Sickle Cell Research Articles

The Impact of Hydroxyurea Therapy on Clinical and Haematological Parameters in Children with Sickle Cell Anaemia

The Impact of Hydroxyurea Therapy on Clinical and Haematological Parameters in Children with Sickle Cell Anaemia

Sickle Cell Anemia and Pregnancy Hemolysis: Clinical Considerations

Sickle cell anemia (SCA) is a hereditary blood disorder characterized by abnormal hemoglobin production, leading to chronic hemolysis and episodic vaso-occlusive crises (VOCs). Pregnancy in women with SCA poses significant clinical challenges due to the increased physiological demands, which exacerbate hemolysis and increase maternal and fetal risks. This review explores the pathophysiology of hemolysis in SCA during pregnancy, its clinical implications, and management strategies aimed at improving maternal and fetal outcomes. Hemolysis can result in severe anemia, acute chest syndrome, increased risk of infections, and adverse fetal outcomes, such as intrauterine growth restriction and preterm delivery. Management strategies for hemolysis in pregnancy include blood transfusions, pharmacological therapies, nutritional supplementation, and emerging treatments like gene therapy. Blood transfusions are widely used to mitigate anemia and reduce the number of circulating sickled cells, while pharmacological agents such as L-glutamine help address oxidative stress. Nutritional support, particularly with folic acid and antioxidants, is essential in promoting healthy red blood cell production and mitigating oxidative damage. Emerging therapies like gene editing offer promising future directions for more effective management of SCA and pregnancy-related hemolysis.

Patient-reported pregnancy loss and maternal complications: Insights from the sickle cell disease implementation consortium.

Sickle cell disease (SCD) is associated with complications during pregnancy and can negatively influence maternal outcomes. Our study aimed to determine the prevalence and predictors of maternal morbidity among participants enrolled in an eight-site SCD Implementation Consortium (SCDIC) registry. We conducted a cross-sectional analysis of female registry participants, aged 15-45 years, with a confirmed diagnosis of SCD. Participants completed a survey of self-reported pregnancies and outcomes. Seven hundred and thirty-eight individuals had at least one pregnancy event, with 1076 live births. Twenty percent reported a pregnancy loss or fetal demise. Of the 1076 live births, 75% involved at least one complication. The most prevalent complications were pain crises (61.1%) and pregnancy requiring blood transfusion(s) (33.0%). Multiparous individuals with a prior occurrence of a complication in a previous pregnancy had higher odds of recurrence of the same complication in subsequent pregnancies (i.e., previous acute crisis was associated with subsequent acute pain events odds ratio [OR]: 3.13; 95% confidence interval [CI]: 2.06-4.76) and prior transfusion requiring another transfusion (OR: 3.22; 95% CI: 2.01-5.16). Individuals reported a high prevalence of pregnancy loss and maternal complications. Our findings underscore the importance of preconception counseling and early initiation of perinatal care in SCD.

Biomechanics of phagocytosis of red blood cells by macrophages in the human spleen

The clearance of senescent and altered red blood cells (RBCs) in the red pulp of the human spleen involves sequential processes of prefiltration, filtration, and postfiltration. While prior work has elucidated the mechanisms underlying the first two processes, biomechanical processes driving the postfiltration phagocytosis of RBCs retained at interendothelial slits (IES) are still poorly understood. We present here a unique computational model of macrophages to study the role of cell biomechanics in modulating the kinetics of phagocytosis of aged and diseased RBCs retained in the spleen. After validating the macrophage model using in vitro phagocytosis experiments, we employ it to probe the mechanisms underlying the kinetics of phagocytosis of mechanically altered RBCs, such as heated RBCs and abnormal RBCs in hereditary spherocytosis (HS) and sickle cell disease (SCD). Our simulations show pronounced deformation of the flexible and healthy RBCs in contrast to minimal shape changes in altered RBCs. Simulations also show that less deformable RBCs are engulfed faster and at lower adhesive strength than flexible RBCs, consistent with our experimental measurements. This efficient sensing and engulfment by macrophages of stiff RBCs retained at IES are expected to temper splenic congestion, a common pathogenic process in malaria, HS, and SCD. Altogether, our combined computational and in vitro experimental studies suggest that mechanical alterations of retained RBCs may suffice to enhance their phagocytosis, thereby adapting the kinetics of their elimination to the kinetics of their mechanical retention, an equilibrium essential for adequately cleaning the splenic filter to preserve its function.

CriteriaMapper: establishing the automatic identification of clinical trial cohorts from electronic health records by matching normalized eligibility criteria and patient clinical characteristics

The use of electronic health records (EHRs) holds the potential to enhance clinical trial activities. However, the identification of eligible patients within EHRs presents considerable challenges. We aimed to develop a CriteriaMapper system for phenotyping eligibility criteria, enabling the identification of patients from EHRs with clinical characteristics that match those criteria. We utilized clinical trial eligibility criteria and patient EHRs from the Mount Sinai Database. The CriteriaMapper system was developed to normalize the criteria using national standard terminologies and in-house databases, facilitating computability and queryability to bridge clinical trial criteria and EHRs. The system employed rule-based pattern recognition and manual annotation. Our system normalized 367 out of 640 unique eligibility criteria attributes, covering various medical conditions including non-small cell lung cancer, small cell lung cancer, prostate cancer, breast cancer, multiple myeloma, ulcerative colitis, Crohn’s disease, non-alcoholic steatohepatitis, and sickle cell anemia. About 174 criteria were encoded with standard terminologies and 193 were normalized using the in-house reference tables. The agreement between automated and manual normalization was high (Cohen’s Kappa = 0.82), and patient matching demonstrated a 0.94 F1 score. Our system has proven effective on EHRs from multiple institutions, showing broad applicability and promising improved clinical trial processes, leading to better patient selection, and enhanced clinical research outcomes.

The Current Role of Hydroxyurea in the Treatment of Sickle Cell Anemia.

Despite advancements in treatment of sickle cell disease (SCD), hydroxyurea, a ribonucleotide reductase inhibitor, remains the cornerstone of therapy. While its primary effect is the elevation of fetal hemoglobin (HbF), hydroxyurea's mechanisms of action are multifaceted. Hydroxyurea (HU) reduces leukocyte and platelet counts, decreases the expression of endothelial adhesion molecules CD36 and CD49d, and increases nitric oxide and cyclic nucleotide levels, which may facilitate vascular dilation and further HbF induction. Numerous studies have demonstrated that hydroxyurea therapy reduces the frequency of painful episodes, acute chest syndrome, and the need for erythrocyte transfusions and hospitalizations. Long-term use of hydroxyurea leads to reduced morbidity and mortality. Hydroxyurea should be initiated in children from 9 months of age, including asymptomatic individuals, and is recommended for adults experiencing pain crises that significantly interfere with daily activities or quality of life, as well as those with severe or recurrent vaso-occlusive crises, ACS, or severe symptomatic anemia. Hydroxyurea is not recommended during pregnancy or lactation due to potential teratogenic effects and transfer into breast milk. However, its use may be considered in high-risk patients, particularly during the second and third trimesters. Concerns about secondary tumor development have not been substantiated in long-term follow-up studies. Alternative therapies, including L-glutamine, crizanlizumab, and voxelotor, are not presently approved or available for clinical use in Europe.

Clinical burden and healthcare resource utilization associated with managing sickle cell disease with recurrent vaso-occlusive crises in France

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

Advanced Bio-sensing Technologies for Sickle Cell Disease Diagnosis.

Sickle cell diseases are widespread in regions encompassing the Mediterranean, Middle East, sub-Saharan Africa, and specific parts of Asia, primarily due to the abnormal production of hemoglobin S. This genetic blood disorder stems from a mutation in the beta-globin gene, a crucial component of hemoglobin and the heme-containing protein found in red blood cells. Point mutations in the hemoglobin gene can be inherited as a heterozygous or homozygous pattern. These mutations disrupt the normal configuration of the protein, impeding its physiological function and altering the cell's shape, giving it a sickle-like appearance. The resulting sickle cells can lead to organ damage, intense physical discomfort, and anemia; in severe cases, the condition can be fatal. Early detection and effective treatment methods have the potential to progressively reduce the associated mortality rate over time. To diagnose sickle cell disease and its carrier states with unparalleled specificity, a variety of approaches have been developed. The most common method includes differential blood cell counts and their assessment, high-performance liquid chromatography (HPLC) and hemoglobin electrophoresis. Furthermore, innovative sensing technologies are currently under development, encompassing user-friendly, cost-effective and portable point-of-care devices that are capable of timely diagnosis at the genetic and molecular levels of these disorders. The review delves into a range of established and innovative strategies utilized in the detection of sickle cell disease, also underscoring the essential role played by diverse bio-sensing techniques in propelling the advancement of early diagnosis of SCD.

Posterior cerebral circulation in children with sickle cell anemia: an uncharted territory.

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Sonographic Assessment of Splenic Manifestations in Sickle Cell Disease Patients and Its Relation to Hematological Parameters: A Cross-Sectional Study in Basra, Iraq

Sonographic Assessment of Splenic Manifestations in Sickle Cell Disease Patients and Its Relation to Hematological Parameters: A Cross-Sectional Study in Basra, Iraq

What Interval of Daily Pain Assessment is Required to Reliably Diagnose Chronic Pain in Sickle Cell Disease? The PiSCES Project

Abstract Background Chronic pain in sickle cell disease has been defined as pain on most days over 6 months. In the landmark Pain in Sickle Cell Epidemiology Study, 60% of patients submitted < 5 of the expected 6 months of pain diaries. Identifying chronic SCD pain using this long daily assessment interval is impractical. We therefore examined whether shorter, less burdensome intervals could accurately identify chronic sickle cell disease pain. Method As the gold-standard sample, we chose the 116 Pain in Sickle Cell Epidemiology Study patients who submitted > 5 months of diaries (153) and >49% of diaries during all months from 1-4. Using the same dataset, we tested daily diary assessment over shorter intervals: 2 weeks, 1 month, 2 months, 3 months, and 4 months. We defined chronic pain as intensity rated as > 0 on > 50% of diary days, regardless of interval. We then calculated the sensitivity and specificity of each diary interval. Results Among the gold-standard sample, 51.3% of patients had diary-defined chronic pain. Collection intervals of two months or more yielded similar chronic pain prevalences with identically high sensitivity (98.3%) and specificity (93%). Intervals of one month and two weeks yielded increasingly lower specificity (80.7%, 73.7% respectively), but preserved sensitivity (≥96.6%). Conclusion In the Pain in Sickle Cell Epidemiology Study, intervals of two months or more of daily diary collection yielded high sensitivity and specificity, compared to an interval of 5-6 months. One may reasonably diagnose chronic sickle cell disease pain using two months of daily diaries.

Genetic Polymorphisms Associated with Fetal Hemoglobin (HbF) Levels and F-Cell Numbers: A Systematic Review of Genome-Wide Association Studies.

Elevated fetal hemoglobin (HbF), which is partly controlled by genetic modifiers, ameliorates disease severity in β hemoglobinopathies. Understanding the genetic basis of this trait holds great promise for personalized therapeutic approaches. PubMed, MedRxiv, and the GWAS Catalog were searched up to May 2024 to identify eligible GWAS studies following PRISMA guidelines. Four independent reviewers screened, extracted, and synthesized data using narrative and descriptive methods. Study quality was assessed using a modified version of the Q-Genie tool. Pathway enrichment analysis was conducted on gene lists derived from the selected GWAS studies. Out of 113 initially screened studies, 62 underwent full-text review, and 16 met the inclusion criteria for quality assessment and data synthesis. A total of 939 significant SNP-trait associations (p-value < 1 × 10-5) were identified, mapping to 133 genes (23 with overlapping variant positions) and 103 intergenic sequences. Most SNP-trait associations converged around BCL11A (chr.2), HBS1L-MYB, (chr.6), olfactory receptor and beta globin (HBB) gene clusters (chr.11), with less frequent loci including FHIT (chr.3), ALDH8A1, BACH2, RPS6KA2, SGK1 (chr.6), JAZF1 (chr.7), MMP26 (chr.11), COCH (chr.14), ABCC1 (chr.16), CTC1, PFAS (chr.17), GCDH, KLF1, NFIX, and ZBTB7A (chr.19). Pathway analysis highlighted Gene Ontology (GO) terms and pathways related to olfaction, hemoglobin and haptoglobin binding, and oxygen carrier activity. This systematic review confirms established genetic modifiers of HbF level, while highlighting less frequently associated loci as promising areas for further research. Expanding research across ethnic populations is essential for advancing personalized therapies and enhancing outcomes for individuals with sickle cell disease or β-thalassemia.

Achieving RoutIne Screening for Emotional health (ARISE) in pediatric subspecialty clinics.

This study aims to describe the experience of implementing a psychosocial distress screening system for children with serious or chronic medical conditions. Achieving RoutIne Screening for Emotional health (ARISE) was developed to systematically evaluate psychosocial distress in children with serious medical or chronic medical illnesses, by integrating patient-reported outcome measures (PROM) into care delivery. ARISE was developed using a user-centered approach with extensive input from patients, families, and healthcare professionals to overcome barriers to routine PROM collection and integration into care as usual. It comprises a system to capture PROMs and then relay results to clinicians for changing care. We sought to implement ARISE at four subspecialty pediatric clinics caring for patients with cystic fibrosis, sickle cell disease, hemophilia, and neurological malignancy. Problems with acceptability, appropriateness, and feasibility represented barriers to implementation which were overcome by modifying the intervention using stakeholder input during the planning phase, leading to broad program acceptance. ARISE was implemented in three of the four clinics, in which 79.8% of eligible children and their family completed PROMs. The ARISE program demonstrated the feasibility and effectiveness of integrating psychosocial screenings into subspecialty pediatric clinics, thereby enhancing the identification and management of psychosocial issues in children with serious and chronic medical illnesses.

Alendronate preserves bone mineral density in adults with sickle cell disease and osteoporosis.

To describe the effects of alendronate in adults with sickle cell disease (SCD) and osteoporosis. We reviewed retrospective clinical data from adults with SCD and osteoporosis treated with alendronate at a single center in Brazil (2009-2019). Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) of the lumbar spine, femoral neck, and total hip. We analyzed BMD changes by alendronate treatment duration (months), stratified by sex, skeletal site, and SCD genotype. Sixty-four SCD adults with osteoporosis (69% females, 73% HbSS, mean age ± standard deviation 42.4 ± 10.9years) received alendronate for a median (interquartile range) of 48 (29, 73) months. Compared with males, females had significantly lower baseline BMD (g/cm2) at the femoral neck (0.72 vs 0.85, p = < 0.001) and total hip (0.79 vs 0.88, p = 0.009). The between-sex differences in BMD changes were insignificant. Mean lumbar spine BMD significantly changed by 0.0357g/cm2 (p = 0.028) in those on alendronate for > 5years. Four adults (6.3%) reported mild therapy-related side effects. An atypical femoral diaphysis fracture, attributed to alendronate, was incidentally noted in a 37-year-old man on treatment for 4years. In this retrospective cohort of adults with SCD and osteoporosis on alendronate for a median of 48months, we found no significant interactions between sex and changes in lumbar spine, femoral neck, or total hip BMD with alendronate. Lumbar spine BMD was stable in those on alendronate for < 5years. Side effects of alendronate were mild, though one patient developed an atypical femoral fracture.

Quality of life in people with sickle cell disease treated with automated red blood cell exchange.

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

A machine learning-based workflow for predicting transplant outcomes in patients with sickle cell disease.

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

Evaluation of Haemoglobin F and Haemoglobin A2 among Sickle Cell Patients in Steady State at Selected Hospital in Ogun State, Nigeria

Background: Sickle cell anemia (SCA) is a genetic disorder characterized by abnormal hemoglobin variants, including hemoglobin F (Hb F) and hemoglobin A2 (Hb A2). Evaluating the levels of these hemoglobin variants in steady-state sickle cell patients can provide insights into disease prognosis and management. This study aimed to assess Hb F and Hb A2 levels among sickle cell patients in steady state at a selected hospital in Ogun State, Nigeria. Objective: To evaluate the levels of hemoglobin F (Hb F) and hemoglobin A2 (Hb A2) in sickle cell anemia patients and determine their associations with demographic factors such as age and gender. Materials and methods: A descriptive cross-sectional study was conducted at the Sickle Cell Center, Abeokuta, Ogun State, Nigeria, from September to October 2020. A total of 60 sickle cell patients in steady state were recruited using convenient sampling. Blood samples were collected, and Hb F and Hb A2 levels were measured using high-performance liquid chromatography (HPLC). Data were analyzed using SPSS version 26.0 with independent t-test and bivariate correlation. Results: The mean levels of Hb F and Hb A2 varied across age groups and genders. Hb F levels were highest in patients over 35 years (10.4 ± 12.16%) and lowest in those aged 26-30 years (3.7 ± 1.3%). The majority of participants had Hb F levels between 2-10%, with a significant association between Hb F levels and age (p = 0.038). Hb A2 levels were consistently above 3.1% in 92.6% of the study population, with no significant association with age or gender. Conclusion: There is a significant association between age and Hb F levels among steady-state sickle cell patients, while Hb A2 levels showed no significant demographic correlations. The findings suggest that Hb F may serve as a potential marker for clinical evaluation in SCA patients.

Migration Medicine: infectious and non-infectious diseases

Approximately one third of the German population has a migration background.According to the federal office for migration, in 2022 around 2,7 million people have taken refuge or have immigrated to Germany, causing major challenges for our health system. In this article, important infectious diseases, and non-infectious conditions like hemoglobinopathies are presented. To date, especially the latter are not common in Germany and must therefore move more into focus when taking care of migrants. Furthermore, new treatment options for hemoglobinopathies have been approved in the last couple of years, starting with the introduction of Luspatercept a few years ago for Beta-Thalassemias and in 2023 the introduction of Voxelotor for sickle cell disease. In 2024 the gene therapy with Exagamglogen-Autotemcel using the CRISPR/Cas molecular scissor was authorized as a new promising treatment for both conditions.

Scientometrics Analysis of Global Researches on Anemia

Background: Anemia is a condition in which the number of red blood cells or the hemoglobin concentration within them is lower than normal. This study aims to show the intellectual structure of knowledge regarding anemia and gives a comprehensive and up-to-date image of research in this area. Materials and Methods: This is a descriptive-analytical study with a scientometric approach. The PubMed database was searched for research publications indexed under "anemia" including 8484 records between 2011 and 2020. Data were analyzed using Co-word analysis, clustering methods, and strategic diagrams with the help of SPSS and Ucinet 6 software. Results: The keyword “Anemia Sickle Cell” and two pairs of frequently used keywords, namely “Anemia, Iron *Iron” were the most frequent in the research area. The results shaped the concepts of anemia in 9 clusters. The clusters "Hydroxyurea and sickle cell anemia", "Fetus transfusion", "Management of Thalassemia Major", "Hemolytic Uremic Syndrome", "Management and Control of Anemia", "Chronic Kidney Failure and Anemia", "Hematopoietic Stem Cell Transplantation" are topics that may be emerging or disappearing. The “Thalassemia and blood transfusion" are immature clusters. Conclusion: This study uses co-word networks that indicate important links between keywords of the research areas. Most research approaches are in the therapeutic aspects. Despite the importance of the effect of anemia on all levels of society, including economics, education, and other types of anemia, as well as its impact on learning and mental disorders, these subjects have not been given sufficient consideration.

Pica in sickle cell disease: nutritional management and implications

Background: Individuals with sickle cell disease (SCD) frequently experience nutritional disturbances, including deficiencies in essential micronutrients. Iron and zinc deficiency anemia has been specifically associated with pica, an atypical eating behavior. Aims: This systematic review aimed to characterize pica among individuals with SCD, focusing on potential nutritional causes. Methods: A comprehensive literature search was conducted across the MEDLINE (PubMed), Latin American and Caribbean Center on Health Sciences Information (Bireme), and Google Scholar databases from July 2017 to January 2024. Eligible articles included original observational studies, interventions, and case reports involving individuals with SCD across all age groups. Literature reviews, doctoral or master's theses, unrelated studies, and duplicate publications were excluded. Results: Ten studies were selected that described the occurrence of pica episodes in the SCD population and explored potential associated nutritional causes. The most prevalent genotype was Hb SS, with ages ranging from 2 to 23 years. Males were more predominant than females in the included studies. Approximately 51.05% of the studied population exhibited pica behavior. Some studies observed that children with pica behavior had low weight and/or height and abnormal laboratory test results. The most commonly consumed objects were paper, foam, fabric, dust, soil, clay, and rubber, although the quantity and frequency of object consumption were not reported in most studies. The most reported symptoms associated with pica behavior included abdominal pain, vomiting, constipation, vaso-occlusive events, dizziness, and fatigue. Clinical interventions in the studies were pain medication, intestinal cleansing, intestinal resection, intravenous hydration, antibiotic therapy, gastric "bezoar" removal, and cognitive-behavioral therapy. The majority of the studied population was monitored by health centers, with frequent return visits. In all studies, physicians were responsible for clinical care. Conclusion: A significant association between SCD and pica was evident in the reviewed studies. Iron and zinc deficiencies emerged as potential contributing factors to this atypical eating behavior. Keywords: Pica, sickle cell disease, iron, zinc, eating disorders.