bims-sicedi 2024-12-08 papers

bims-sicedi

Biomed News

on Sickle cell disease

Issue of 2024–12–08
thirteen papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Coexistent sickle cell anemia and autoimmune hemolytic anemia in two adolescents.
Computational analysis of flow and transport suggests reduced oxygen levels within intracranial aneurysms, especially in individuals with sickle-cell disease.
Prevalence and Predictive Factors of Sickle Cell Emergencies Readmission in the Clinical Hematology Department of Dakar, Senegal.
Cerebral hemodynamics and oxygen metabolism in patients with milder and severe forms of sickle cell disease and thalassemia.
Contextualizing prophylactic red blood cell antigen matching in the lifelong care of sickle cell disease and thalassaemia patients.
Low-dose iron chelation as anti-oxidative therapy in patients with sickle cell disease: A single-centre pilot study.
Reduced GATA1 levels are associated with ineffective erythropoiesis in sickle cell anemia.
Elevated Posterior Insula Glutamate in Patients with Sickle Cell Disease.
Sex-stratified association of variants in the Serotonin 1A receptor gene with acute crisis pain among African American sickle cell disease patients.
A qualitative enquiry into lived experience and coping strategies of undergraduates with sickle cell disease in Nigeria.
Sickle Trait and Alpha Thalassemia Increase NOS-Dependent Vasodilation of Human Arteries Through Disruption of Endothelial Hemoglobin-eNOS Interactions.
A Telemedicine Triage Model for Infusion Center-Based Management of Adult Sickle Cell Pain Episodes.
A Comparative Analysis of Hydroxyurea Treatment on Coagulation Profile Among Sickle Cell Anaemia Children in Lagos, Nigeria.

Einstein (Sao Paulo). 2024 ;pii: S1679-45082024000100508. [Epub ahead of print]22 eRC1105

Coexistent sickle cell anemia and autoimmune hemolytic anemia in two adolescents.

Vinícius Reis Soares, Bruna Paccola Blanco, Carla Luana Dinardo, Marlene Pereira Garanito.

The development of alloantibodies or autoantibodies is a complication observed in sickle cell disease. Autoimmunization occurs in 7.6-12% of chronically or intermittently transfused patients with sickle cell disease; however, the clinical implications of autoAbs are unclear. Few studies have focused on pediatric sickle cell disease and autoimmune hemolytic anemia. Herein, we present the coexistence of sickle cell disease and autoimmune hemolytic anemia in two adolescent patients, focusing on their pathophysiology, diagnosis, clinical management, and outcomes.

DOI: https://doi.org/10.31744/einstein_journal/2024RC1105
J Biomech Eng. 2024 Dec 05. 1-26

Computational analysis of flow and transport suggests reduced oxygen levels within intracranial aneurysms, especially in individuals with sickle-cell disease.

Marisa Bazzi, Hadi Wiputra, David Wood, Victor H Barocas.

Sickle cell disease (SCD) is a genetic condition characterized by an abundance of sickle hemoglobin in red blood cells. SCD patients are more prone to intracranial aneurysms (ICA) compared to the general population, with distinctive features such as multiple intracranial aneurysms: 66% of SCD patients with ICAs have multiples ICAs, compared to 20% in non-sickle patients. The exact mechanism behind these associations is not fully understood, but there is a hypothesized link between hypoxia and impaired synthesis of extracellular matrix, which may weaken the vessel walls, favoring aneurysm formation and rupture. SCD patients experience reduced blood oxygen levels, potentially exacerbating hypoxia in ICAs, and potentially contributing to aneurysm development and early onset in these patients. In this work, we performed a series of computational studies (Fluent) using idealized geometries to investigate the key differences in the oxygen transport and blood flow dynamics inside an aneurysm formation for sickle and non-sickle cases. We found that using SCD parameters resulted in a 14% to 68% reduction in blood flow and a 37% to 70% reduction in oxygen availability within the aneurysm, depending on the vessel curvature and the aneurysm throat diameter, due to factors including oxygen-dependent viscosity and alteration in the oxygen transport. The results indicate that depending on geometry and flow characteristics, some degree of hypoxia maybe present in aneurysm bulb and would be more severe in SCD patients. This study hopes to bring into attention the potential presence of hypoxic environment in the aneurysm bulb.

DOI: https://doi.org/10.1115/1.4067323
Anemia. 2024 ;2024 7143716

Prevalence and Predictive Factors of Sickle Cell Emergencies Readmission in the Clinical Hematology Department of Dakar, Senegal.

Alioune Badara Diallo, Moussa Seck, Sokhna Aissatou Touré, Mohamed Keita, Elimane Seydi Bousso, Blaise Félix Faye, Saliou Diop.

Introduction: Sickle cell emergencies are the most common cause of hospitalization for patients with sickle cell disease (SCD). Hospital readmissions represent a considerable financial burden for healthcare systems and increase patient morbidity and mortality. The aim of this study was to assess the prevalence and predictive factors of sickle cell emergencies readmission. Materials and Methods: We conducted a prospective, cross-sectional, descriptive, and analytical study over a 4-month period, including all adult patients admitted for an emergency related to SCD: vaso-occlusive crisis (VOC), acute chest syndrome (ACS), severe anemia, infections, priapism, and stroke. Readmission was considered when the patient returned to the emergency within a period of <30 days, either due to recurrence, persistence of the same complication, or the occurrence of another acute complication related to SCD. Results: We recorded 151 sickle cell emergencies for 112 patients, representing 0.33 emergencies/month/patient. Fifty-eight cases of readmission were recorded, resulting in a readmission rate of 38.41%. Among these patients, 53 (91.37%) had two admissions, and 5 (8.62%) had three admissions. The median age of the patients was 28.41 years (16-70 years), and the sex ratio was 0.57. The SS sickle cell phenotype was predominant in 97 patients (86.61%). The reasons for readmission were VOC (82.75%), ACS (13.72%), and severe anemia (3.44%). The main factors that predicted readmission were the existence of professional activity, a low fetal hemoglobin (HbF) level, the existence of neutrophilia, lymphocytosis, and/or thrombocytosis (p values of 0.0084, 0.043, and 0.020 respectively). Conclusion: The 30-day readmission rate after a sickle cell emergency is high in our study. The main factors that predicted readmission were the existence of professional activity, a relatively low level of fetal Hb, the existence of neutrophilia, lymphocytosis, and/or thrombocytosis.

DOI: https://doi.org/10.1155/anem/7143716
Hemasphere. 2024 Dec;8(12): e70022

Cerebral hemodynamics and oxygen metabolism in patients with milder and severe forms of sickle cell disease and thalassemia.

Liza Afzali-Hashemi, Koen P A Baas, Anouk Schrantee, Erfan Nur, Chau Vu, Soyoung Choi, Silvie Suriany, John C Wood, Aart J Nederveen, Bart J Biemond.

Silent cerebral infarcts (SCIs) are present in patients with sickle cell disease (SCD) and thalassemia, but the pathophysiology of SCIs is not fully understood. Previous studies mainly focused on cerebral hemodynamics and oxygen metabolism in patients with severe SCD (HbSS/HbSβ°) but not in milder forms of SCD (HbSC/HbSβ+) and thalassemia despite the high prevalence of SCIs in these patients. In this work, we studied the cerebral hemodynamics and oxygen metabolism, and SCI lesion load in 75 severe and 26 mild adult SCD patients, 18 thalassemia patients (as anemic comparison group), and 30 healthy controls before and after a vasodilatory challenge with acetazolamide. Cerebral blood flow was significantly higher in patients with severe SCD and thalassemia compared to patients with mild SCD and controls (p < 0.05). Conversely, oxygen extraction fraction and cerebral metabolic rate of oxygen (CMRO2) were significantly lower in patients with severe SCD and thalassemia compared to other groups (p < 0.01). In contrast, no difference in SCI volumes was found between mild and severe SCD and thalassemia patients. After acetazolamide administration, oxygen delivery increased less in severe SCD and thalassemia patients compared to other groups (p < 0.01) and CMRO2 decreased only in severe SCD patients (p < 0.01). Given the reduced CMRO2 values in severe SCD and thalassemia patients, we conclude that reduced cerebral oxygen consumption in these patient groups is mostly related to anemia. Our data suggest that the pathophysiology of SCIs in patients with milder forms of SCD might be more related to prior episodes of anemia or other sickle cell-related factors.

DOI: https://doi.org/10.1002/hem3.70022
Br J Haematol. 2024 Dec 02.

Contextualizing prophylactic red blood cell antigen matching in the lifelong care of sickle cell disease and thalassaemia patients.

Eric A Gehrie, Garrett S Booth.

  Alloimmunization to minor red blood cell antigens has been linked to patient morbidity and mortality, especially among people living with sickle cell disease and transfusion-dependent thalassaemia. Prophylactic antigen matching is commonly used to prevent alloimmunization, but the evidence supporting this common practice is very limited. The report by Wolf et al. summarizes the latest literature on this topic and importantly finds that there is insufficient evidence to recommend prophylactic extended antigen matching (beyond ABO, RhD, RhCcEe and K). In an era of chronic blood shortages, this approach may help to assure patient access to elective surgery and cellular therapies, while preserving the supply of extensively antigen-matched red cells for patients with specific needs. Commentary on: Wolf et al. Red cell specifications for blood group matching in patients with haemoglobinopathies: An updated systematic review and clinical practice guideline from the International Collaboration for Transfusion Medicine Guidelines. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19837.

Keywords:  B thalassaemia; clinical transfusion medicine; sickle cell disease

DOI:  https://doi.org/10.1111/bjh.19878
Br J Haematol. 2024 Dec 06.

Low-dose iron chelation as anti-oxidative therapy in patients with sickle cell disease: A single-centre pilot study.

Aafke E Gaartman, Boukje M Beuger, Lydian A de Ligt, Martijn Veldthuis, Hanke L Matlung, Joost C M Meijers, Casper G Schalkwijk, Koen de Heer, Jarom Heijmans, Rob van Zwieten, Bart J Biemond, Robin van Bruggen, Erfan Nur.

DOI: https://doi.org/10.1111/bjh.19943
Haematologica. 2024 Dec 05.

Reduced GATA1 levels are associated with ineffective erythropoiesis in sickle cell anemia.

Sara El Hoss, Panicos Shangaris, John Brewin, Maria Eleni Psychogyiou, Cecilia Ng, Lauren Pedler, Helen Rooks, Érica M F Gotardo, Lucas F S Gushiken, Pâmela L Brito, Kypros H Nicolaides, Nicola Conran, David C Rees, John Strouboulis.

Ineffective erythropoiesis (IE) is defined as the abnormal differentiation and excessive destruction of erythroblasts in the marrow, accompanied by an expanded progenitor compartment and relative reduction in the production of reticulocytes. It is a defining feature of many types of anemia, including beta-thalassemia. GATA1 is an essential transcription factor for erythroid differentiation, known to be implicated in hematological conditions presenting with IE, including beta-thalassemia and congenital dyserythropoietic anemia. However, little is known about the role of GATA1 in the erythropoietic defects recently described in sickle cell anemia (SCA). In the present study, we performed a detailed characterization of the role of GATA1 and ineffective erythropoiesis in SCA using both invitro and in-vivo assay systems. We demonstrate a significant decrease in GATA1 protein levels during SCA erythropoiesis and a concomitant increase in oxidative stress. Furthermore, we found that an increase in the activity of the inflammatory caspase, caspase 1, was driving the decrease in GATA1 levels during SCA erythropoiesis and that, upon inhibition of caspase 1 activity, SCA erythropoiesis was rescued and GATA1 levels partially restored. Our study further elucidates the defect in erythropoiesis in SCA, and may therefore help in the development of novel approaches to normalise the bone marrow niche prior to stem cell transplantation, or facilitate the production of healthy stem cells for gene therapy.

DOI: https://doi.org/10.3324/haematol.2024.286010
J Pain. 2024 Nov 28. pii: S1526-5900(24)00721-1. [Epub ahead of print] 104743

Elevated Posterior Insula Glutamate in Patients with Sickle Cell Disease.

Xiaopeng Zhou, Eric Ichesco, Andrew Q Pucka, Ziyue Liu, Andrew Rw O'Brien, Steven E Harte, Richard E Harris, Ying Wang.

  Sickle cell disease (SCD) is an inherited hemolytic disorder accompanied by chronic pain and recurrent acute painful episodes known as vaso-occlusive crises (VOCs). Increased Glx (glutamate+glutamine) and lowered insula GABA concentration has been reported in the insula of patients with fibromyalgia, a nociplastic chronic pain condition, and may affect the pathophysiology of pain-related syndromes. Therefore, proton magnetic resonance spectroscopy (1H-MRS) was conducted to measure levels of Glx and other brain metabolites using a single voxel (size: 2×3×3 cm3) in the right posterior insula cortex (PIC) in 17 individuals with SCD and 17 ethnicity-, age- and sex-matched healthy controls (HCs). The frequency of VOCs in the preceding 12 months was recorded. The concentration of Glx (p=0.019) and the ratio of Glx to tCr (total creatine, p=0.035) in the PIC were significantly higher in patients with SCD as compared to matched HCs (n=17). Secondary analyses with the unpaired full sample of 24 SCD also showed a significantly higher level of Glx/tCr than HCs (n=19), with a positive correlation between the level of Glx/tCr and the number of VOCs (p=0.034, r=0.476), as well as a negative correlation between Glx and sensory sensitivity assessed by tonic pressure pain in gastrocnemius area of the non-dominant leg (p=0.040, r=-0.462). The unpaired full sample additionally revealed a significant difference in sensory sensitivity (p=0.050). Altered metabolites such as GABA and myoinositol were also observed between SCD and HCs. These results suggest that elevated excitatory neurotransmission in the insula might contribute to nociplastic pain in SCD. PERSPECTIVE: Our work highlighted the innovative finding of elevated levels of the excitatory neurotransmitter glutamate with glutamine in patients with SCD compared to healthy controls. The trend of positive relationship between Glx/tCr and the frequency of VOCs suggests that an excitatory brain neurotransmitter imbalance may be involved in VOCs.

Keywords:  (1)H-MRS; brain metabolites; glutamate; pain; sickle cell disease; vaso-occlusive crisis

DOI:  https://doi.org/10.1016/j.jpain.2024.104743
Exp Hematol. 2024 Nov 28. pii: S0301-472X(24)00556-3. [Epub ahead of print] 104692

Sex-stratified association of variants in the Serotonin 1A receptor gene with acute crisis pain among African American sickle cell disease patients.

Nilanjana Sadhu, Ying He, Yavnika Kashyap, Giokdjen Ilktach, Michael A Wang, Yingwei Yao, Diana J Wilkie, Robert E Molokie, Zaijie Jim Wang.

  Patients with sickle cell disease (SCD) suffer from pain in their daily lives. Both the acute and chronic pain phenotypes of this disease exhibit high variability, making pain management a challenge. The underlying reasons for the phenotypic variability are poorly understood. Given the importance of serotonergic neurotransmission in pain signaling, we aimed to explore the role of variants in the 5-HT1A receptor gene (HTR1A) on pain variability in SCD. Four variants (rs6449693, rs878567, rs6294, and rs10042486) in HTR1A were genotyped in a cohort of 131 African Americans with SCD. Acute and chronic pain were measured by the acute care utilization and the McGill Pain Questionnaire, respectively. Association analyses were performed for three genetic models (additive, dominant, and recessive). Three variants (rs6449693, rs6294, and rs10042486) in HTR1A showed significant association with crisis pain in both the additive and dominant models. While the G allele of rs6449693 and the C allele of rs10042486 associated with lower acute crisis pain, the T allele of rs6294 associated with increased acute crisis pain. Sex-stratified analyses revealed that the associations of these three variants with acute pain were significant only in males, and not in females. Furthermore, the A allele rs878567 that did not reach statistical significance in the overall cohort, showed a significant association with lower crisis pain in males. As the first study to explore the role of HTR1A variants in sickle cell pain, we identified that four variants across the gene are associated with acute crisis pain in SCD in a sex-stratified manner.

Keywords:  HTR1A; hemoglobinopathies; painful crisis; sex differences; sickle cell disease

DOI:  https://doi.org/10.1016/j.exphem.2024.104692
BMC Public Health. 2024 Dec 05. 24(1): 3388

A qualitative enquiry into lived experience and coping strategies of undergraduates with sickle cell disease in Nigeria.

Olumide Thomas Adeleke, Yetunde Toyin Olasinde, Olufemi Ebenezer Folaranmi, Yusuf Larry Ayuba, Efeturi Agelebe, Mofoluke Modupe Rufai, Oludamola Victoria Adeleke, Oyelola Eyinade Adeoye, Aderemi Temitayo Olabode, Dolapo Emmanuel Ajala, Titilola Stella Akingbola.

   BACKGROUND: Sickle cell disease (SCD) is of serious public health concern. Paucity of literature exists on qualitative experiences of people with SCD, despite substantial research on the clinical signs and management of the disease. This study examined how SCD affects a range of undergraduate students' experiences, their academic achievements, relationships, mental health and healthcare utilization.
METHODS: This was an exploratory qualitative study that interviewed 22 participants selected by thematic saturation between September 2023 and February 2024. The study was conducted in Bowen University, Iwo, Osun State and Bowen University Teaching Hospital, Ogbomoso, Oyo State, annex of Bowen University, Nigeria. Thematic analysis of qualitative data was conducted.
RESULTS: Eight distinct themes emerged and were linked to the study objectives. Findings show resilience and determination of the students in navigating the complexities of living with sicknesses while pursuing their academic goals and daily activities. This underscores the need for increased community awareness, support for undergraduates living with SCD, and access to effective healthcare to better assist undergraduates with SCD in managing their health and academic responsibilities effectively.
CONCLUSION: Health professionals and lecturers working with undergraduates with SCD should be aware of diverse coping strategies for them and prioritize integrating such into clinical conversations and support in appropriate contexts.

Keywords:  Coping strategies; Lived experience; Sickle cell disease (SCD); Undergraduates

DOI:  https://doi.org/10.1186/s12889-024-20927-6
Circulation. 2024 Dec 05.

Sickle Trait and Alpha Thalassemia Increase NOS-Dependent Vasodilation of Human Arteries Through Disruption of Endothelial Hemoglobin-eNOS Interactions.

Steven D Brooks, A Parker Ruhl, Xianke Zeng, Phillip Cruz, Sergio A Hassan, Olena Kamenyeva, Md Abdul Hakim, Lauryn A Ridley, Bianca M Nagata, Juraj Kabat, Sundar Ganesan, Rachel L Smith, Mary Jackson, Jessica Nino de Rivera, Alison J McLure, Jarrett M Jackson, Robert O Emeh, Naomi Tesfuzigta, Kyeisha Laurence, Stacy Joyce, Christina Yek, Sophana Chea, Derron A Alves, Brant E Isakson, Jessica Manning, Jeremy L Davis, Hans C Ackerman.

   BACKGROUND: Severe malaria is associated with impaired nitric oxide (NO) synthase (NOS)-dependent vasodilation, and reversal of this deficit improves survival in murine models. Malaria might have selected for genetic polymorphisms that increase endothelial NO signaling and now contribute to heterogeneity in vascular function among humans. One protein potentially selected for is alpha globin, which, in mouse models, interacts with endothelial NOS (eNOS) to negatively regulate NO signaling. We sought to evaluate the impact of alpha globin gene deletions on NO signaling and unexpectedly found human arteries use not only alpha but also beta globin to regulate eNOS.
METHODS: The eNOS-hemoglobin complex was characterized by multiphoton imaging, gene expression analysis, and coimmunoprecipitation studies of human resistance arteries. Novel contacts between eNOS and hemoglobin were mapped using molecular modeling and simulation. Pharmacological or genetic disruption of the eNOS-hemoglobin complex was evaluated using pressure myography. The association between alpha globin gene deletion and blood pressure was assessed in a population study.
RESULTS: Alpha and beta globin transcripts were detected in the endothelial layer of the artery wall. Imaging colocalized alpha and beta globin proteins with eNOS at myoendothelial junctions. Immunoprecipitation demonstrated that alpha globin and beta globin form a complex with eNOS and cytochrome b5 reductase. Modeling predicted negatively charged glutamic acids at positions 6 and 7 of beta globin to interact with positively charged arginines at positions 97 and 98 of eNOS. Arteries from donors with a glutamic acid-to-valine substitution at beta globin position 6 (sickle trait) exhibited increased NOS-dependent vasodilation. Alpha globin gene deletions were associated with decreased arterial alpha globin expression, increased NOS-dependent vasodilation, and lower blood pressure. Mimetic peptides that targeted the interactions between hemoglobin and eNOS recapitulated the effects of these genetic variants on human arterial vasoreactivity.
CONCLUSIONS: Alpha and beta globin subunits of hemoglobin interact with eNOS to restrict NO signaling in human resistance arteries. Malaria-protective genetic variants that alter the expression of alpha globin or the structure of beta globin are associated with increased NOS-dependent vasodilation. Targeting the hemoglobin-eNOS interface could potentially improve NO signaling in diseases of endothelial dysfunction such as severe malaria or chronic cardiovascular conditions.

Keywords:  alpha globin; alpha thalassemia; beta globin; endothelial nitric oxide synthase; hemoglobin; nitric oxide; sickle cell

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.066003
Blood Adv. 2024 Dec 06. pii: bloodadvances.2024013973. [Epub ahead of print]

A Telemedicine Triage Model for Infusion Center-Based Management of Adult Sickle Cell Pain Episodes.

John Bliamptis, Alan You, Jessica Groesbeck, Stefanie Sacknoff, Sinead Byrne, Srila Gopal.

DOI: https://doi.org/10.1182/bloodadvances.2024013973
Adv Hematol. 2024 ;2024 5002373

A Comparative Analysis of Hydroxyurea Treatment on Coagulation Profile Among Sickle Cell Anaemia Children in Lagos, Nigeria.

Blessing E Kene-Udemezue, Abideen O Salako, Adeseye M Akinsete, Oluwatosin O Odubela, Titilope A Adeyemo.

  Background: Hydroxyurea (HU) is a disease-modifying therapy with significant clinical and laboratory efficacy among individuals living with sickle cell anaemia (SCA). This is evident through increased fetal haemoglobin, higher packed cell volume, improved red cell hydration, reduced leukocytes, and platelet function. The effect on the coagulation pathway and pathophysiologic mechanism remains unclear, especially in children living with SCA. This study evaluated the coagulation profile using D-dimer and thrombin antithrombin complex (TAT) in children with SCA. Methods: The cross-sectional study was conducted over three months at LUTH among 80 children living with SCA in steady state aged 2-18 years (40 HU exposed and 40 HU naïve, respectively). Blood samples were assayed for D-dimer, TAT, and complete blood count. Descriptive analysis such as mean and standard deviation for normally distributed variables or median and interquartile range for skewed data were used to summarize continuous variables, while proportion or percentages for categorical variables. Univariate analysis and bivariate analysis were done and statistical significance was set at p < 0.05. Results: The mean age (±SD) of study participants in both groups was 11.35 (±4.6 years). D-dimer levels (23.27 ng/mL) and TAT (29.79 pg/mL) were significantly lower among HU exposed compared to HU naïve children (62.73 ng/mL and 109.34 pg/mL, respectively) p < 0.001. There was a negative correlation between D-dimer and TAT with the duration of HU use (r = -0.499, p=0.001, and r = -0.401, p=0.010), respectively. There was a positive correlation between D-dimer and TAT with total WBC (r = 0.368, p=0.019, and r = 0.385, p=0.014, respectively) among the HU naïve participants and a negative correlation between D-dimer and TAT with haemoglobin level (r = -0.303, p=0.047, and r = -0.311, p=0.041, respectively) among HU exposed children. Conclusion: HU modulates the D-dimer and TAT levels of children living with SCA toward the normal reference range, thus reducing the risk of hypercoagulability and associated sequelae. Therefore, continuous advocacy for HU use should entail close monitoring of adverse effects.

Keywords:  D-dimer; hydroxyurea; sickle cell anaemia; thrombin antithrombin complex

DOI:  https://doi.org/10.1155/ah/5002373