bims-sicedi Biomed News
on Sickle cell disease
Issue of 2024–10–06
fourteen papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Therapeutics for sickle cell disease intravascular hemolysis.
  2. The spectrum of sickle cell disease.
  3. Gene-environmental influence of space and microgravity on red blood cells with sickle cell disease.
  4. How I Treat Sickle Cell Disease with Gene Therapy.
  5. Potassium dynamics in sickle cell anemia: clinical implications and pathophysiological insights.
  6. Targeting ICAM1 to Ameliorate Vaso-Occlusion and Inflammation in Sickle Cell Disease.
  7. Advancing life: innovative approaches to enhance survival in sickle cell anemia patients.
  8. Non-invasive optical and laboratory hematologic biomarkers correlate in patients with sickle cell disease.
  9. How do we manage hyperhemolysis syndrome.
  10. Adverse clinical outcomes associated with sickle cell trait at high altitude.
  11. Lung ultrasound score to predict development of acute chest syndrome in children with sickle cell disease.
  12. Sickle cell drug is withdrawn over safety concerns just months after rollout.
  13. Social Vulnerability and Sickle Cell Disease Mortality in the US.
  14. Dengue Fever in a Sickle Cell-Positive Pregnant Woman: A Case Report.
  1. Front Physiol. 2024 ;15 1474569
    Therapeutics for sickle cell disease intravascular hemolysis.
    Jianyao Xue, Xiang-An Li.
      Sickle cell disease (SCD) is a genetic disorder predominantly affecting individuals of African descent, with a significant global health burden. SCD is characterized by intravascular hemolysis, driven by the polymerization of mutated hemoglobin within red blood cells (RBCs), leading to vascular inflammation, organ damage, and heme toxicity. Clinical manifestations include acute pain crises, hemolytic anemia, and multi-organ dysfunction, imposing substantial morbidity and mortality challenges. Current therapeutic strategies mitigate these complications by increasing the concentration of RBCs with normal hemoglobin via transfusion, inducing fetal hemoglobin, restoring nitric oxide signaling, inhibiting platelet-endothelium interaction, and stabilizing hemoglobin in its oxygenated state. While hydroxyurea and gene therapies show promise, each faces distinct challenges. Hydroxyurea's efficacy varies among patients, and gene therapies, though effective, are limited by issues of accessibility and affordability. An emerging frontier in SCD management involves harnessing endogenous clearance mechanisms for hemolysis products. A recent work by Heggland et al. showed that CD-36-like proteins mediate heme absorption in hematophagous ectoparasite, a type of parasite that feeds on the blood of its host. This discovery underscores the need for further investigation into scavenger receptors (e.g., CD36, SR-BI, SR-BII) for their possible role in heme uptake and detoxification in mammalian species. In this review, we discussed current SCD therapeutics and the specific stages of pathophysiology they target. We identified the limitations of existing treatments and explored potential future developments for novel SCD therapies. Novel therapeutic targets, including heme scavenging pathways, hold the potential for improving outcomes and reducing the global burden of SCD.
    Keywords:  heme toxicity; hemolysis; scavenging receptors; sickle cell disease; transfusion
    DOI:  https://doi.org/10.3389/fphys.2024.1474569
  2. Am J Hematol. 2024 Oct 01.
    The spectrum of sickle cell disease.
    Barbara J Bain.
      
    DOI:  https://doi.org/10.1002/ajh.27494
  3. NPJ Genom Med. 2024 Sep 30. 9(1): 44
    Gene-environmental influence of space and microgravity on red blood cells with sickle cell disease.
    Norris E Igbineweka, Jack J W A van Loon.
      A fundamental question in human biology and for hematological disease is how do complex gene-environment interactions lead to individual disease outcome? This is no less the case for sickle cell disease (SCD), a monogenic disorder of Mendelian inheritance, both clinical course, severity, and treatment response, is variable amongst affected individuals. New insight and discovery often lie between the intersection of seemingly disparate disciplines. Recently, opportunities for space medicine have flourished and have offered a new paradigm for study. Two recent Nature papers have shown that hemolysis and oxidative stress play key mechanistic roles in erythrocyte pathogenesis during spaceflight. This paper reviews existing genetic and environmental modifiers of the sickle cell disease phenotype. It reviews evidence for erythrocyte pathology in microgravity environments and demonstrates why this may be relevant for the unique gene-environment interaction of the SCD phenotype. It also introduces the hematology and scientific community to methodological tools for evaluation in space and microgravity research. The increasing understanding of space biology may yield insight into gene-environment influences and new treatment paradigms in SCD and other hematological disease phenotypes.
    DOI:  https://doi.org/10.1038/s41525-024-00427-7
  4. Blood. 2024 Oct 02. pii: blood.2024024519. [Epub ahead of print]
    How I Treat Sickle Cell Disease with Gene Therapy.
    Akshay Sharma.
      In 2023, two different gene therapies were approved for individuals with severe sickle cell disease (SCD). The small number of patients treated on the pivotal clinical trials that led to these approvals have experienced dramatic short-term reductions in the occurrence of painful vaso-occlusive crises, but the long-term safety and efficacy of these genetic therapies are yet to be ascertained. Several challenges and treatment-related concerns have emerged in regard to administering these therapies in clinical practice. In this article, I discuss the selection and preparation of individuals with SCD who wish to receive autologous gene therapies. I also review salient features of the care needed to support them through the long and arduous treatment process. I specifically focus on post-infusion care, as it relates to immune monitoring and infection prevention. Compared with allogeneic hematopoietic cell transplantation, delivering autologous gene therapy to an individual with SCD has distinct nuances that require awareness and special interventions. Using clinical vignettes derived from real-life patients, I provide perspectives on the complex decision-making process for gene therapy for SCD, based on currently available data, and I make recommendations for evaluating and supporting these patients.
    DOI:  https://doi.org/10.1182/blood.2024024519
  5. Ann Med Surg (Lond). 2024 Oct;86(10): 6037-6045
    Potassium dynamics in sickle cell anemia: clinical implications and pathophysiological insights.
    Emmanuel Ifeanyi Obeagu.
      Potassium dynamics are critical in the pathophysiology of sickle cell anemia (SCA), a genetic disorder characterized by the presence of abnormally shaped red blood cells that lead to various complications such as vaso-occlusive crises and hemolytic anemia. This review focuses on the clinical implications and pathophysiological insights of potassium regulation in SCA, highlighting its impact on disease progression and potential therapeutic strategies. The dysregulation of potassium transport in SCA leads to significant K+ efflux and cellular dehydration, exacerbating the sickling process. Dehydrated sickle cells, due to potassium loss, become more rigid and prone to causing blockages in small blood vessels, leading to painful vaso-occlusive crises and ischemia. Furthermore, chronic hemolysis in SCA, aggravated by potassium imbalance, contributes to severe anemia and systemic complications. These insights underscore the importance of maintaining potassium homeostasis to mitigate disease severity and improve patient outcomes. Therapeutic strategies targeting potassium regulation show promise in managing SCA. Inhibitors of the Gardos channel, such as senicapoc, have demonstrated potential in reducing sickling and hemolysis. Additionally, hydration therapy plays a crucial role in maintaining electrolyte balance and preventing RBC dehydration. A comprehensive approach that includes monitoring and correcting electrolyte imbalances, along with standard treatments like hydroxyurea and blood transfusions, is essential for effective disease management.
    Keywords:  cell dehydration; hemolytic anemia; potassium dynamics; sickle cell anemia; vaso-occlusion
    DOI:  https://doi.org/10.1097/MS9.0000000000002551
  6. Eur J Haematol. 2024 Oct 01.
    Targeting ICAM1 to Ameliorate Vaso-Occlusion and Inflammation in Sickle Cell Disease.
    Parul Gupta, Ravindra Kumar.
      Sickle cell disease (SCD) is a hereditary disorder characterized by vaso-occlusion, inflammation, and tissue damage. Intercellular adhesion molecule 1 (ICAM-1) plays a crucial role in the pathophysiology of SCD by promoting the adhesion of sickle cells to the endothelium, contributing to vaso-occlusion and tissue damage. The ICAM-1 gene encodes a glycoprotein that interacts with lymphocyte function-associated antigen 1 (LFA-1) and macrophage 1-antigen (Mac-1) receptors, perpetuating inflammation, and oxidative stress. The NF-κB signaling pathway regulates ICAM-1 expression, which is elevated in patients with SCD, leading to increased endothelial cell activation and damage. Targeting ICAM-1 and its interactions with sickle cells and the endothelium has emerged as a potential therapeutic strategy for managing SCD. This review highlights the complex interplay between ICAM-1, sickle cells, and the endothelium, and discusses the potential of ICAM-1-targeted therapies for mitigating VOC and improving the quality of life for patients with SCD.
    Keywords:  ICAM‐1; endothelium; inhibitor; sickle cell disease; vaso‐occlusive crisis
    DOI:  https://doi.org/10.1111/ejh.14313
  7. Ann Med Surg (Lond). 2024 Oct;86(10): 6021-6036
    Advancing life: innovative approaches to enhance survival in sickle cell anemia patients.
    Emmanuel Ifeanyi Obeagu, Teddy Charles Adias, Getrude Uzoma Obeagu.
      Sickle cell anemia (SCA) is a severe genetic disorder characterized by the production of abnormal hemoglobin S, leading to the formation of sickle-shaped red blood cells that cause chronic anemia, pain, and organ damage. This review explores recent innovative strategies aimed at improving survival rates and quality of life for SCA patients. Genetic therapies, particularly gene editing with CRISPR-Cas9 and gene therapy using lentiviral vectors, have shown significant potential in correcting the genetic defects responsible for SCA. Clinical trials demonstrate that these approaches can reduce sickle cell crises and minimize the need for blood transfusions by enabling the production of healthy red blood cells. Novel pharmacological treatments such as voxelotor, crizanlizumab, and L-glutamine provide additional mechanisms to prevent hemoglobin polymerization, reduce vaso-occlusive episodes, and decrease oxidative stress, respectively. These therapies offer new hope for patients, particularly those who do not respond adequately to existing treatments. Improved blood transfusion protocols, including automated red cell exchange and advanced donor-matching techniques, have enhanced the safety and efficacy of transfusions, reducing complications like alloimmunization. Comprehensive care models, integrating multidisciplinary care teams, patient education, and telemedicine, have further contributed to better disease management. By providing holistic care that addresses both medical and psychosocial needs, these models improve patient adherence to treatment and overall health outcomes. This review highlights the importance of these innovative strategies and calls for continued research and development to sustain and expand these advancements in SCA care.
    Keywords:  blood transfusions; genetic therapies; medical interventions; mortality rates; sickle cell anemia
    DOI:  https://doi.org/10.1097/MS9.0000000000002534
  8. Biomed Opt Express. 2024 Aug 01. 15(8): 4829-4841
    Non-invasive optical and laboratory hematologic biomarkers correlate in patients with sickle cell disease.
    Timothy Quang, Golnar Mostashari, Elise Berning, Bindu Parachalil Gopalan, Maria A Lizarralde-Iragorri, Dianna Lovins, Arun S Shet, Bruce J Tromberg.
      The goal of this study is to identify non-invasive optical hemodynamic biomarkers that can index laboratory hematology measurements in sickle cell disease (SCD). We acquired frequency-domain NIRS (FD-NIRS) and diffuse correlation spectroscopy (DCS) data from the forearms and foreheads of 17 participants in a randomized, double-blind, placebo-controlled trial evaluating effects of isoquercetin (IQ) on thromboinflammation in SCD. We observed multiple, significant correlations between optical and hematology biomarkers including cerebral tissue oxygen saturation (StO2) and hematocrit (HCT); oxyhemoglobin ([O2Hb]) recovery rate and intercellular adhesion molecule 1 (ICAM-1); and blood flow index (BFI) reperfusion rate and coagulation index (CI). The potential of these non-invasive optical biomarkers for assessing vascular pathophysiology for the management of SCD warrants further exploration.
    DOI:  https://doi.org/10.1364/BOE.527770
  9. Transfusion. 2024 Oct 03.
    How do we manage hyperhemolysis syndrome.
    Brian D Adkins, Samer Z Kaylani, Alecia Nero, Ibrahim F Ibrahim, Yu-Min Shen, Ravindra Sarode.
       BACKGROUND: Hyperhemolysis syndrome (HHS) is a catastrophic anemia characterized by destruction of both donor and patient red blood cells (RBC). HHS occurs after transfusion and can cause significant morbidity and mortality. Given the difficulty in diagnosing and managing this process, we provide a detailed overview of our treatment protocol.
    STUDY DESIGN AND METHODS: Members of the Transfusion Medicine and Hematology faculty at our institution collaborated in an iterative process to produce a consensus approach to patients with HHS.
    RESULTS: We present diagnostic criteria for HHS: recent transfusion within past 7 days (up to 21 days), rapid hemoglobin decline to below the pretransfusion level (usually hemoglobin drop >25% from pretransfusion), a significant decrease in HbA% (in patients with sickle cell disease or beta thalassemia), low or decreasing reticulocyte count in a patient with worsening anemia, and laboratory evidence of hemolysis. We also describe an in-depth approach to management focusing on optimizing hematopoiesis while dampening the immune response.
    CONCLUSION: We provide a comprehensive approach to the diagnosis and management of HHS based on contemporary literature and clinical experience designed to optimize outcomes for patients.
    Keywords:  RBC transfusion; hematology – red cells; transfusion complications‐non infectious
    DOI:  https://doi.org/10.1111/trf.17995
  10. Haematologica. 2024 Oct 03.
    Adverse clinical outcomes associated with sickle cell trait at high altitude.
    Katherine A Stafford, Soravis Osataphan, Rushad Patell, Nigel S Key.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2024.285832
  11. Hematol Transfus Cell Ther. 2024 Sep 23. pii: S2531-1379(24)00322-5. [Epub ahead of print]
    Lung ultrasound score to predict development of acute chest syndrome in children with sickle cell disease.
    Pedro P M G Vieira, Josefina A P Braga, Rodrigo Regacini.
       OBJECTIVE: This study aims to identify lung ultrasound (LUS) findings associated with acute chest syndrome (ACS) at the time of admission and 24-48 h later, to compare these to chest radiography (CXR) findings and to establish a score to predict the development of this pulmonary complication in sickle cell disease (SCD) children METHODS: A prospective observational study of SCD children presenting signs or symptoms of ACS evaluated by LUS and CXR at admission and 24-48 h later. A score was conceived to predict the evolution of ACS during hospitalization based on ultrasonographic findings.
    RESULTS: Seventy-eight children were evaluated; 61 (78.2 %) developed ACS. A score greater than one at admission showed sensitivity, specificity, accuracy, and positive predictive value (PPV) of 75.4 %, 88.2 %, 78.2 %, and 95.8 %, respectively to predict ACS, while only 32 (52.5 %) CXR showed alterations. The development of ACS during hospitalization was unlikely for a score of zero and very likely for a score greater than one at admission. Regarding follow-up exams, a score greater than one showed sensitivity, specificity, accuracy, and PPV of 98.4 %, 76.5 %, 93.6 %, and 92.8 %, respectively to predict the development of ACS. ACS development was very unlikely for a score of zero and very likely for a score greater than zero in the follow-up.
    CONCLUSION: LUS is an effective tool to assess risk for the development of ACS in SCD children with clinical suspicion.
    Keywords:  Acute chest syndrome; Children; Lung ultrasound; Pediatrics; Point of care ultrasound; Sickle cell disease
    DOI:  https://doi.org/10.1016/j.htct.2024.07.003
  12. BMJ. 2024 10 01. 387 q2147
    Sickle cell drug is withdrawn over safety concerns just months after rollout.
    Elisabeth Mahase.
      
    DOI:  https://doi.org/10.1136/bmj.q2147
  13. JAMA Netw Open. 2024 Sep 03. 7(9): e2440599
    Social Vulnerability and Sickle Cell Disease Mortality in the US.
    Jia Yi Tan, Boon Jian San, Yong-Hao Yeo, Kok Hoe Chan, Hamid S Shaaban, Daniel E Ezekwudo, Modupe Idowu.
       Importance: Social determinants of health (SDOH) influence health outcomes, including those of sickle cell disease (SCD), despite advancements in treatments like disease-modifying therapies.
    Objective: To investigate the association of SDOH with SCD mortality rates from 2016 to 2020.
    Design, Setting, and Participants: This cross-sectional study combined county-level data from the Centers for Disease Control and Prevention and Agency for Toxic Substances and Disease Registry Social Vulnerability Index (SVI) with SCD mortality data from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database from January 1, 2016, to December 31, 2020. US counties were divided into 4 quartile (Q) models according to their SVI scores. Deaths from SCD in the US among patients of all ages were included. Data analysis occurred from March to April 2024.
    Exposure: SVI score.
    Main Outcomes and Measures: Age-adjusted mortality rates (AAMRs) per 1 000 000 individuals were measured. Rate ratios (RRs) were obtained by comparing county-specific AAMRs of SVI-Q4 with SVI-Q1.
    Results: From 2016 to 2020, among a total population of 1 633 737 771 individuals, there were 2635 deaths from SCD (1289 male [49.1%] and 1336 female [50.9%]). There were 1480 deaths in Q4, 687 deaths in Q3, 344 deaths in Q2, and 114 deaths in Q1. Higher SVI was associated with 2.11 excess deaths per 1 000 000 individuals (RR, 4.90; 95% CI, 4.81-5.00). Similar trends were seen for both males (RR, 4.56; 95% CI, 4.44-4.69) and females (RR, 5.85; 95% CI, 5.68-6.03). Middle-aged patients with SCD had the highest mortality rate in Q4, with 3.45 excess deaths per 1 000 000 individuals (RR, 4.97; 95% CI, 4.85-5.09). Higher SVI was associated with 2.29 excess deaths per 1 000 000 individuals in African American individuals with SCD (RR, 1.24; 95% CI, 1.22-1.27]). In White individuals with SCD, higher SVI was associated with 0.12 excess deaths per 1 000 000 individuals (RR not available due to unreliable data in Q1). When stratifying by census region, the highest level of SCD-related mortality was in the Northeast, with higher SVI associated with 3.16 excess deaths per 1 000 000 individuals (RR, 8.02; 95% CI, 7.66-8.40).
    Conclusions: In this cross-sectional study of the association of SVI with SCD mortality rates, higher SVI was associated with higher SCD mortality across US counties. These findings underscore the importance of addressing social determinants of health to improve mortality outcomes among patients with SCD.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2024.40599
  14. Cureus. 2024 Aug;16(8): e67966
    Dengue Fever in a Sickle Cell-Positive Pregnant Woman: A Case Report.
    Lucky Srivani Reddy, Manjusha Agrawal, Arpita Jaiswal, Deepika Dewani, Rishabh Dhabalia, Shaikh Muneeba.
      Cases of sickle cell disease with dengue during pregnancy have rarely been reported. Sickle cell disorder is one of the most commonly inherited genetic disorders, especially in certain regions of India. Sickle cell disease, especially in pregnancy, has varying clinical severity, which may potentially lead to serious complications, negatively affecting the maternal and fetal outcomes. Dengue is commonly seen in tropical countries. Serotypes 1, 2, 3, and 4 of the dengue virus cause dengue, an infection spread by Aedes aegypti mosquitos. A 24-year-old primigravida with 36 weeks of gestation, with a known case of sickle cell disease and a history of multiple blood transfusions, presented to the emergency department with a history of fever for four days associated with body pains and chills. Her fever profile was sent, and the patient was diagnosed with dengue. She was treated with packed red cell transfusion and conservatively managed. She went into spontaneous preterm labour and delivered a healthy female child. Pregnancy-related pathophysiological changes, such as elevated blood volume, elevated metabolic demand, elevated blood viscosity, and hypercoagulability, combined with dengue fever complications, cause sickle cell disease patients to experience a higher rate of morbidity and mortality.
    Keywords:  complications; dengue fever; dual diagnosis; haematological disorders; health challenges; immunity; sickle cell crisis; sickle cell disease; treatment strategies
    DOI:  https://doi.org/10.7759/cureus.67966
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