bims-sicedi 2025-12-21 papers

Br J Haematol. 2025 Dec 14.

Iron deficiency is associated with reduced levels of inflammation and haemolysis in patients with HbSS and HbSC and reduced clinical admissions in those with HbSC.

Simone Villaboni, Sara Stuart-Smith, Arne De Kreuk, David C Rees, John N Brewin.

Evidence suggests that iron deficiency may reduce sickle cell disease (SCD) complications by decreasing sickle haemoglobin polymerization through reduced red cell haemoglobin concentration. The aim is to investigate the effects of iron deficiency in SCD patients. We reviewed clinical and laboratory data from 512 patients (408 HbSS, 104 HbSC) at King's College Hospital (2008-2020). Outpatient data were collected from patients with no blood transfusions or hydroxyurea (hydroxycarbamide) use in the prior 90 days. Patients were categorized as hypoferritinaemic (<45 μg/L), normoferritinaemic (45-800 μg/L) or hyperferritinaemic (>800 μg/L) and analysed for laboratory markers and clinical complications. In HbSC patients, hypoferritinaemia was associated with significantly fewer hospital admissions and inpatient days per year compared to normoferritinaemia. Although this was not seen in HbSS patients, hypoferritinaemia correlates with lower haemolysis and inflammation markers, with no differences in total haemoglobin or erythropoietin in both groups. In HbSS patients, haemoglobin F was significantly lower in hypoferritinaemic compared to normoferritinaemic patients. Iron deficiency may reduce inflammation and haemolysis in both HbSS and HbSC, with clinical benefits demonstrable in HbSC. Low ferritin levels were not associated with increased anaemia, suggesting improved red cell survival. Iron-restricted erythropoiesis may benefit SCD patients in certain circumstances.

Keywords: HbSC; HbSS; iron deficiency; sickle cell disease (SCD)

DOI: https://doi.org/10.1111/bjh.70262

Blood Adv. 2025 Dec 23. 9(24): 6547-6548

Sickle cell disease and thalassemia go to the PROm.

Miguel R Abboud, Biree Andemariam.

DOI: https://doi.org/10.1182/bloodadvances.2025017436

Haematologica. 2025 Dec 18.

Left ventricular strain and chamber dimensions in pediatric sickle cell disease: agerelated reduction in myocardial deformation independent of hemolysis and hydroxyurea therapy.

Ziad Bulbul, Rana Zareef, Tania Abi Nassif, Theresia Tannouri, Francesca Rodigari, Hani Tamim, Maya El Khoury, Fadi F Bitar, Miguel R Abboud.

Sickle cell disease (SCD) is associated with cardiovascular complications. Speckle-tracking echocardiography enables early detection of myocardial dysfunction before abnormalities appear in conventional echocardiographic parameters. This study evaluated left ventricular (LV) global longitudinal strain (GLS) in pediatric SCD patients, and its relationship with traditional LV function indices, disease complications, hemolysis markers, and diseasemodifying therapy. We retrospectively analyzed 278 echocardiograms from 185 participants (118 SCD patients, mean age 12.2 years; 67 age- and sex-matched controls, mean age 11.8 years) obtained between 2015 and 2023. Among the SCD cohort, 66.1% had the HbSS genotype, 9.3% had HbSβ°-thalassemia, and 17.8% had HbSβ⁺-thalassemia; the majority (83.9%) were on hydroxyurea. Compared to controls, SCD patients had significantly lower, but still normal, GLS (-21.5% vs. -22.3%; p < 0.001), along with significantly larger chamber diameters, elevated mitral valve E velocity, E/A ratio, and tricuspid regurgitation maximal velocity. Prior stroke (β = 0.9) and avascular necrosis (β = 1.51) were independently associated with worse GLS. The different genotypes did not exhibit significant difference in GLS. The strain values did not correlate with hemolysis markers, suggesting that other mechanisms may underlie myocardial impairment. A significant age-related decline in GLS was detected, with an inflection point at approximately 9.9 years. Longitudinal analysis of LV strain in the SCD cohort demonstrated a small decline from -21.6% to -21.2% over a 3.7-year follow-up period. Finally, pediatric SCD patients exhibit significant cardiac remodeling and diastolic dysfunction with preserved, yet lower, LV GLS, underscoring the need for further research in this population.

DOI: https://doi.org/10.3324/haematol.2025.288573

Front Bioinform. 2025 ;5 1671626

Genomics-driven drug repurposing and novel targets identification for sickle cell disease in Saudi patients.

Ali Alghubayshi, Mohammad A Alshabeeb, Dayanjan Wijesinghe, Mohammed AlAwadh, Suad Alshammari, Khalifa Alrajeh, Mona A Alkhairi, Imadul Islam, Ahmed Alaskar.

Background: Sickle cell disease (SCD) is an inherited blood disorder characterized by chronic hemolysis, inflammation, and vaso-occlusive crises (VOC), leading to multiple complications and reduced life expectancy in affected individuals. Limited effective treatment options are currently available; however, recent genomic findings from underrepresented populations (Saudi Arabians) have offered new hope for predicting molecularly guided treatments. This study aimed to identify approved drugs suitable for repurposing based on their interactions with SCD-associated genetic variants and to discover novel druggable targets within genetic pathways linked to disease severity by utilizing genome-wide association study (GWAS) data from Saudi SCD patients.
Methods: Bioinformatic pipelines were used to evaluate drug-gene interactions and identify potential therapeutic targets based on GWAS data derived from the Saudi population. Approved drugs were suggested for repurposing according to their interactions with genes known to impact SCD pathophysiology, using the Drug-Gene Interaction Database (DGIdb 5.0). New drug targets were also proposed by assessing the simulated binding pockets of gene products, using 3D protein structures from the Protein Data Bank (PDB) and the AlphaFold database. Molecules with higher druggability scores, as estimated by the DoGSiteScorer database, were predicted to have a higher success rate for new SCD treatment development.
Results: Our analysis identified 78 approved medications with potential for repurposing in SCD; this list was narrowed to 21 candidates based on safety profiles and interactions with key genetic pathways. Among these, simvastatin, allopurinol, omalizumab, canakinumab, and etanercept were suggested as the most promising agents. Furthermore, novel drug targets encoded by olfactory receptor (OR) gene clusters (OR51V1, OR52A1, OR52A5, OR51B5, and OR51S1), TRIM genes, SIDT2, and CADM3 displayed high druggability scores.
Conclusion: This study provides a robust framework for drug repurposing and novel drug discovery in SCD, particularly tailored to the Saudi population. The findings underscore the potential of leveraging genomic data to identify targeted therapies, offering a pathway to more personalized and effective treatments for SCD patients. Future clinical trials are essential to validate these findings and translate them into clinical practice.

Keywords: Saudi population; drug repurposing; genome-wide association studies; pharmacogenomics; precision medicine; sickle cell disease

DOI: https://doi.org/10.3389/fbinf.2025.1671626

Blood. 2025 Dec 18. pii: blood.2025028895. [Epub ahead of print]

p27Kip1 regulates γ-globin production.

Ginette Balbin-Cuesta, Claire Drysdale, Claire Kerpet, Lei Yu, Greggory Myers, Zesen Lin, Beth McGee, Ann Friedman, Xiaofeng Liu, Sharon A Singh, James Douglas Engel, Laura Buttitta, Rami Khoriaty.

Sickle cell disease (SCD) and β-thalassemia are devastating genetic disorders resulting from defects in the β-globin subunit of adult hemoglobin (HbA). Both disorders are ameliorated by the induction of γ-globin, a component of fetal hemoglobin (HbF). Therefore, the development of safe, effective, and widely available inducers of HbF is needed. Here, we discovered that slow cycling erythroid cells exhibit increased γ-globin expression. To understand the molecular basis of this, we screened all cyclin-dependent kinase inhibitors (CDKIs) for their ability to induce HbF using CRISPR activation (CRISPRa). We found that overexpression of CDKN1B, which encodes p27Kip1 (but not overexpression of other CDKIs), induces γ-globin expression at the transcriptional level. CDKN1B mutants expressing proteins unable to bind/inhibit CDKs and/or cyclins revealed that γ-globin induction by p27Kip1 depends largely on the domains involved in its cell cycle function. Pharmacological inhibition and genetic reduction of CDK4/6 also results in increased HbF. In genetic rescue experiments, we show that p27Kip1 induces HbF by inhibiting CDK4/6, through a mechanism that is likely BCL11A and ZBTB7A independent. Furthermore, palbociclib, an oral CDK4/6 inhibitor, significantly increases HbF in a murine SCD model at doses that are well tolerated. Moreover, we show that HbF induction by hydroxyurea, a drug currently in use to treat SCD, may be mediated in part by CDK4/6 inhibition. Overall, our findings establish a causal relationship between CDK4/6 activity and γ-globin production and suggest that single or dual CDK4/6 inhibitors might be therapeutically beneficial for SCD and β-thalassemia.

DOI: https://doi.org/10.1182/blood.2025028895

Am J Hematol. 2025 Dec 16.

Autoimmune Features in Sickle Cell Patients: A New Explanation for Liver Damage?

Aude Mausoleo, Pascale Chretien, Astrid Laurent-Bellue, Laurence Rocher, Lisa Fredeau, Catherine Guettier, Paul-Albert Domnariu, Olivier Lambotte, Stephanie El Hajj, Chahinez Hani Dekimeche, Salima Hacein-Bey-Abina, Jean-Charles Duclos-Vallée, Christelle Chantalat-Auger, Eleonora De Martin, Nicolas Noel.

Keywords: anti‐liver kidney microsome antibody; autoimmune hepatitis; autoimmunity; sickle cell disease

DOI: https://doi.org/10.1002/ajh.70168

NEJM Evid. 2025 Dec 18. EVIDoa2500074

Validation and Application of a Predictive Score of Acute Chest Syndrome.

BACKGROUND: Vaso-occlusive crisis (VOC) is the most common manifestation of sickle cell disease, and acute chest syndrome (ACS) is a frequent complication with a substantial risk of death. The aim of this study was to validate the previously developed PREdictive SEVerity (PRESEV) score for the occurrence of ACS in adult patients with sickle cell disease hospitalized for VOC and to assess the safety of outpatient management of patients with a low-risk score.
METHODS: To validate the PRESEV score, a prospective observational study was conducted in 13 centers across 5 countries in Africa and Europe. The score ranges from 0 to 16, with values of 5 or less considered low risk. The safety of a low-risk score (≤5) for outpatient management was then assessed in 100 patients. The primary outcome was the occurrence of ACS.
RESULTS: A total of 393 patients were included for the validation of the score: 206 (52.4%) from Europe and 187 (47.6%) from Africa. Of these, 76 patients (19.3%) developed ACS. Of the 50 patients (12.7%) with a low-risk score, 3 (6.0%) developed ACS (negative predictive value 94.0%). Of the 76 patients who developed ACS, 73 (96.1%) did not have a low-risk score (sensitivity 96.1%). A total of five deaths (1.3%) was recorded; no individuals who died had a low-risk score. Score performance was similar across both continents. When the score was used to guide outpatient management in 100 patients with VOC, one case of ACS (1.0%) was recorded.
CONCLUSIONS: This international study validated the PRESEV predictive risk score to identify adult patients at low risk for ACS. (Funded by the Support for Actions against Red Blood Cell Diseases Association and others; trial registration number, IRB 00003835; ClinicalTrials.gov number, NCT03032055.).

DOI: https://doi.org/10.1056/EVIDoa2500074