bims-sicedi Biomed News
on Sickle cell disease
Issue of 2024–10–13
eight papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. CYB5R3 T117S tempers fetal hemoglobin induction by hydroxyurea in patients with sickle cell disease.
  2. Nitrosyl Hemoglobin Formation from Nitrite in Normal and Sickle Blood.
  3. Sickle Cell Disease.
  4. Opioid-related emergency admissions in people with opioid dependence/use disorder with and without sickle cell disease: An analysis of multi-state insurance claims.
  5. A contemporary evaluation of the frequency & factors associated with overt stroke across the lifespan: A Ghanaian sickle cell disease registry analysis.
  6. TR4 and BCL11A Repress γ-globin Transcription via Independent Mechanisms.
  7. Respiratory phenotype and healthcare utilization patterns by adults with sickle cell disease.
  8. Vestibular Dysfunction in Patients With Sickle Cell Disease: A Systematic Review.
  1. Blood Adv. 2024 Oct 07. pii: bloodadvances.2024013801. [Epub ahead of print]
    CYB5R3 T117S tempers fetal hemoglobin induction by hydroxyurea in patients with sickle cell disease.
    Fabliha A Chowdhury, Malini Sharma, Desiree Schafer, Seyed Mehdi Nouraie, Mark T Gladwin, Adam C Straub, Katherine C Wood.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2024013801
  2. Free Radic Biol Med. 2024 Oct 08. pii: S0891-5849(24)00972-9. [Epub ahead of print]
    Nitrosyl Hemoglobin Formation from Nitrite in Normal and Sickle Blood.
    Laxman Poudel, Elmira Alipour, Silvie Suriany, Honglei Liu, Stephen R Baker, Thilini Karunarathna, Alex George, Jon Detterich, Daniel B Kim-Shapiro.
      Sickle cell anemia is caused by a single mutation in the gene encoding the beta subunit of hemoglobin. Due to this mutation, sickle cell hemoglobin (HbS) polymerizes under hypoxic conditions, decreasing red blood cell deformability and leading to multiple pathological effects that cause substantial morbidity and mortality. Several pre-clinical and human studies have demonstrated that the anion nitrite has potential therapeutic benefits for patients with sickle cell disease. Nitrite is reduced to nitric oxide (NO) by deoxygenated hemoglobin contributing to vasodilation, decreasing platelet activation, decreasing cellular adhesion to activated endothelium, and decreasing red cell hemolysis; all of which could ameliorate patient morbidities. Previous work on extracellular hemoglobin has shown that solution phase HbS reduces nitrite to NO faster than normal adult hemoglobin (HbA), while polymerized HbS reduces nitrite slower than HbA. In this work, we compared the rate of nitrite reduction to NO measured by the formation of nitrosyl hemoglobin in sickle and normal red blood cells at varying hemoglobin oxygen saturations. We found the overall rate of nitrite reduction between normal and sickle red blood cells was similar and confirmed this result under partially oxygenated conditions, but normal red blood cells reduced nitrite faster than sickle red blood cells under anoxia where HbS polymerization is maximal. These results are consistent with previous work using extracellular hemoglobin where the rate of reduction by solution phase HbS makes up for the slower reduction by polymer phase HbS under partially oxygenated conditions, but the polymer phase kinetics dominates in the complete absence of oxygen.
    Keywords:  Electron Paramagnetic Resonance; Hemoglobin: Blood; Kinetics; Nitric Oxide; Nitrite; Sickle Cell Disease
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.271
  3. Transfus Med Hemother. 2024 Oct;51(5): 332-344
    Sickle Cell Disease.
    Joachim B Kunz, Laura Tagliaferri.
       Background: Sickle cell disease (SCD) is among the most frequent hereditary disorders globally and its prevalence in Europe is increasing due to migration movements.
    Summary: The basic pathophysiological event of SCD is polymerization of deoxygenated sickle hemoglobin, resulting in hemolysis, vasoocclusion, and multiorgan damage. While the pathophysiological cascade offers numerous targets for treatment, currently only two disease-modifying drugs have been approved in Europe and transfusion remains a mainstay of both preventing and treating severe complications of SCD. Allogeneic stem cell transplantation and gene therapy offer a curative option but are restricted to few patients due to costs and limited availability of donors.
    Key Message: Further efforts are needed to grant patients access to approved treatments, to explore drug combinations and to establish new treatment options.
    Keywords:  Gene therapy; Hydroxyurea; Sickle cell disease; Stem cell transplantation; Transfusion
    DOI:  https://doi.org/10.1159/000540149
  4. Gen Hosp Psychiatry. 2024 Sep 24. pii: S0163-8343(24)00202-0. [Epub ahead of print]91 83-88
    Opioid-related emergency admissions in people with opioid dependence/use disorder with and without sickle cell disease: An analysis of multi-state insurance claims.
    Shiyuan A Liu, Tashalee R Brown, Allison A King, Lewei Allison Lin, Sana S Rehman, Richard A Grucza, Kevin Y Xu.
       OBJECTIVE: We estimated rates of opioid-related admissions in people with sickle cell disease (SCD) diagnosed with opioid-related disorders.
    METHOD: We analyzed ten years (1/2006-12/2016) of multi-state claims data from 191,638 people receiving treatment for opioid-related disorders in the U.S. We used multivariable cox regression to estimate the association between admissions for opioid-related adverse events after initiating treatment and SCD status (SCD[n = 320] vs no SCD[n = 191,318]) among people with opioid-related disorders, controlling for sociodemographic variables and comorbidities. In secondary analyses, we excluded events occurring simultaneously as vaso-occlusive crises (VOCs) and computed rates of admissions for non-opioid substance-related events (i.e., alcohol, cannabis).
    RESULTS: Whereas 287(90 %) of the SCD cohort had >1 all-cause admission, of which 199 were for VOCs, only 78(20 %) experienced an opioid-related adverse event. The SCD cohort experienced higher rates of opioid-related admissions than the non-SCD cohort (aHR = 1.82[95 % CI = 1.51-2.19), a finding that remained robust even after excluding events that occurred at the same time as a VOC. SCD diagnoses were not associated with admissions for non-opioid substance-related events.
    CONCLUSIONS: Even though clinicians may perceive people with SCD as being at elevated risk for substance use disorders, opioid-related admissions made up only a small fraction of all-cause admissions among people with SCD diagnosed with opioid-related disorders, in contrast to VOCs that comprised the majority of admissions. Opioid-related admissions, while modestly higher among those with SCD than among peers without SCD, were relatively uncommon.
    DOI:  https://doi.org/10.1016/j.genhosppsych.2024.09.013
  5. J Neurol Sci. 2024 Sep 30. pii: S0022-510X(24)00399-X. [Epub ahead of print]466 123263
    A contemporary evaluation of the frequency & factors associated with overt stroke across the lifespan: A Ghanaian sickle cell disease registry analysis.
    Fred Stephen Sarfo, Vivian Paintsil, Isaac Nyanor, Emmanuel Kofi Asafo-Adjei, Eunice Agyemang Ahmed, Samuel Blay Nguah, Evans Xorse Amuzu, Suraj Yawnumah Abubakar, Lawrence Osei Tutu, Yaa Gyamfuah Oppong Mensah, Aaron Kwasi Nartey, Agnes Asare Bediako, Leslie Osei, Abigail Adjei Mantey, Evelyn Acheampong, Daniel Ansong, Alex Osei Akoto.
       BACKGROUND: Stroke is a devastating complication of Sickle Cell Disease (SCD) with significant mortality and substantial morbidity. The burden of prevalent stroke in SCD is highest in sub-Saharan Africa and estimated at 4.2 % to 6.4 % in the era where evidence-based prevention strategies such as use of hydroxyurea therapy and transcranial doppler ultrasound were not routine care.
    PURPOSE: To assess the contemporary frequency and factors associated with prevalent stroke across the lifespan in an SCD registry at the tertiary medical center in Ghana.
    METHODS: This is a cross-sectional study conducted at the Komfo Anokye Teaching Hospital, a tertiary medical center in the middle belt of Ghana. The center has comprehensive Sickle Cell Clinics for children, adolescents, and adults with a patient registry established as part of the Sickle Pan-African Research Consortium (SPARCo)-Ghana study from 2017 to date. Data captured in the registry and analyzed for the present study include demographics, stroke status using the WHO criteria supplemented by the Questionnaire for Verifying Stroke Free Status (QVSFS), use of hydroxyurea, and complete blood count. Logistic regression modeling was utilized to assess factors associated with stroke.
    RESULTS: Among a registry cohort of 4115 individuals with confirmed SCD, 35 (0.85 %, 95 % CI: 0.59-1.18 %) had overt or clinically confirmed stroke. The frequency of stroke differed significantly across the lifespan being 0.38 % (95 % CI: 0.12-0.64 %) among children <10 years, 1.23 % (95 % CI: 0.73-1.94 %) among adolescents aged 10 to 17 years, and 1.44 % (95 % CI: 0.66-2.71 %) among adults 18 years or more, p = 0.007. In adjusted analysis, each 10-year increase in age was associated with odds ratio, OR (95 % CI) of 1.90 (1.42-2.54) and hydroxyurea use, OR of 6.09 (2.65-13.99). The association between hydroxyurea and stroke observed in this cross-sectional study is not causal.
    CONCLUSION: Approximately 1 in 120 SCD patients in this large Ghanaian cohort had clinically overt stroke. The gradual uptake of hydroxyurea therapy into routine care for SCD in this resource-limited setting, may partly explain the lower frequency of stroke.
    Keywords:  Africa; Hydroxyurea; Risk factors; Sickle cell disease; Stroke
    DOI:  https://doi.org/10.1016/j.jns.2024.123263
  6. Blood. 2024 Oct 11. pii: blood.2024024599. [Epub ahead of print]
    TR4 and BCL11A Repress γ-globin Transcription via Independent Mechanisms.
    Yu Wang, Greggory Myers, Lei Yu, Kaiwen Deng, Ginette Balbin-Cuesta, Sharon A Singh, Yuanfang Guan, Rami Khoriaty, James Douglas Engel.
      Nuclear receptor TR4 was previously shown to bind to the -117 position of the -globin gene promoters in vitro, which overlaps the more recently described BCL11A binding site. The role of TR4 in human -globin gene repression has not been extensively characterized in vivo, while any relationship between TR4 and BCL11A regulation through the -globin promoters is unclear at present. We show here that TR4 and BCL11A competitively bind in vitro to distinct, overlapping sequences, including positions overlapping -117 of the -globin promoter. We found that TR4 represses -globin transcription and HbF accumulation in vivo in a BCL11A-independent manner. Finally, examination of the chromatin occupancy of TR4 within the -globin locus, when compared to BCL11A, shows that both bind avidly to the locus control region and other sites, but that only BCL11A binds to the -globin promoters at statistically significant frequency. These data resolve an important discrepancy in the literature, and thus clarify possible approaches to the treatment of sickle cell disease and -thalassaemia.
    DOI:  https://doi.org/10.1182/blood.2024024599
  7. Blood Adv. 2024 Oct 05. pii: bloodadvances.2023010808. [Epub ahead of print]
    Respiratory phenotype and healthcare utilization patterns by adults with sickle cell disease.
    Atu Agawu, Nii N Nortey, Charleen Jacobs, Alexis M Zebrowski, Michelle P Lin, Jeffrey Glassberg.
      Adults with sickle cell disease (SCD) and asthma have increased mortality and health care utilization, however there are individuals with respiratory symptoms (including cough and wheeze) without asthma. These individuals may have similar patterns of increased mortality and healthcare utilization. Objective is to characterize the association between respiratory phenotype and healthcare utilization by adults with SCD. Cross-sectional study of adults with SCD presenting for emergency and inpatient hospital care from 2012-2014 in Florida, Iowa, and New York using state level healthcare utilization databases. Outcomes of interest All-cause, SCD-related, painful episode, and ACS related care. Respiratory phenotype was defined as SCD + Asthma, SCD + Respiratory symptoms, and SCD + none. We built multivariable logistic regression and negative binomial regression models to evaluate the association adjusting for demographics, social determinant of health proxies, year of care, and state. Of 29,952 identified individuals, 3.4% had intermittent respiratory symptoms and a larger proportion (15.6%) had asthma. There was a high rate of inpatient hospitalizations (43%)) and ED visits (60%). Compared to individuals with intermittent respiratory symptoms, Individuals with asthma had a higher annual risk of inpatient hospitalizations (48% vs. 37%) but lower annual risk of an ED visit (62% vs. 86%). The pattern of increased healthcare utilization amongst individuals with intermittent respiratory symptoms was consistent across each utilization type. In this large cohort adults with SCD we identified some with intermittent respiratory symptoms who had significantly increased healthcare utilization. This warrants further evaluation to understand potential etiologies and interventions.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010808
  8. Otol Neurotol. 2024 Sep 25.
    Vestibular Dysfunction in Patients With Sickle Cell Disease: A Systematic Review.
    Jonathan Laredo, Sofia Torres-Small, Lin Wu, Tomoko Makishima, Celine Richard.
       INTRODUCTION: Sickle cell disease (SCD) often leads to sensorineural hearing loss due to vaso-occlusive events in the cochlear vasculature. Although the vestibule and cochlea share a blood supply, information on vestibulopathy in SCD is limited. This systematic review aims to consolidate current knowledge on vestibular dysfunction in SCD patients.
    METHODS: This study, registered on PROSPERO, involved a thorough electronic search using MEDLINE-Ovid, Embase, Google Scholar, The Cochrane Library, and Scopus databases from inception to December 2023. Data extraction adhered to PRISMA guidelines. Authors independently assessed bias and evidence quality using NIH Study Quality Assessment tools. Inclusion criteria covered articles mentioning vestibular symptoms in SCD patients, whereas exclusion criteria comprised non-English articles and vestibular symptoms limited to treatment side effects.
    RESULTS: Out of 2,495 studies, only 12 met the criteria. Among SCD patients undergoing head imaging, 19% reported inner ear complaints, and 70% experienced dizziness/imbalance. In a group of SCD children, there was a significant relationship between endothelial dysfunction and vertigo duration. The recommended imaging sequence was T1-weighted thin-section temporal bone MRIs, which revealed abnormal findings even without clinical symptoms. Imaging showed labyrinthine hemorrhage and labyrinthitis ossificans, mostly unilateral. Vestibular symptoms emerged with older age, suggesting cortical compensation kept most subjects asymptomatic. In asymptomatic adult SCD patients, there was no significant difference compared with controls in tracking test batteries and positional tests; however, saccadic latency was longer in SCD patients.
    CONCLUSION: The existing data on vestibulopathy in SCD were limited and often of poor quality. Although a connection between SCD and vestibular symptoms was noted, information on treatment approaches was scant. Further research in this area could contribute to the early diagnosis of vestibular dysfunction, potentially enhancing outcomes for SCD patients.
    DOI:  https://doi.org/10.1097/MAO.0000000000004327
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