Search Results (123)

Sickle cell disease (SCD) is an inherited hemoglobinopathy in which hemoglobin S polymerization drives hemolysis and vaso-occlusion with progressive organ morbidity. Male reproductive impairment is increasingly recognized but remains underreported. This narrative review summarizes mechanistic pathways, clinical manifestations, and fertility preservation options relevant to men with SCD. PubMed, the Cochrane Library, and Medscape were searched through 31 December 2025 for human studies addressing endocrine changes, semen quality, priapism and erectile dysfunction, oxidative stress, and treatment-related gonadotoxicity. Evidence supports converging mechanisms: recurrent vaso-occlusion and chronic hypoxia may injure the seminiferous epithelium and impair Leydig cell steroidogenesis; oxidative stress and inflammation contribute to sperm DNA and membrane damage; and disease-modifying or curative therapies such as hydroxyurea and hematopoietic stem cell transplantation can further compromise spermatogenesis. Clinically, men with SCD may present with oligozoospermia, azoospermia, hypogonadism, and sexual dysfunction, particularly after recurrent ischemic priapism. Fertility preservation should be discussed early, ideally before prolonged hydroxyurea exposure or transplantation, and may include semen cryopreservation and testicular sperm extraction (TESE) with assisted reproduction when needed. Prospective longitudinal studies are required to define reproductive trajectories and optimize counseling and management. Full article

Sickle cell disease is an autosomal recessive hemoglobin disorder affecting about 100,000 people in the United States, predominantly those of African descent. A point mutation in the β-globin gene in red blood cells causes these cells to sickle under hypoxemic conditions, reducing blood flow and oxygen delivery to tissues. This manifests in the form of painful vaso-occlusive episodes, acute chest syndrome, and acute infarction of various organs, including the spleen, bone, and lung. While sickle cell disease complications such as hemolytic anemia, tissue hypoxia, and chronic organ damage are well studied, attention to the unique reproductive challenges faced by patients with sickle cell disease remains underrecognized and underappreciated. This review aims to explore key reproductive health issues in patients with sickle cell disease, including diminished ovarian reserve, infertility, and obstetric and perinatal risk. Secondly, this review aims to identify key counseling and care opportunities for providers to support patients with sickle cell disease in meeting their reproductive goals. Full article

Haemoglobinopathies, including β-thalassaemia and sickle cell disease (SCD), are among the most common monogenic disorders worldwide and remain major causes of morbidity and early mortality. Historically, management of these life-altering diseases has relied on supportive treatment and symptom management and, although these treatments reduce symptoms and ease disease burden, they do not correct the underlying genetic defect. Allogenic haematopoietic stem cell transplantation (HSCT) has been the only established curative option; however, it comes with substantial risks that significantly restrict its applicability. Over the past two decades, haematopoietic stem cell (HSC) gene therapy for haemoglobinopathies has rapidly progressed from experimental proof-of-concept to approved therapies. Lentiviral gene addition approaches have demonstrated durable expression of functional β-like globin transgenes, achieving transfusion independence in β-thalassaemia patients and significant reductions in vaso-occlusive events in SCD patients. Alternative therapeutic approaches to promote HbF expression have proved to be highly successful. Gene silencing strategies targeting BCL11A have been successful clinically and, more recently, gene editing technologies such as CRISPR/Cas9 have enabled precise disruption of regulatory elements controlling γ-globin repression, leading to the approval of the first CRISPR-based therapy for SCD and β-thalassaemia. Emerging base editing technologies promise even more precise genetic modification and are advancing through clinical evaluation. Despite these advances, access to gene therapy remains restricted due to the need for highly specialised manufacturing, toxic myeloablative conditioning regimens, and high treatment costs. Ongoing improvements and adaptations in these areas are essential to ensure that gene therapies fulfil their potential as accessible, curative treatments for patients suffering from haemoglobinopathies worldwide. Full article

Sickle cell disease (SCD) is the most common monogenic disorder worldwide and remains a major cause of morbidity and mortality. Sickle cell anemia (SCA), the homozygous HbSS genotype, represents the most severe and frequent form within the spectrum of SCD. Hydroxyurea (HU), a ribonucleotide reductase inhibitor, represents the first and most widely used disease-modifying therapy for SCA. This review summarizes current evidence on the mechanisms of action, clinical efficacy, systemic effects, and long-term safety of chronic HU therapy in patients with SCA. A comprehensive literature search was conducted in PubMed up to 2025 using the terms “sickle cell disease,” “sickle cell anemia”, “hydroxyurea,” and “children” or “paediatric.” Eligible studies included randomized controlled trials, cohort studies, and systematic reviews evaluating HU therapy in SCA. Literature analysis showed that HU exerts pleiotropic effects by inducing fetal hemoglobin (HbF) synthesis, improving red blood cell deformability, reducing leukocyte and platelet counts, and enhancing nitric oxide bioavailability. These mechanisms lead to decreased vaso-occlusive crises, acute chest syndrome, transfusion requirements, and overall mortality. Beyond hematologic improvement, HU confers neuroprotective benefits, modulates inflammatory and immune pathways, and supports normal growth and endocrine development in children. Adverse events, primarily mild bone marrow suppression, are dose-dependent and reversible with appropriate monitoring. No evidence supports an increased risk of malignancy with long-term use. In conclusion, chronic HU therapy is a safe, effective, and multifaceted treatment that substantially improves survival and quality of life in patients with SCA. Early initiation and individualized dosing maximize its therapeutic benefits and help prevent irreversible organ damage. Full article

Sickle cell disease (SCD) is a hemoglobinopathy characterized by hemolysis, vaso-occlusion, and systemic inflammation. Epidemiological studies identified an increased risk of leukemia, especially acute myeloid leukemia (AML), in individuals with SCD, whereas data regarding other tumors are conflicting. SCD-associated AMLs frequently display high-risk features with unfavorable karyotypes and a dismal prognosis. SCD is associated with multiple phenomena linked to carcinogenesis in other contexts, including chronic inflammation, oxidative stress, ineffective erythropoiesis, accelerated hematopoietic aging, impaired tumor immunosurveillance, and increased clonal hematopoiesis. The role and respective contribution of these disease-intrinsic mechanisms in SCD remain to be studied. Although therapies used in SCD could theoretically modulate the risk of malignancies, no data exist to support an increased or reduced risk associated with their use. The most notable exception is hematopoietic stem cell transplantation and, to a lesser extent, gene therapy, for which the conditioning and/or procedure itself is known to increase the risk of leukemia. In sum, the effect of SCD on carcinogenesis is an emerging area of investigation with data supporting specificities in SCD-associated AML. Future research is required to determine the role of treatments to mitigate the increased risk and improve the outcome of SCD-associated AML. Full article

Sickle cell anemia (SCA) is characterized by hematological events that lead to vaso-occlusion and the onset of clinical manifestations. Fetal hemoglobin (HbF) has been shown to positively influence the clinical outcomes of individuals with SCA. Genetic polymorphisms are known to modulate clinical phenotypes by increasing HbF levels, with the BCL11A gene being an important marker in this regard for future therapies. However, while the BCL11A gene plays a role in the regulation of several genes during hematopoiesis, its various effects are not yet fully understood. The study aimed to investigate association between laboratory biomarkers in the presence of rs766432 and rs6732518 polymorphisms in the BCL11A gene. Hematological and biochemical markers were analyzed using automated methods, while genetic markers were identified by PCR-RFLP techniques. Elevated HbF levels were significantly associated with the presence of rs766432 and rs6732518 polymorphisms. High concentrations of HDL were associated with rs766432 polymorphism, and elevated levels of alpha-1antitrypsin were linked to the rs6732518 polymorphism. No correlation was found between HbF and HDL concentrations. The low sample size represents a major constraint, making the results only suggestive. In conclusion, polymorphisms in the BCL11A gene are important for variations in HbF levels and may have a pleiotropic effect by influencing laboratory parameters unrelated to HbF levels. Full article

Background/Objectives: The main contraceptive options for men are condoms, vasectomy and coitus interruptus. Clinical and preclinical trials are being conducted to develop a new male contraceptive (NMC), which can be either hormonal or non-hormonal. A patent landscape and literature review of clinical studies from the last 10 years were carried out to discuss clinical perspectives and sociocultural aspects related to the use of NMC. Methods: An integrative review of clinical aspects was conducted using eleven clinical trials, and a discussion of sociocultural aspects was conducted using thirteen articles. Results: Studies of non-hormonal contraceptives, particularly vaso-occlusive methods, are in more advanced clinical phases, demonstrating contraceptive potential and reversibility. In addition to clinical trials, efforts to develop NMC include addressing gender disparities and understanding masculinity. Alternative technologies and methods for contraception were identified as key to the development of NMC. Despite clinical and technological advances, there is a need to expand clinical studies on male contraceptives, involving larger samples, long-term follow-ups, and reversibility tests. There is a global social need that both men and women should have a wide variety of contraceptive options. Conclusions: This review emphasizes the importance of exploring new technologies for male contraceptives to expand options while optimizing the satisfaction and safety of these contraceptive options for the population. Full article

Background: Patients with sickle cell disease (SCD) experience severe and life-threatening complications over their lifespans. However, research on SCD age-related complications is limited. Objective: This study examined differences in the number and type of SCD-related complications by age group among Texas Medicaid pediatric patients, and the factors associated with salient complications. Methods: This retrospective study used Texas Medicaid prescription and medical claims (2012–2021). Subjects aged 2 to 18 years, with ≥3 SCD hospitalizations or outpatient visits, and continuously enrolled for ≥12 months after the first SCD diagnosis claim were included. Complications were characterized by number and type of organ systems affected. Sociodemographic and clinical factors were used as potential factors associated with the most salient complications. Descriptive and inferential (ANOVA, Chi-square, and multivariable logistic regression) analyses were employed. Results: The included 1555 patients (mean age = 9.5 ± 5.1) were categorized into four age groups: 2–4 (23.4%), 5–9 (26.9%), 10–14 (27.4%), and 15–18 (22.3%) years. Documented number and type of complications differed significantly (all p < 0.0001) by age group, with the 2–14 years group having more documented complications compared to the 15–18 years group. Neurological complications were most common (~65%), followed by infections (~42%), and cardio-pulmonary complications (~30%). Young age group, hydroxyurea use, and having mental health comorbidities were associated with greater likelihood of experiencing vaso-occlusive crises, respiratory infections, and acute chest syndrome. Conclusions: Patterns of SCD-related complications (e.g., VOCs, respiratory infections, and acute chest syndrome) differ significantly by age group, leading to increased morbidity and acute care utilization. Despite its reported association with better outcomes, hydroxyurea utilization was found to be poor, with only 16% of patients receiving it for at least 180 days annually. Access to appropriate healthcare and improved utilization of hydroxyurea are needed to improve health outcomes of this population over their lifespan. Full article

Sickle cell disease (SCD) is a hereditary hemoglobin disorder characterized by chronic hemolysis and recurrent vaso-occlusive crises, leading to a wide spectrum of complications. While common SCD manifestations have well-established management protocols, rare and atypical complications pose significant diagnostic and therapeutic challenges. A critical barrier is diagnostic overshadowing, where common SCD symptoms (pain, fever, respiratory distress) mask infrequent but life-threatening conditions, resulting in delayed recognition and suboptimal outcomes. This narrative review synthesizes the literature from 2000–2025 on rare SCD complications, including atypical neurological events (e.g., spontaneous epidural or subdural hematoma, central retinal artery occlusion, cerebral arteriovenous malformations, posterior reversible encephalopathy syndrome), uncommon hematologic syndromes (acute leukemia, extramedullary hematopoiesis in unusual sites, hemophagocytic lymphohistiocytosis), severe cardiopulmonary emergencies (acute multiorgan failure and fat embolism syndromes), unusual hepatic crises (acute hepatic sequestration, intrahepatic cholestasis), and others (e.g., compartment syndrome). Key insights underscore the need for high clinical suspicion and prompt use of advanced diagnostics (e.g., MRI, specialized laboratory tests) when patients present with atypical or disproportionate symptoms. Clinical implications: Heightening clinician awareness of these rare complications and implementing structured diagnostic strategies can facilitate earlier intervention, improving outcomes and reducing the high morbidity and mortality associated with these infrequent but severe events. Full article

Sickle cell disease (SCD) is the most common hemoglobinopathy, caused by a mutation in the β-globin gene of hemoglobin. It predisposes patients to painful Vaso-occlusive crises (VOC) and multi-organ dysfunctions. The disease exhibits significant phenotypic variability, making it challenging to predict severity and outcomes. This study aimed to characterize the whole blood gene expression profile of Bahraini SCD patients, identifying differentially expressed genes during steady-state (n = 10) and VOC (n = 10) compared to healthy controls (n = 8). Analysis revealed 2073 and 3363 dysregulated genes during steady-state and VOC, respectively, compared to controls, with 1078 genes differentially expressed during VOC versus steady-state. Gene Ontology (GO) enrichment analysis highlighted significant deregulation in immune and hematopoietic pathways, including down-regulation of critical genes for immune modulation and hematopoietic balance. Notably, the transcription factor RUNX3, involved in immune cell differentiation and inflammation, was among the 668 down-regulated genes. RUNX3 was four-fold down-regulated in microarray analysis, three-fold in PCR, and showed a mean protein concentration of 11.13 pg/mL during VOC compared to 457.93 pg/mL during steady-state (p < 0.01). These findings suggest that RUNX3 may serve as a potential biomarker for VOC. Future large-scale validation, additional proteomic studies, and functional investigations are recommended to confirm its clinical utility and significance. Full article

Sickle cell disease (SCD) affects millions globally, with approximately 0.26% of the Saudi population impacted. Despite standard treatments, patients frequently experience vaso-occlusive crises (VOCs). This retrospective observational study evaluated the real-world effectiveness of L-glutamine (Endari^®) in reducing SCD-related complications in the Saudi population, where data remain limited. Patients aged five and older who received L-glutamine from June 2019 to June 2023 were included. The primary endpoint was VOC frequency through week 48. Descriptive statistics and paired t-tests compared outcomes before and after treatment. Fifteen patients (median age 12 years, 53% female) met the inclusion criteria; all were on maximum tolerated hydroxyurea. Eleven completed 48 weeks, showing a median VOC reduction from 4 to 3 (p = 0.44). Hospital stay duration remained unchanged (median 7 days, p = 0.72). Laboratory parameters were largely stable, except for a 61.9% increase in reticulocyte count (p = 0.03). The estimated annual treatment cost exceeded SAR 2 million (USD ~547,840). L-glutamine did not produce statistically significant improvements in VOC frequency, though numerical trends were observed. Given the small sample size and limited statistical power, the findings are exploratory. Larger, well-powered, multicenter studies are needed to confirm L-glutamine’s potential benefits in this population. Full article

Sickle cell disease (SCD) is a group of recessive diseases caused by the β^S sickling mutation of HBB in homozygosity or in compound heterozygosity with other pathogenic HBB mutations. Patients with severe SCD typically experience painful vaso-occlusive crises and other pain-related phenomena, including acute chest syndrome, priapism, dactylitis, avascular necrosis, and splenic sequestration and infarction. High variability of pain-related phenomena per SCD genotype indicates genetic disease modifiers (GDMs) as pathology determinants and, thus, as critical to prognosis, treatment choice, and therapy development. Articles likely holding genetic information for SCD pain phenomena were identified in PubMed and SCOPUS for article quality assessment and extraction of corresponding GDMs and observations indicative of development areas in our understanding of SCD GDMs. This process led to the initial selection of 183 articles matching the search terms, which, after two-step selection, resulted in the inclusion of 100 articles for content analysis and of significant findings for GDMs from 37 articles. Published data point to gender effects and to 51 GDM SNVs, deletions, and regions, including globin genes and significant overrepresentation of gene ontology pathways related, e.g., to oxidative stress, hypoxia, and regulation of blood pressure. Analyzed articles further pointed to additional candidate GDMs affecting SCD VOC and pain phenomena and to potential confounding factors for GWAS analyses. We found that despite the critical importance of VOC and pain phenomena for SCD pathology, corresponding clinically relevant genetic insights are held back by a shortage of large-scale, systematic multi-ethnic efforts, as undertaken by the INHERENT Network. Full article

Background/Objectives: This study aimed to estimate the proportion of pediatric emergency admissions related to sickle cell disease. Methods: This is a cross-sectional study. The data were collected over a period of 9 years, from 1 January 2014 to 31 December 2022. Results: 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. Conclusions: 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. Full article

Sickle cell disease (SCD) is a monogenic blood disorder characterized by abnormal hemoglobin S production, which polymerizes under hypoxia conditions to produce chronic red blood cell hemolysis, widespread organ damage, and vasculopathy. As a result of vaso-occlusion and ischemia-reperfusion injury, individuals with SCD have recurrent pain episodes, infection, pulmonary disease, and fall victim to early death. Oxidative stress due to chronic hemolysis and the release of hemoglobin and free heme is a key driver of the clinical manifestations of SCD. The net result is the generation of reactive oxygen species that consume nitric oxide and overwhelm the antioxidant system due to a reduction in enzymes such as superoxide dismutase and glutathione peroxidase. The primary mechanism for handling cellular oxidative stress is the activation of antioxidant proteins by the transcription factor NRF2, a promising target for treatment development, given the significant role of oxidative stress in the clinical severity of SCD. In this review, we discuss the role of oxidative stress in health and the clinical complications of SCD, and the potential of NRF2 as a treatment target, offering hope for developing effective therapies for SCD. This task requires our collective dedication and focus. Full article

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. Full article