bims-sicedi Biomed News
on Sickle cell disease
Issue of 2025–02–02
ten papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. A replication study of novel fetal hemoglobin-associated genetic variants in sickle cell disease-only cohorts.
  2. Sleep Problems in Sickle Cell Disease.
  3. Strengthening advanced therapy for sickle cell disease in Africa: experience from sickle cell disease centre in Dar es Salaam, Tanzania.
  4. Recipient Cells Are the Source of Hematologic Malignancies After Graft Failure and Mixed Chimerism in Adults with SCD.
  5. Prophylactic vs therapeutic blood transfusions impact on pregnant sickle cell patients.
  6. Factors Associated with Microalbuminuria among Children with Sickle Cell Disease in a Tertiary Centre in South-South Nigeria.
  7. Sickle Cell Trait Does Not Cause "Sickle Cell Crisis" Leading to Exertion-Related Death: A Systematic Review.
  8. Babesiosis and Sickle Red blood Cells: Loss of Deformability, Heightened Osmotic fragility, and Hypervesiculation.
  9. TARGETING LUNG HEME IRON BY AEROSOL HEMOPEXIN ADMINSTRATION IN SICKLE CELL DISEASE PULMONARY HYPERTENSION.
  10. Mitapivat: a step forward across different hemolytic diseases.
  1. Hum Mol Genet. 2025 Jan 31. pii: ddaf015. [Epub ahead of print]
    A replication study of novel fetal hemoglobin-associated genetic variants in sickle cell disease-only cohorts.
    Yann Ilboudo, Nicolas Brosseau, Ken Sin Lo, Hicham Belhaj, Stéphane Moutereau, Kwesi Marshall, Marvin Reid, Abdullah Kutlar, Allison E Ashley-Koch, Marilyn J Telen, Philippe Joly, Frédéric Galactéros, Pablo Bartolucci, Guillaume Lettre.
      Sickle cell disease (SCD) is the most common monogenic disease in the world and is caused by mutations in the β-globin gene (HBB). Notably, SCD is characterized by extreme clinical heterogeneity. Inter-individual variation in fetal hemoglobin (HbF) levels strongly contributes to this patient-to-patient variability, with high HbF levels associated with decreased morbidity and mortality. Genetic association studies have identified and replicated HbF levels-associated variants at three loci: BCL11A, HBS1L-MYB, and HBB. In SCD patients, genetic variation at these three loci accounts for ~ 50% of HbF heritability. Genome-wide association studies (GWAS) in non-anemic and SCD patients of multiple ancestries have identified 20 new HbF-associated variants. However, these genetic associations have yet to be replicated in independent SCD cohorts. Here, we validated the association between HbF levels and variants at five of these new loci (ASB3, BACH2, PFAS, ZBTB7A, and KLF1) in up to 3740 SCD patients. By combining CRISPR inhibition and single-cell transcriptomics, we also showed that sequences near non-coding genetic variants at BACH2 (rs4707609) and KLF1 (rs2242514, rs10404876) can control the production of the β-globin genes in erythroid HUDEP-2 cells. Finally, we analyzed whole-exome sequence data from 1354 SCD patients but could not identify rare genetic variants of large effect on HbF levels. Together, our results confirm five new HbF-associated loci that can be functionally studied to develop new strategies to induce HbF expression in SCD patients.
    Keywords:  DNMT1; fetal hemoglobin; genome-wide association study; replication; sickle cell disease
    DOI:  https://doi.org/10.1093/hmg/ddaf015
  2. Am J Respir Crit Care Med. 2025 Feb;211(2): P3-P4
    Sleep Problems in Sickle Cell Disease.
    Krista Reiling, Sonal Malhotra.
      
    DOI:  https://doi.org/10.1164/rccm.v211i2p3
  3. BMJ Glob Health. 2025 Jan 27. pii: e017878. [Epub ahead of print]10(1):
    Strengthening advanced therapy for sickle cell disease in Africa: experience from sickle cell disease centre in Dar es Salaam, Tanzania.
    Muhimbili Sickle Cell Programme
      Despite progress in healthcare services for individuals living with sickle cell disease (SCD) in Africa, substantial gaps remain in advanced treatments for SCD. To help address this burden, Tanzania has established one of the largest single-centre SCD programmes in the world and developed an advanced therapy programme for SCD focused on patient engagement and advocacy, clinical activities involving exchange blood transfusion (ExBT) and haematopoietic stem cell transplant (HSCT), gene therapy (GT) preparedness, and enabling partnerships. This report describes the programme's genesis, structure and progress achieved. Patient engagement camps and patient-focused workshops conducted since early 2021 have involved more than 150 patients, family caregivers and healthcare providers. A patient registry was established by screening 1500 patients eligible for advanced therapies with 157 identified to benefit from advanced treatments for SCD. Out of which 22 patients received ExBT, and human leucocyte antigen typing was conducted on 127 individuals to establish a registry of family members with potential to be HSCT donors. Target product profiles were devised for minimum and optimum criteria of GT products to guide drug discovery and development efforts, and qualitative research was conducted to investigate factors anticipated to influence successful adoption of GTs for SCD in Africa. The programme's multifaceted components have been enabled by institutional networks and collaborations established at national, regional and global levels. The programme presented opportunities to deliver cost-effective advanced treatment and curative options for SCD in Tanzania and lessons learnt may be applicable to inform similar efforts in other African regions where SCD is highly endemic.
    Keywords:  Blood disorders; Global Health; Public Health
    DOI:  https://doi.org/10.1136/bmjgh-2024-017878
  4. medRxiv. 2025 Jan 18. pii: 2025.01.17.25320670. [Epub ahead of print]
    Recipient Cells Are the Source of Hematologic Malignancies After Graft Failure and Mixed Chimerism in Adults with SCD.
    Mohamed A E Ali, Emily M Limerick, Matthew M Hsieh, Kalpana Upadhyaya, Xin Xu, Oswald Phang, Jean Pierre Kambala Mukendi, Katherine R Calvo, Maria Lopez-Ocasio, Pradeep Dagur, Courtney D Fitzhugh.
      Non-myeloablative hematopoietic cell transplantation (HCT) is a curative option for individuals with sickle cell disease (SCD). Our traditional goal with this approach has been to achieve a state of mixed donor/recipient chimerism. Recently, we reported an increased risk of hematologic malignancies (HMs) in adults with SCD following graft failure or mixed chimerism. To evaluate the origin of HMs, we performed chimerism analyses of 5 patients with SCD who developed HMs after non-myeloablative HCT. DNA was extracted from sorted peripheral blood or bone marrow cells representing mature cell lineages or leukemic blasts and subjected to chimerism analysis by PCR amplification of polymorphic short tandem repeats. Unlike mature cell lineages in patients with mixed chimerism, which still showed a donor-derived fraction of cells, leukemic blast cells were found to be 99-100% recipient-derived in all patients. Non-myeloablative conditioning allows for the survival of patients' cells that might harbor pre-leukemic clones that possess the capacity to evolve under genotoxic or environmental stress into malignancies; therefore, we have modified our HCT protocols with the goal of full donor chimerism to mitigate the risk of HM development.
    DOI:  https://doi.org/10.1101/2025.01.17.25320670
  5. Pak J Med Sci. 2025 Jan;41(1): 44-48
    Prophylactic vs therapeutic blood transfusions impact on pregnant sickle cell patients.
    Iffat Imran, Imran Nazir, Rakan Tariq J Al Rfaai, Khalid Khalil.
       Objective: To observe the fetomaternal outcome of therapeutic versus prophylactic blood transfusions in patients with sickle cell disease (SCD) during pregnancy.
    Method: This single-center retrospective observational study was conducted on consecutive pregnant women with SCD between January 2018 and December 2020. All the pregnant women with SCD were included in this study. Sickler women carrying sickle cell traits (HbAS, HbAC), multiple pregnancy, or other medical diseases were excluded from the study. We used non-random, convenience sampling and collected their demographic details, medical history, course of SCD before & during pregnancy, maternal/fetal outcome, laboratory parameters, and other information using the questionnaire. Patients were sub-grouped into three according to blood transfusion categories (therapeutic, prophylactic, or not transfused) during the pregnancy. Descriptive data were represented as numbers and mean ± SD values. The medical and obstetrical complications and fetomaternal outcomes among the three groups were analyzed by Chi-square/Fisher's Extract test.
    Results: The study included 62 patients, 37 were in the therapeutic group, 11 were in the prophylactic group, and 14 were in the non-transfusion group. Hemolytic crises, painful crises, acute chest syndrome, pregnancy-induced hypertension (PIH), preeclampsia, preterm births, intrauterine growth retardation (IUGR), and neonatal ICU admission were significantly lower among the prophylactic group (P = 0.000, p = 0.000, p = 0.001, p = 0.002, p = 0.009, p = 0.007, p =0.001 & p= 0.016 respectively) compared with other two groups.
    Conclusions: Our study demonstrates that prophylactic blood transfusion in SCD positively alters the course of pregnancy by reducing fetomaternal complications.
    Keywords:  Blood transfusion; Pregnancy; Sickle cell disease
    DOI:  https://doi.org/10.12669/pjms.41.1.9783
  6. Niger Med J. 2024 Nov-Dec;65(6):65(6): 885-898
    Factors Associated with Microalbuminuria among Children with Sickle Cell Disease in a Tertiary Centre in South-South Nigeria.
    Datonye Christopher Briggs, Chioma Okechukwu, Josiah Apollus, Ijeoma Amadi, Hannah Omunakwe, Linda Anucha Dublin-Green, Dorathy Okoh.
       Background: Microalbuminuria, an early indicator of kidney damage in Sickle Cell Disease (SCD) patients, is linked to a heightened risk of chronic kidney disease (CKD) in adulthood. This study investigates the determinants of microalbuminuria in paediatric SCD patients in South-South Nigeria.
    Methodology: This cross-sectional study was conducted over six months at the Rivers State University Teaching Hospital, Nigeria, involving 60 children with [HbSS genotype, SCD] in a steady state. Data collection included demographics, past medical history, clinical measurements, and laboratory assessments of urine and blood samples. 'Steady state' was defined as SCD with a known 'steady state' haemoglobin level and stable clinical state for ≥ 3 months. Microalbuminuria was defined spot urine albumin-creatinine ratio of 30mg/g to <300 mg/g.
    Results: Of the 60 children recruited, 31 children (51.7%) were males. The mean age was 9.6 ± 4.3 years. The prevalence of microalbuminuria was 16.7% (CI: 8.29 - 28.5%) and associated risk factors were hypertension (p = 0.017), use of Hydroxyurea (p = 0.008), and Ciklavit (p = 0.025), but not NSAIDs (p = 0.046). There was a significant negative correlation (ɼ = -0.28; p = 0.032) between haemoglobin level and microalbuminuria.
    Conclusion: This study provides insights into the factors associated with microalbuminuria in children with SCD in our setting and highlights the need for early screening for markers of CKD among children with SCD. Further research is needed to ascertain the potential benefits of addressing anaemia and reducing haemolysis in mitigating the occurrence of microalbuminuria among children with SCD.
    Keywords:  Children; Microalbuminuria; Risk Factors; Sickle Cell Disease; Sickle Cell Nephropathy
    DOI:  https://doi.org/10.60787/nmj-v65i6.493
  7. Blood. 2025 Jan 30. pii: blood.2024026899. [Epub ahead of print]
    Sickle Cell Trait Does Not Cause "Sickle Cell Crisis" Leading to Exertion-Related Death: A Systematic Review.
    Lachelle D Weeks, Allecia M Wilson, Rakhi P Naik, Yvonne A Efebera, Mohammad Hassan Murad, Anjlee Mahajan, Patrick T McGann, Madeleine Verhovsek, Angela C Weyand, Ahmar Urooj Zaidi, Michael R DeBaun, Chancellor Donald, Roger A Mitchell.
      Globally, an estimated 300 million individuals have sickle cell trait (SCT), the carrier state for sickle cell disease. While sickle cell disease (SCD) is associated with increased morbidity and shortened lifespan, SCT has a lifespan comparable to that of the general population. However, "sickle cell crisis" has been used as a cause of death for decedents with SCT in reports of exertion-related death in athletes, military personnel, and individuals in police custody. To appraise this practice, the American Society of Hematology (ASH) convened an expert panel of hematologists and forensic pathologists to conduct a systematic review of the literature relating to the occurrence of sickle cell pain crises and exertion-related mortality in people with SCT. Multiple bibliographic databases were searched with controlled vocabulary and keywords related to "sickle cell trait," "vaso-occlusive pain," and "death," yielding 18 of 1,474 citations. Independent pairs of reviewers selected studies and extracted data. We found no studies comparing uncomplicated acute pain crises in individuals with SCT and SCD. Additionally, no study was identified to support the occurrence of acute vaso-occlusive pain crises in individuals with SCT. Further, this systematic review did not identify any evidence to support an association between SCT and sudden-unexplained death in the absence of exertion-related rhabdomyolysis. We conclude that there are no data to support the diagnosis of acute vaso-occlusive sickle cell crisis as a cause of death in SCT, nor does the available evidence support the use of SCT as a cause of exertion-related death without rhabdomyolysis.
    DOI:  https://doi.org/10.1182/blood.2024026899
  8. Blood. 2025 Jan 27. pii: blood.2024027602. [Epub ahead of print]
    Babesiosis and Sickle Red blood Cells: Loss of Deformability, Heightened Osmotic fragility, and Hypervesiculation.
    Divya Beri, Marilis A Rodriguez, Manpreet Singh, Daniel McLaughlin, Yunfeng Liu, Hui Zhong, Avital Mendelson, Xiuli An, Deepa G Manwani, Karina Yazdanbakhsh, Cheryl A Lobo.
      Babesiosis in sickle cell disease (SCD) is marked by severe anemia but the underlying red blood cell (RBC) rheological parameters remain largely undefined. Here, we describe altered RBC deformability from both primary (host RBC sickle hemoglobin mediated) and secondary changes (Babesia parasite infection mediated) to the RBC membrane using wild type AA, sickle trait AS and sickle SS RBCs. Our ektacytometry (LORRCA) analysis demonstrates that the changes in the host RBC bio-mechanical properties, pre- and post- Babesia infection, reside on a spectrum of severity, with wild type infected AA cells, despite showing a significant reduction of deformability under both shear and osmolarity gradients, exhibiting only a mild phenotype; compared to infected AS RBCs which show median changes in deformability and infected SS RBCs which exhibit the most dramatic impact of infection on cellular rheology, including an increase in Point of Sickling values. Further, using Image stream cytometric technology to quantify changes in cellular shape and area along with a tunable resistive pulse sensor to measure release of extra-cellular vesicles (EV) from these host RBCs, before and after infection, we offer a potential mechanistic basis for this extreme SS RBC rheologic profile, which include enhanced sickling rates and osmotic fragility, loss of RBC surface area and hypervesiculation in infected SS host RBCs. These results underly the importance of understanding the impact of intra-erythrocytic parasitic infections of SCD RBCs, especially on their cellular membranes and studying the mechanisms that lead to hyper hemolysis and extreme anemia in the SCD patient population.
    DOI:  https://doi.org/10.1182/blood.2024027602
  9. Free Radic Biol Med. 2025 Jan 23. pii: S0891-5849(25)00056-5. [Epub ahead of print]
    TARGETING LUNG HEME IRON BY AEROSOL HEMOPEXIN ADMINSTRATION IN SICKLE CELL DISEASE PULMONARY HYPERTENSION.
    Melissa Lucero, Christina Lisk, Francesca Cendali, Delaney Swindle, Saini Setua, Kiruphagaran Thangaraju, David I Pak, Quintin O'Boyle, Shuwei Lu, Robert Tolson, Seth Zaeske, Nishant Rana, Saqib Khan, Natalie Westover, Pavel DavizonCastillo, Gemlyn George, Kathryn Hassell, Rachelle Nuss, Nathan Brinkman, Thomas Gentinetta, Andre F Palmer, Angelo D'Alessandro, Paul W Buehler, David C Irwin.
      Lung tissue from human patients and murine models of sickle cell disease pulmonary hypertension (SCD-PH) show perivascular regions with excessive iron accumulation. The iron accumulation arises from chronic hemolysis and extravasation of hemoglobin (Hb) into the lung adventitial spaces, where it is linked to nitric oxide depletion, oxidative stress, inflammation, and tissue hypoxia, which collectively drive SCD-PH. Here, we tested the hypothesis that intrapulmonary delivery of hemopexin (Hpx) to the deep lung is effective at scavenging heme-iron and attenuating the progression of SCD-PH. Herein, we evaluated in a murine model of hemolysis driven SCD-PH, if intrapulmonary Hpx administration bi-weekly for 10 weeks improves lung iron deposition, exercise tolerance, cardiovascular function, and multi-omic indices associated with SCD-PH. Data shows Hpx delivered with a micro-sprayer deposits Hpx in the alveolar regions. Hpx extravasates into the perivascular compartments but does not diffuse into the circulation. Histological examination shows Hpx therapy decreased lung iron deposition, 4-HNE, and HO-1 expression. This was associated with improved exercise tolerance, cardiopulmonary function, and multi-omic profile of whole lung and RV tissue. Our data provides proof of concept that treating lung heme-iron by direct administration of Hpx to the lung attenuates the progression of PH associated with SCD.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.045
  10. Expert Opin Emerg Drugs. 2025 Jan 29. 1-3
    Mitapivat: a step forward across different hemolytic diseases.
    Mohammad Hassan Hodroj, Joseph Klim, Nicole Charbel, Ali Taher.
      
    Keywords:  Mitapivat; Pyruvate Kinase activator; Sickle Cell Disease; Thalassemia
    DOI:  https://doi.org/10.1080/14728214.2025.2458063
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