bims-sicedi 2025-05-11 papers

Blood. 2025 Apr 25. pii: blood.2024028136. [Epub ahead of print]

A Novel Mouse Model of Hemoglobin SC Disease Reveals Mechanisms Underlying Beneficial Effects of Hydroxyurea.

Tahereh Setayesh, Mengna Chi, Zachery Oestreicher, Masahide Sakabe, Katie Giger Seu, Zhenqi Zhu, Harsimran Kaur, Anifat Tijani, Mei Xin, Amy Shova, Kenneth D Greis, Tim M Townes, Jozsef Balla, Katherine VandenHeuvel, Yueh-Chiang Hu, Punam Malik.

Sickle cell hemoglobin-C (HbSC) disease results from compound heterozygosity of hemoglobin-S (HbS) and hemoglobin-C (HbC), comprising 30% of sickle cell disease (SCD). HbC induces RBC dehydration/xerocytosis, which promotes sickling. HbSC-SCD causes significant morbidity despite being milder than homozygous HbSS-SCD. Current research/treatment strategies have focused on HbSS-SCD, while HbSC patients are deprived of disease-modifying/transformative therapies due to lack of preclinical models. We generated HbSC mice, which resemble human HbSC-SCD: HbSC erythrocytes showed marked xerocytosis. Anemia, hemolysis, inflammation and organ damage were milder than HbSS mice, but hypoxia/reperfusion injury was similar. Retinopathy developed at higher frequency than HbSS mice (66.7% versus 16.7%; p<0.05), like HbSC-SCD patients. While HbSC RBCs sickled at lower pO2 than HbSS RBCs (43mmHg versus 24mmHg; P<0.0001), they did not completely recover deformability after hypoxia-reoxygenation. Using the HbSC mice developed herein, we studied the mechanism by which hydroxyurea causes significant clinical benefit in HbSC-SCD patients, despite minimal/modest increases in fetal-hemoglobin (HbF). We found hydroxyurea had distinct non-HbF and HbF effects. Hydroxyurea did not increase HbF in adult HbSC/HbSS mice, but reduced RBC ROS, Ferryl-hemoglobin, Heinz-body formation, thereby reducing membrane damage; however, RBC hydration was unaffected. When given to unborn pups before they switch off g-globin expression and continued postnatally, we could induce HbF in both HbSC/HbSS mice (higher HbF in HbSS versus HbSC mice). Minimal increases in HbF (~1%) improved HbSC RBC hydration. Peak HbF levels of 7% in HbSC mice abrogated sickling. Overall, this HbSC model will help bridge the knowledge-gap in mechanistic/therapeutic studies in this neglected disease.

DOI: https://doi.org/10.1182/blood.2024028136

Int J Mol Sci. 2025 Apr 13. pii: 3675. [Epub ahead of print]26(8):

Crosstalk Between Sickle Cell Disease and Ferroptosis.

Annamaria Russo, Giuseppe Tancredi Patanè, Antonella Calderaro, Davide Barreca, Ester Tellone, Stefano Putaggio.

Sickle cell disease (SCD) is an inherited hemoglobin disorder that is widespread across the globe. It is characterized by a very complex pathogenesis, but at the basis of the disease is the mutation of the HBB gene, which determines the production of a mutated hemoglobin: sickle cell hemoglobin (HbS). The polymerization of HbS, which occurs when the protein is in a deoxygenated state, and the greater fragility of sickle cell red blood cells (sRBCs) determine the release of iron, free heme, and HbS in the blood, favoring oxidative stress and the production of reactive oxygen species (ROS). These features are common to the features of a new model of cell death known as ferroptosis, which is characterized by the increase of iron and ROS concentrations and by the inhibition of glutathione peroxidase 4 (GPx4) and the System Xc-. In this context, this review aims to discuss the potential molecular and biochemical pathways of ferroptosis involved in SCD, aiming to highlight possible tags involved in treating the disease and inhibiting ferroptosis.

Keywords: GPx4; cell death; iron overload; oxidative stress; sickle cell hemoglobin; system Xc−; transfusion

DOI: https://doi.org/10.3390/ijms26083675

Sci Rep. 2025 May 07. 15(1): 15864

A novel red blood cell deformability biomarker is associated with hemolysis and vaso-occlusive crises in sickle cell disease.

Maxime Sahun, Emmanuelle Bernit, Scott Atwell, Alexander Hornung, Anne M Charrier, Imane Agouti, Nathalie Bonello-Palot, Mathieu Cerino, Emmanuèle Helfer, Catherine Badens, Annie Viallat.

Sickle cell disease (SCD) is among the most prevalent genetic disorders worldwide. It is characterized by unpredictable and potentially fatal vaso-occlusive crises, directly linked to the stiffening of red blood cells (RBCs) due to the formation of hemoglobin fibers in their cytoplasm. Here, we propose a new mechanical marker: the proportion of RBCs in a blood sample deformable enough to exhibit a specific tank-treading motion, in shear flow at a given shear rate. This marker is significantly lower in SCD patients than in controls and is sensitive to RBC density and dehydration, two factors that influence hemoglobin polymerization in SCD. The marker was tested in a cohort of 21 SCD patients, with weekly monitoring conducted over a period of 6 months. It correlates with key biological parameters of SCD including fetal hemoglobin levels, reticulocyte count, serum LDH levels, and the use of antihypertensive treatments. The marker significantly decreases before vaso-occlusive crises requiring hospitalization. These findings indicate that this marker may act as a comprehensive indicator of RBC deformability, offering valuable insights for the continuous clinical monitoring of SCD patients. It could play a role in managing or preventing vaso-occlusive crises and holds potential for the development of new diagnostic tests such as point-of-care or companion diagnostic devices for personalized medicine.

Keywords: RBC deformability; RBC motion; Red blood cell density; Shear flow; Sickle cell disease; Vaso-occlusive crisis

DOI: https://doi.org/10.1038/s41598-025-00152-w

Blood. 2025 May 07. pii: blood.2024028006. [Epub ahead of print]

Novel, potent, and orally bioavailable LSD1 inhibitors induce fetal hemoglobin synthesis in a sickle cell disease mouse model.

Yu Wang, Lei Yu, Kaiwen Deng, Mathivanan Packiarajan, Angelo Aguilar, Sojin An, Greggory Myers, Hoon Oh, Sharon A Singh, Uhn-Soo Cho, Shaomeng Wang, Yuanfang Guan, Andrew White, Rami Khoriaty, James Douglas Engel.

Small molecules that inhibit LSD1 (lysine-specific demethylase 1, KDM1A) have been shown to induce abundant fetal hemoglobin (HbF) levels in red blood cells both in vitro and in vivo, therefore potentially serving as potent and cost-effective therapeutics to treat the β-globinopathies, sickle cell disease (SCD) and β-thalassaemia major (TM). However, most LSD1 inhibitors (LSD1i) that induce HbF in vivo are covalent and irreversible, which leads to adverse effects. In this study, we utilized structure-aided drug design to develop potent new reversible LSD1i's leading to robust γ-globin expression in vitro. Moreover, in a mouse model of SCD, oral administration of these novel inhibitors lead to significant HbF elevation and alleviation of multiple features of disease pathology that are the usual consequences of SCD. In addition, we discovered that combined treatment of an LSD1i with a BRD4 degrader (BD-9136) represses the induction of RUNX1 and PU.1, thereby rescuing the erythroid to myeloid lineage conversion that accompanies LSD1i in hematopoiesis. The data indicate that this new generation of LSD1i can effectively induce HbF levels, reduce SCD pathologies, and are well-tolerated by oral administration in SCD mice. We anticipate that the combination of these or related binary compounds offer exciting new therapeutic possibilities for treating SCD and TM.

DOI: https://doi.org/10.1182/blood.2024028006

EJHaem. 2025 Jun;6(3): e70044

Sickle Cell Disease in Africa: SickleInAfrica Registry in Ghana, Nigeria and Tanzania.

Members of SPARCO Nigeria

Introduction: Sickle cell disease (SCD) is most prevalent in Sub-Saharan Africa (SSA), where incomplete patient profiles and limited management strategies hinder research and healthcare standards.
Methods: We describe the first large-scale and multinational assessment of 13,403 SCD patients enrolled from 2017-2021 across 31 facilities in Ghana, Nigeria, and Tanzania into the SickleInAfrica consortium registry. We used hierarchical regression models to estimate and analyze the demographics, adoption levels of SCD diagnosis and therapies.
Results: The average age at diagnosis was 3 months, 19 months and 3 years in Ghana, Nigeria and Tanzania respectively, reflecting differences in country-specific newborn screening programs and policies. Hydroxyurea (HU) use was highest in Ghana (21%), followed by Nigeria (12%) and Tanzania (6%), with significant variability across facilities. Sex differences in SCD management were observed, with males more likely to receive HU and blood transfusions. At the consortium level, HU initiation correlated with enrolment age rather than age at diagnosis, highlighting the need for earlier intervention.
Conclusions: Our findings highlight the potential of the SickleInAfrica registry toward enhancing understanding of regional disparities in SCD care and potential gender inequalities, emphasizing the need for enabling policies toward strengthened SCD research and improved quality of life and care of patients in Africa.

Keywords: SickleInAfrica; disease management; meta‐analysis; registry; regression models; sickle cell disease

DOI: https://doi.org/10.1002/jha2.70044

Clin Case Rep. 2025 May;13(5): e70483

Red Blood Cell Exchange Apheresis in the Management of Acute Chest Syndrome: Case Study at Greater Accra Regional Hospital (Ghana)- Bone Marrow Transplant Unit (BMT-Ghana).

George Awuku Asare, Coker Amin, Kate Fiador, Israel Hagbevor, Ernest Tsede, Blessing Ampofo, Benjamin Mensah.

The most prevalent genetic disease in Africa and sub-Saharan Africa is sickle cell disease. Crisis often leads to severe pain in the limbs and chest region accompanied by oxygen deprivation to tissues. In children and adults, acute chest syndrome (ACS) which is a complication of vaso-occlusive crisis (VOC), is a life-threatening condition. A 24-year-old female with known Sickle Cell Disease (SCD) complained of generalized diffuse chest pains and was administered diclofenac at a peripheral hospital. The pains subsided. However, the condition relapsed and at another clinic, she was treated with i.v. paracetamol, morphine, pethidine, and i.v. fluids. Three (3) days had already gone by since the crisis started before a further transfer was made to the Greater Accra Regional Hospital. On arrival, she was diagnosed with chest and leg pains, shortness of breath, and VOC. Chest x-ray demonstrated patchy consolidation, infiltrates bilaterally, with right atrial enlargement. Clexane 80 mg BD, i.v. Omeprazole 40 mg b.d., Azithromycin tablets 500 mg, morphine syrup 10 mg/5 mL, Injection Rocephin 2 g, and infusion paracetamol 1 g were administered, followed by a continuous treatment review plan. Oxygen saturation was however generally constant at 99%. On day five (post admission-D5) the patient was moaning and restless. Her WBC started increasing [5.9-10.1 × 103/μL (D5-D9)], platelets were still low (45 × 103/μL), with Hb showing signs of fluctuations [6.3-9.0 g/dL (D2-D9)]. Blood culture results showed Gram-positive bacillus. Acute phase reactants, CRP (103.65 mg/dL) and ferritin (741.3 μg/L) were very high. RBC exchange transfusion by apheresis commenced at 10 pm (for 3 h). By 6 am the following day, the patient was described as having a calm night. Further drug modifications were made and by day 9 (D9) patient was only on Cap Omeprazole 20 mg once for 5 days, and tab dexamethasone 6 mg daily. The patient was discharged on day 11 post admission. Thus, from the onset of the crisis to the application of apheresis, 8 days had elapsed. However, five (5) hours after the RBC exchange transfusion by apheresis, pains subsided considerably. The key clinical message is that prompt resolution of ACS by therapeutic apheresis application will subsequently reduce the long-term pulmonary complications in SCD patients, hospitalization time, the overall financial burden, anxiety, and discomfort to patient and family.

Keywords: Vaso‐occlusive crisis; acute chest syndrome; sickle cell disease; therapeutic apheresis

DOI: https://doi.org/10.1002/ccr3.70483