bims-sicedi 2025-09-07 papers

bims-sicedi

Biomed News

on Sickle cell disease

Issue of 2025–09–07
fourteen papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Adhesion molecules in focus: mechanistic pathways and therapeutic avenues in sickle cell vaso-occlusion - a narrative review.
Dual Assessment of the RBC Fraction Abnormally Retaining Mitochondria and of the RBC Mitochondrial Load Provides a New Clinical Parameter for Sickle Cell Disease Patients.
Use of Fructosamine for Glycemic Monitoring in Patients With Sickle Cell Disease and Diabetes: A Systematic Review.
Acupressure alleviates pain and clinical symptoms in patients with sickle cell disease.
Impact of red blood cell exchange on echocardiographic parameters among adults with sickle cell disease.
Acute chest syndrome (ACS) in sickle cell disease (SCD): pathogenesis and pharmacotherapies in early clinical development.
Analytical considerations affecting plasma free haemoglobin, the haemolysis index, and correlation with clinical outcomes in sickle cell disease.
Iron Deficiency in HbSC Disease Treated With Repetitive Phlebotomy Is Associated With Fewer Sickle Cell Disease-Related Complications.
Twin pregnancy in patients with sickle cell disease: A French cohort study.
Safety, Pharmacokinetics, and Pharmacodynamics of Osivelotor for Sickle Cell Disease: First-in-Human Studies in Healthy Participants and Patients.
Neutrophil gelatinase-associated lipocalin and fibrinogen-to-albumin ratio are indicators of kidney disease in sickle cell disease patients with microalbuminuria: a multicentre case-control study in Ghana.
The ASH Research Collaborative Sickle Cell Disease Research Network: Past, Present and Future.
Severe Hemolytic Phenotype in Children With Sickle Cell Anemia and Co-Inherited Red Blood Cell Variants.
Ten-year trends in opioid prescribing and vaso-occlusive crises in sickle cell disease: a population-based national cohort study (2011-2022).

Ann Med Surg (Lond). 2025 Sep;87(9): 5775-5783

Adhesion molecules in focus: mechanistic pathways and therapeutic avenues in sickle cell vaso-occlusion - a narrative review.

Emmanuel Ifeanyi Obeagu.

  Sickle cell disease (SCD) is a genetic disorder characterized by the presence of sickle-shaped red blood cells (sRBCs), which are prone to occluding small blood vessels, leading to severe pain and organ damage. One of the critical mechanisms driving vaso-occlusion in SCD is the interaction between sRBCs, leukocytes, platelets, and endothelial cells, mediated by adhesion molecules. These molecules, including intercellular adhesion molecule-1, vascular cell adhesion molecule-1, selectins, and integrins, play a significant role in promoting the adhesion of these cells to the vascular endothelium, exacerbating inflammation, and contributing to the obstruction of blood flow. Understanding how these adhesion molecules participate in the pathophysiology of vaso-occlusion offers valuable insights into potential therapeutic strategies to mitigate the impact of this debilitating condition. The role of adhesion molecules in SCD-induced vaso-occlusion has been well-documented, with multiple studies showing that their upregulation enhances the interaction between sickled and non-sickled cells and the endothelium. This interaction initiates a cascade of inflammatory responses that worsen microvascular occlusion, leading to tissue ischemia and chronic complications. The expression of adhesion molecules such as E-selectin, P-selectin, and integrins on both the endothelial surface and the sickle cell membrane is critical for the progression of these vaso-occlusive events. Inflammation-induced overexpression of these molecules increases cell adhesion, exacerbating the frequency and severity of vaso-occlusive crises and contributing to long-term organ damage in SCD patients.

Keywords:  adhesion molecules; endothelial dysfunction; inflammation; sickle cell disease; vaso-occlusion

DOI:  https://doi.org/10.1097/MS9.0000000000003619
EJHaem. 2025 Aug;6(4): e70130

Dual Assessment of the RBC Fraction Abnormally Retaining Mitochondria and of the RBC Mitochondrial Load Provides a New Clinical Parameter for Sickle Cell Disease Patients.

Eric Soupene, Hart Horneman, Mikail Alejandro, Kenzy Mohammed, Yaw Ofosu Nyansa Ansong-Ansongton, Angela Rivers.

Background: Mitochondria and other organelles are normally eliminated in a process called mitophagy during the maturation of hematopoietic precursors, leading to the release of enucleated red blood cells (RBCs) in circulation. In sickle cell disease (SCD), a significant fraction of the RBCs of patients abnormally retain mitochondria. This process increases the oxygen consumption rate and formation of reactive oxygen species, augmenting known pathways of hemolysis and playing a significant role in SCD pathophysiology. The retention of mitochondria in RBC is detectable by flow cytometry analysis of whole blood, but this approach does not quantify the number of mitochondria in individual cells.
Methods: Mitochondrial DNA was isolated from sorted RBC (106 cells) of a cohort of pediatric sickle patients (HbSS, n = 19; HbSC/HbSE, n = 8) and quantified by qPCR with a standard curve.
Results: The methodology is suitable for the clinical quantification of the severity of mitochondrial retention in RBC of individuals with SCD. The number of mitochondria in RBCs are obtained from quantification of the copy numbers of mtDNA (HbSS,x¯ = 21 copies/total RBC) and the mitochondria positive RBCs fraction is determined by flow cytometry ( HbSS,x¯ = 11%), which provides the number of mitochondria present in the population of RBCs retaining mitochondria ( HbSS,x¯ = 400 copies/positive RBC).
Conclusion: With this approach, future therapies that circumvent mitophagy defects could be assessed for their efficacy in reducing both the size of the RBC fraction retaining mitochondria and the mitochondrial load in each cell.

DOI: https://doi.org/10.1002/jha2.70130
Cureus. 2025 Jul;17(7): e89130

Use of Fructosamine for Glycemic Monitoring in Patients With Sickle Cell Disease and Diabetes: A Systematic Review.

Mohammed Gaffar Mohammed, Nada A Alsiddig, Lobna A Ibrahim Hag.

  Sickle cell disease is characterized by various forms of hemoglobin that interfere with hemoglobin A1c (HbA1c) testing, which is commonly used to diagnose and monitor diabetes. This interference puts patients with sickle cell disease at risk of inaccurate monitoring and misdiagnosis due to improperly planned HbA1c testing. Despite awareness of these issues, there is still disagreement regarding the most appropriate method of measuring HbA1c in patients with sickle cell disease, along with a lack of clear guidance on using fructosamine as an alternative marker in patients with diabetes and sickle cell disease. We employed a systematic review technique to assess the efficacy of fructosamine in diagnosing and monitoring diabetes in patients with sickle cell disease. The study showed that fructosamine is highly associated with fasting blood glucose levels in patients with sickle cell trait, and even more so in those with sickle cell disease and poorly controlled diabetes. It also demonstrated a fair association with HbA1c, as measured by some of the recommended instruments for use in patients with sickle cell disease. These results suggest that fructosamine can play a valuable role in managing diabetes in patients with sickle cell trait and disease, along with HbA1c, as HbA1c is widely used to monitor diabetes, even in patients with diseases that might affect the accuracy of HbA1c measurement.

Keywords:  fructosamine and haemoglobin a1c in sickle cell; fructosamine in diabetes; fructosamine in diabetes with sickle cell; fructosamine in sickle cell patient; hyperglycemia and fructosamine; sickle cell anemia

DOI:  https://doi.org/10.7759/cureus.89130
Blood Adv. 2025 Sep 03. pii: bloodadvances.2025016995. [Epub ahead of print]

Acupressure alleviates pain and clinical symptoms in patients with sickle cell disease.

Lina Houran, Andrew Q Pucka, Mio Jiang, Ziyue Liu, Andrew Rw O'Brien, Steven E Harte, Richard E Harris, Zahra Pakbaz, Ying Wang.

DOI: https://doi.org/10.1182/bloodadvances.2025016995
Br J Haematol. 2025 Sep 02.

Impact of red blood cell exchange on echocardiographic parameters among adults with sickle cell disease.

Jules Mercier-Ross, Renata Bahous, Marie-Claude Beaulieu, Arman Sarshoghi, Denis Soulières, Stéphanie Forté, Brian J Potter.



Keywords:  echocardiography; pulmonary hypertension; red blood cell exchange; sickle cell disease; tricuspid regurgitant jet velocity

DOI:  https://doi.org/10.1111/bjh.70120
Expert Opin Investig Drugs. 2025 Aug 31. 1-9

Acute chest syndrome (ACS) in sickle cell disease (SCD): pathogenesis and pharmacotherapies in early clinical development.

Subarna Chakravorty, Anne Greenough.

   INTRODUCTION: Sickle cell disease (SCD) is a monogenic disorder caused by a point mutation in the HBB gene, leading to the production of sickle hemoglobin (HbS). Under hypoxic or acidic conditions, HbS polymerizes within erythrocytes, leading to a series of downstream events resulting in tissue ischemia. Acute chest syndrome (ACS) is a severe and often life-threatening complication of SCD and the leading cause of intensive care unit admission and mortality in children.
AREAS COVERED: This review covers the latest understanding of ACS pathology involving infectious triggers, pulmonary fat embolism, endothelial activation, hypercoagulability, and sterile inflammation. We discuss the role of neutrophil extracellular traps, inflammasomes, and platelet - leukocyte aggregates in pulmonary microvasculature causing tissue infarction, ventilation perfusion mismatch, and respiratory failure. We explore the emergence of targeted therapies in preventing and treating ACS.
EXPERT OPINION: Although understanding of ACS pathogenesis has improved, current treatments are mainly supportive, with hydroxyurea as the primary preventive therapy. Newer treatments focus on specific mechanisms such as heme scavenging, P-selectin inhibition, toll-like receptor blockade, nitric oxide pathway modulation, and anti-thrombotic strategies. Given ACS's complex nature, a multi-drug targeted approach is likely needed. Scaling up hydroxyurea use remains essential to improving outcomes for millions affected globally by this life-threatening condition.

Keywords:  Acute chest syndrome; hydroxyurea; sickle cell disease; vaso-occlusion

DOI:  https://doi.org/10.1080/13543784.2025.2551353
Ann Hematol. 2025 Sep 01.

Analytical considerations affecting plasma free haemoglobin, the haemolysis index, and correlation with clinical outcomes in sickle cell disease.

Guillaume Feugray, Julie Fettig, Valéry Brunel.

DOI: https://doi.org/10.1007/s00277-025-06534-4
Am J Hematol. 2025 Sep 04.

Iron Deficiency in HbSC Disease Treated With Repetitive Phlebotomy Is Associated With Fewer Sickle Cell Disease-Related Complications.

Marissa J M Traets, Aida S Kidane Gembremeskel, Jennifer Eijkelenboom-Bos, Birgitte A van Oirschot, Sigrid van der Veen, Henk Russcher, Wouter W van Solinge, Mandy N Lauw, Erfan Nur, Bart J Biemond, Marjon H Cnossen, Anita W Rijneveld, Richard van Wijk, Eduard J van Beers, Minke A E Rab.



Keywords:  iron; phlebotomy; sickle cell disease

DOI:  https://doi.org/10.1002/ajh.70045
Br J Haematol. 2025 Aug 31.

Twin pregnancy in patients with sickle cell disease: A French cohort study.

Edouard Leyne, Louise Strube, François Lionnet, Alexandra Benachi, Cyril Touboul, Emile Darai, Fernanda Volt, Eliane Gluckman, Aline Santin, Anne-Gael Cordier.



Keywords:  acute chest syndrome; prematurity; pre‐eclampsia; sickle cell disease; twin pregnancy; vaso‐occlusive crisis

DOI:  https://doi.org/10.1111/bjh.70121
Clin Pharmacol Ther. 2025 Sep 02.

Safety, Pharmacokinetics, and Pharmacodynamics of Osivelotor for Sickle Cell Disease: First-in-Human Studies in Healthy Participants and Patients.

Eleanor A Lisbon, R Clark Brown, Andrew Redfern, Ken Duchin, Aline Barth, Erika S Roberts, Polo Gaputan, Kobina Dufu, Arthur Lo, Mira Patel Pochron, David R Archer, Wai Chin, Karena Kong, Carla B Washington, Adeyemi Adenola, Eric I Zimmerman.

The investigational agent osivelotor, a small molecule hemoglobin (Hb) modifier in development for the treatment of sickle cell disease (SCD), acts by increasing Hb-oxygen affinity and inhibiting the polymerization of sickle Hb. We report safety, pharmacokinetic (PK), and pharmacodynamic (PD) data from the first two phase 1 clinical trials of osivelotor in healthy participants and participants with SCD. Healthy participants (N = 129) were randomized to receive either osivelotor or placebo in single-ascending doses (50-3,000 mg) or multiple-ascending doses (loading doses, then 15-100 mg once-daily maintenance doses through 14 days). A population PK-based adaptive design was used to inform loading- and maintenance-dose regimens from emerging data. Osivelotor was generally well tolerated, demonstrated dose-dependent PK exposure increase, and had a terminal elimination half-life of 19.9 to 30.7 days, with high partitioning into the red blood cell (RBC) compartment in healthy participants. In participants with SCD (N = 6), osivelotor treatment for up to 6 weeks was generally well tolerated; no participants discontinued due to treatment-emergent adverse events. Disease-dependent PK was observed in participants with SCD; notably, the terminal elimination half-life was shorter (~10 days) than in healthy participants. The percentage of Hb bound by osivelotor (%Hb occupancy) increased in a dose-dependent fashion, and improvements in Hb concentration and markers of hemolysis appeared related to osivelotor concentration. Furthermore, Hb-oxygen affinity and RBC deformability improved, whereas dense RBCs and circulating sickled cells decreased. In conclusion, once-daily osivelotor was generally well tolerated at exposures associated with meaningful PD activity, supporting the ongoing clinical investigation.

DOI: https://doi.org/10.1002/cpt.70028
BMC Nephrol. 2025 Aug 29. 26(1): 499

Neutrophil gelatinase-associated lipocalin and fibrinogen-to-albumin ratio are indicators of kidney disease in sickle cell disease patients with microalbuminuria: a multicentre case-control study in Ghana.

Stephen Twumasi, Enoch Odame Anto, Christian Obirikorang, Richard Kobina Dadzie Ephraim, Benedict Sackey, Vivian Paintsil, Richard Owusu Ansah, Alfred Effah, Allwell Adofo Ayirebi, Angela Opoku, Godfred Yawson Scott, Leslie Osei, Joyce Duku, Emmanuel Asafo Adjei, Lilian Antwi Boateng.

   BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is present in secondary granules of neutrophils and it is a relatively newly recognized marker of kidney diseases. The fibrinogen-to-albumin ratio (FAR) is a marker of inflammation but its diagnostic value has not been determined in sickle cell disease patients with kidney diseases. This study investigated the diagnostic roles of serum neutrophil gelatinase-associated lipocalin (sNGAL) and FAR for kidney diseases in steady-state adult sickle cell disease (SCD) patients.
METHODS: This study employed a prospective case-control design and recruited 104 SCD participants and 80 non-SCD patients. Participants' information was thoroughly documented using a structured questionnaire and patient case records. To evaluate the hematobiochemical parameters, 5 ml of venous blood was drawn from each participant and a clean catch of midstream urine was collected from each participant. The cases and controls were further categorized into microalbuminuria and non-microalbuminuria subjects, following three consecutive urine albumin-to-creatinine ratio (UACR) measurements.
RESULTS: The prevalence of microalbuminuria was 32.7% among adult steady-state SCD patients. Significant higher levels of sNGAL and FAR were detected in SCD patients with microalbuminuria than in SCD patients without microalbuminuria and controls (p < 0.001). A moderate positive correlation was observed between sNGAL and UACR (r = 0.45, p = 0.007). A unit increase in sNGAL (cOR: 3.25 (2.11-5.00); p < 0.001), aOR: 3.35(2.09-5.36); p < 0.0001)) and FAR (Log cOR: 12.26 (1.82-25.09); p = 0.022) were significantly associated with increased odds of kidney disease among SCD participants. sNGAL emerged as a highly early predictive marker for kidney disease in SCD patients, with a cutoff value of > 5.72 µg/L yielding a high area under the curve (AUC = 0.854, p < 0.0001). sNGAL also demonstrated an excellent sensitivity (91.2%) and moderate specificity (74.7%). The FAR at a cutoff of > 0.09 also demonstrated significant predictive value (AUC = 0.630, p = 0.009) for kidney disease in SCD patients, with a moderate sensitivity (67.6%) and specificity (61.3%).
CONCLUSION: Based on our findings, sNGAL could serve as an independent early predictor of kidney disease compared with urea and creatinine. Additionally, the fibrinogen-to-albumin ratio can be used as inflammatory marker for kidney diseases in SCD patients.
CLINICAL TRIAL NUMBER: Not applicable.

Keywords:  Fibrinogen-to-albumin ratio; Kidney disease; Microalbuminuria; NGAL; Serum neutrophil gelatinase- associated lipocalin; Sickle cell disease; Sickle cell nephropathy

DOI:  https://doi.org/10.1186/s12882-025-04427-2
Blood Adv. 2025 Sep 03. pii: bloodadvances.2025016394. [Epub ahead of print]

The ASH Research Collaborative Sickle Cell Disease Research Network: Past, Present and Future.

Fuad El Rassi, Biree Andemariam, Abdullah Kutlar, Betty Sue Pace, Aliza Fink, Kathleen Torres, Christopher Dowd, Charles S Abrams.

Historically, Sickle Cell Disease (SCD) has been overshadowed by progress in other hematologic disorders, but recent advances are reshaping its clinical and research landscape. Despite SCD reducing life expectancy by more than 20 years even with optimal care, transformative initiatives are fostering hope for improved outcomes. The American Society of Hematology (ASH) established the ASH Research Collaborative Sickle Cell Disease Research Network as a comprehensive program to revolutionize SCD research in the United States. This Network comprises a collection of innovative, research-focused cooperative sites and a robust Data Hub that aggregates extensive real-world datasets to enhance clinical insights and streamline research designs. Community Advisory Boards at both local and national levels ensure that the perspectives of individuals living with SCD guide research priorities. This report includes an overview of the initial demographics, including the number of records, encounters, laboratory data, prescriptions, years of follow-up, and co-morbidities per patient, within the context of the ASH Research Collaborative Sickle Cell Disease Research Network. These coordinated efforts are poised to significantly transform the landscape of SCD care, and this report details the initiative's mission, history, achievements to date, and its promising trajectory toward improving the lives of individuals affected by this chronic condition.

DOI: https://doi.org/10.1182/bloodadvances.2025016394
Pediatr Blood Cancer. 2025 Oct;72(10): e31937

Severe Hemolytic Phenotype in Children With Sickle Cell Anemia and Co-Inherited Red Blood Cell Variants.

Meghana Srinivas, Sue Jaspersen, David B Wilson, Monica L Hulbert.

  Remarkable phenotypic variability exists among individuals with sickle cell anemia (SCA), which may be explained by co-inheritance of traits affecting red blood cell (RBC) biology, such as genes affecting globin expression or glucose-6-phosphate dehydrogenase enzyme activity. Here, we describe three children with severe SCA who have co-inherited variants in genes for membrane proteins (SPTA1 and EPB1) and PIEZO1. These cases suggest that variants in RBC membrane proteins may contribute to SCA severity and phenotypic variation. Co-Inheritance of such variants could, in theory, affect outcomes of emerging SCA therapies, including genetic modification treatments.

Keywords:  PIEZO1; elliptocytosis; genetic modifiers; glucose‐6‐phosphate dehydrogenase deficiency; hemolytic anemia; sickle cell anemia; sickle cell disease

DOI:  https://doi.org/10.1002/pbc.31937
Lancet Reg Health Am. 2025 Oct;50 101214

Ten-year trends in opioid prescribing and vaso-occlusive crises in sickle cell disease: a population-based national cohort study (2011-2022).

Kevin Y Xu, Terri V Newman, Lakeya S McGill, Enrico M Novelli, Cheryl A Hillery, Joanna L Buss, Lisa Gong, Ruizhi Huang, Fanghong Dong, Dustin Stwalley, Joanne Salas, Shiyuan A Liu, Jeffrey F Scherrer, Tashalee R Brown, Tae Woo Park, Marc R LaRochelle, Richard A Grucza, Charles R Jonassaint.

   Background: Patterns of opioid prescribing and vaso-occlusive crises (VOCs) are poorly characterized among individuals with sickle cell disease (SCD) across diverse insurance types and age groups. We aimed to evaluate opioid prescribing and VOC trends in publicly and commercially insured individuals with SCD over a 10-year time period in the United States (US).
Methods: We conducted a retrospective cohort study of US administrative claims (2011-2022), analyzing 45,726 commercial and Medicaid beneficiaries with SCD. Primary outcomes were monthly rates of outpatient opioid prescriptions and VOC-related acute care encounters. We used joinpoint regression models to estimate trends without pre-specifying breakpoints, stratified by insurance type (Medicaid vs commercial) and age group (1-12, 13-17, 18-27, 28-45, 46-64 years). Primary outcomes were monthly rates of outpatient opioid prescriptions and VOC-related acute care encounters. We used joinpoint regression models to estimate trends without pre-specifying breakpoints, stratified by insurance type (Medicaid vs commercial) and age group.
Findings: Among 45,726 individuals with SCD (mean age [SD] = 25.1 [16.2]; 39.7% female; 52.9% Medicaid, 47.1% commercial insurance), Medicaid beneficiaries had higher rates than commercial beneficiaries for monthly opioid prescribing (18.3 vs 14.0 per 100) and VOC encounters (16.6 vs 8.2 per 100). Monthly opioid prescribing per 100 people increased with age: 1-12 y = 5.1; 13-17 y = 11.3; 18-27 y = 22.5; 28-45 y = 24.6; 46-64 y = 20.6 per 100. Both Medicaid and commercial beneficiaries experienced declining opioid prescribing beginning in 2011 (commercial monthly percentage change [MPC] = -0.3% [95% CI: -0.3%, -0.2%]; Medicaid MPC = -0.5% [-0.6%, 0.5%]). Down-trending opioid prescribing was not consistently accompanied by up-trending VOCs until the COVID-19 pandemic's onset. Particularly among children and adolescents, VOC-related encounters increased significantly after 2020 across both commercial (MPC = 1.8% [1.5%, 2.2%]) and Medicaid (MPC = 0.6% [0.1%, 1.6%]) beneficiaries.
Interpretation: Opioid prescribing and VOC admissions vary by insurance and age. Opioid prescribing declined from 2011 but was not consistently accompanied by increased VOCs until after COVID-19.
Funding: Analyses of Merative MarketScan Commercial and Multi-State Medicaid Database were funded by grants NIH K12 DA041449 (PI: KYX; data analysts: JLB, DS). Effort for some personnel was supported by P50 MH122351 (KYX, PI: Eric Lenze MD, Michael Avidan MBBCh), K08 K08 DA061258 (KYX), the American Psychiatric Association (APA) Psychiatric Research Fellowship (with funding by NIDA and the APA, KYX), NIH K12NS130673 (LSM), NIH L60HL170453 (LSM), and the St. Louis University Research Institute Fellowship (RAG, JS, JFS, RH); these grants did not fund Merative MarketScan Commercial and Multi-State Medicaid Database data pull.

Keywords:  Administrative claims; Age disparities; COVID-19; Insurance; Opioid prescribing; Sickle cell disease; Vaso-occlusive crises

DOI:  https://doi.org/10.1016/j.lana.2025.101214