIZ degraders as a promising therapy for sickle cell disease.

Managing the challenges of paying for gene therapy: strategies for market action and policy reform in the United States.

Gene therapies delivered through a single administration have revolutionized treatment possibilities for many patients living with serious or fatal conditions such as spinal muscular atrophy, hemophilia and sickle cell disease. However, shadowing the excitement about the transformational potential of many gene therapies has been widespread concern about the combination of uncertainty in the durability of their benefits over the long term and the short-term financial shock of high prices. As the healthcare payment ecosystem prepares for the growing number of gene therapies entering the market, three key interconnected challenges must be addressed: determining a fair price, managing clinical uncertainty and managing short-term budget impacts. This paper identifies specific policy reforms and market-based tools to help the US health system address these challenges to achieve more equitable and affordable access for patients to the growing number of gene therapies expected to be approved in the coming years.

Inpatient Hospitalized Sickle Cell Disease for Adults in Al-Ahsa Saudi Arabia Chart Review Study, 2015-2017

Background: Sickle cell disease (SCD) is an autosomal recessive disease characterized by production of abnormal hemoglobin S. The aim of this study is to review the history of SCD adults patients who were admitted to inpatient ward in Al-Ahsa, Saudi Arabia. Method: A retrospective cross sectional study was conducted through medical records chart review in King Fahad Hospital (KFH) in Al Ahsa to detect all SCD adults patients who were admitted to inpatient ward during 2013 to 2015. A structured Self designed questionnaire was reviewed and used during data collection from patients files. Results: A total of 130 patients were admitted to inpatient ward, consanguinity reported in 96.2 %. In the last visit, 64.3 % had diagnosed with vaso-occlusive crises, 10.1 % had sequestration crises, 13/2 % had acute chest syndrome, and 12.4% had gall stone. Complications of SCD included spleen removed (46.4%), infection (93%), anemia (93%) and acute chest syndrome (40.6%). Conclusion: SCD is considered as a load in the secondary health care services. Further studies need to be conducted in this subject.

ORGAN-SPARING AND ORGAN- REMOVING SURGICAL PROCEDURES FOR PATHOLOGICAL CONDITIONS OF THE SPLEEN IN CHILDREN. QUESTIONS AND ANSWERS.

Introduction. Nowadays splenic surgery is a rather urgent problem in pediatric surgery. There are diseases where only splenectomy allows a child to live a full life. These are: sickle cell anemia (SCA), idiopathic thrombocytopenic purpura, hereditary spherocytosis (Minkowski- Chauff ard disease), thalassemia, and autoimmune hemolytic anemia. The spleen is involved in 25-30 % of cases of blunt abdominal trauma in children. The loss of more than 45 % of the circulating blood volume leads to an unstable hemodynamic state in the child. The question of surgical treatment and preservation of the spleen in hemoperitoneum due to its injury is of vital importance. Aim: To study the possibilities of surgical treatment of diseases and injuries of the spleen in children. Materials and methods. An analysis of surgical interventions for diseases and injuries of the spleen in children aged 2 to 17 years from 2019 to 2024 was performed. The study was conducted in the surgical departments of the «Clinical Center of Pediatric Medicine» of the «Okhmatdyt Hospital» of the «Western Ukrainian Specialized Center» (Lviv) and the «Chernivtsi City Children’s Clinical Hospital» (Chernivtsi). 27 children (17 girls, 10 boys) had spleen diseases and 43 children (23 girls, 20 boys) had spleen injuries. Splenectomy was performed for the following splenic diseases: sickle cell anemia (9 children), idiopathic thrombocytopenic purpura (4 children), hereditary spherocytosis (Minkowski- Chauff ard disease) (6 children), thalassemia (1 child), and autoimmune hemolytic anemia (1 child). Six children had splenic cysts: 3 children had posttraumatic cysts and 3 children had parasitic cysts. Twenty children underwent surgery for splenic injuries. The following surgical procedures were performed: laparoscopic abdominal cavity repair with spleen preservation followed by conservative therapy (13 children); laparoscopic splenectomy (2 children); laparotomy, splenic suture (2 children); and open splenectomy (3 children).Results. Conservative management of splenic injuries of varying degrees according to the American Association for the Surgery of Trauma (AAST) was performed in 23 (53.49 %) children. Resorption of hemoperitoneum in cases of conservative treatment of splenic injuries occurred 11-14 days after the start of treatment. Safe, full physical activity was resumed after 6 weeks of conservative treatment of splenic injury. Surgical procedures were performed in 20 (46.51 %) children using various techniques. 17 patients underwent laparoscopy. 2 children underwent laparoscopic splenectomy for grade IV AAST injury and hemodynamic instability. In 15 cases, treatment was started with conservative therapy, but during monitoring an increase in hemoperitoneum was observed, indicating the need for laparoscopy. Laparoscopy was performed in 13 children. A minimum of 100 ml and a maximum of 400 ml of blood was collected laparoscopically in the children. The abdominal cavity was examined and hemostasis was confi rmed. In cases where the spleen was «wrapped» with the omentum, the omentum was not separated from the spleen. The operation was completed by placing a drainage tube in the perisplenic space. In 2 children, grade IV AAST injuries were converted to an open procedure in which the spleen was sutured to stop bleeding and a drain was left near the splenic bed. Grade V AAST splenic injury in 3 children was an indication for left subcostal laparotomy and splenectomy. For splenic disease, laparoscopic splenectomy was performed in 12 (44.44 %) children, with high effi cacy in Minkowski- Chauff ard disease combined with gallstones (3 children) where simultaneous cholecystectomy was possible. Laparoscopic removal of splenic cysts was also justifi ed in 3 (11.11 %) children. However, removal of parasitic cysts required open splenectomy in 3 patients. Open splenectomy was performed in 9 children with splenic disease. In 5 children the inappropriateness of laparoscopy was due to severe perisplenitis, large spleen weight and young age of the children.Conclusions1. The morpho- functional structure of the spleen promotes spontaneous hemostasis, which is the basis for conservative treatment of spleen injuries in 53.49 % of children.2. The AAST classifi cation of splenic injuries from grade I to V, hemodynamic indicators and ultrasound monitoring of blood in the abdominal cavity can be used as a basis for choosing the method of treatment of closed blunt splenic injuries in children.3. Ineff ectiveness of conservative treatment, hemodynamic instability and increase of blood in the abdominal cavity in a child with splenic injury within 4 hours is an indication for laparoscopy.4. Splenic suturing and laparoscopic monitoring should be the preferred methods for treating closed splenic injuries in children to preserve the organ.5. The choice of surgical intervention for splenic diseases in children should be individualized and depend on the disease, the child’s age, the size of the spleen, and the presence of complications of the disease.

Red cell specifications for blood group matching in patients with haemoglobinopathies: An updated systematic review and clinical practice guideline from the International Collaboration for Transfusion Medicine Guidelines.

Red blood cell (RBC) antigen matching beyond ABO and RhD is commonly recommended for patients with sickle cell disease (SCD) and thalassaemia. We present an updated systematic literature review to inform evidence-based guidelines on RBC matching. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool was used to develop recommendations. Six new observational studies (4 prospective, 2 retrospective) were identified. The six studies reported on 583 patients in total, including cross-over designs, with sample sizes from 10 to 343. Studies were heterogeneous, utilising varying degrees of RBC matching and different definitions for 'extended' matching. All reported on alloimmunisation. One study reported on molecular matching. The reported prevalence of alloimmunisation using limited matching was 0%-50% and with extended matching was 0%-24%. Eighty-two patients were alloimmunised before study entry. The risk of bias across studies was moderate to critical. The guideline panel recommends that ABO, RhDCcEe, and K-compatible RBCs are selected for individuals with SCD and thalassaemia, even in the absence of alloantibodies, and that RBCs which are antigen-negative to already existing clinically significant antibodies are chosen. There is a need for comparative research to define the benefit, impact, cost-effectiveness, and feasibility of extended RBC matching strategies to prevent alloimmunisation.

Promising role of Voxelotor in managing sickle cell disease in children: a narrative review.

Sickle cell disease (SCD) is characterized by chronic hemolytic anemia and intermittent vaso-occlusive crises. To date, four 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.

Microalbuminuria in Children With Sickle Cell Disease in the Eastern Province of Saudi Arabia.

Sickle cell disease (SCD) complications, such as sickle cell nephropathy (SCN), may begin in childhood and progress insidiously to chronic kidney disease in adulthood. In Saudi Arabia (SA), there is a lack of studies evaluating kidney function in children with SCD. This study aims to assess microalbuminuria (MA) as an early marker of renal dysfunction in SCD children living in the Eastern region of SA, to potentially institute appropriate early treatment. A prospective cross-sectional study was conducted on 114 Saudi children with SCD under the age of 14 years who attended the pediatric hematology clinic for routine follow-up. Demographic and clinical information were collected from the patients and their parents, who provided informed consent. Morning urine samples were collected and tested for the presence of MA using the urinary albumin/creatinine ratio (ACR). Blood samples were also collected for basic laboratory investigations. The prevalence of MA and its correlation with various clinical and laboratory data were analyzed. Additionally, a comparison of clinical characteristics and MA was conducted between children originating from the Southwestern (SW) and Eastern regions of the country, all of whom lived in the Eastern Province. A total of 114 children with SCD were included in the study. The mean age was 8.8 ± 3.2 years, with a male-to-female ratio of 1.3:1. Based on their region of origin, they were divided into two groups: Eastern (n = 26/114) and SW (n = 88/114). MA was detected in 28 patients (24.6%), with no significant difference in prevalence between the two groups. There was no significant statistical difference in clinical and laboratory data between the groups, except for hemoglobin F (HBF) levels and the use of hydroxyurea (HU). HBF levels were significantly higher in children from the Eastern region, while more SW patients used HU. No correlation was found between MA and any of the studied variables. MA is common in children with SCD in the Eastern region of SA, with no difference in its prevalence between children of the two different ancestries carrying the Arab-Indian (AI) and African haplotypes. It is not associated with any of the studied clinical variables in this report. Further studies are needed to confirm these findings.

Managing emotional and physical stress in sickle cell anemia: a review of effective strategies and approaches

Sickle cell anemia (SCA) is a genetic blood disorder characterized by recurrent pain episodes, chronic complications, and significant emotional and physical stress. This review article explores effective strategies for managing both the emotional and physical aspects of stress in SCA patients. A comprehensive literature search was conducted across multiple databases, including PubMed, Scopus, and Google Scholar, using keywords such as “sickle cell anemia,” “stress management,” “psychological support,” and “pain management.” Emotional stress in SCA arises from chronic pain, frequent hospitalizations, and disease uncertainty, leading to conditions such as anxiety and depression. Effective management of emotional stress involves a combination of psychological counseling, cognitive-behavioral therapy (CBT), and support groups, which help patients develop coping strategies and address the mental health challenges of living with a chronic illness. This review evaluates various psychological interventions and their impact on patient outcomes, emphasizing the need for integrated mental health support in the management of SCA. Physical stress in SCA is primarily due to acute vaso-occlusive crises and chronic pain, which require effective pain management and preventive measures. The review explores pharmacological treatments, such as opioids and hydroxyurea, as well as non-pharmacological approaches, including physical therapy and lifestyle modifications. Additionally, the article discusses innovative therapies like gene therapy and stem cell transplantation, which hold promise for long-term disease management.