bims-sicedi 2024-10-20 papers

bims-sicedi

Biomed News

on Sickle cell disease

Issue of 2024–10–20
eight papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Zinc finger nuclease-mediated gene editing in hematopoietic stem cells results in reactivation of fetal hemoglobin in sickle cell disease.
Venous Thromboembolism in Individuals with Sickle Cell Disease: A Narrative Review.
Post-exchange neutrophil count, but not post-hematocrit, predicts endogenous erythropoiesis in patients with sickle cell disease undergoing chronic red cell exchange.
Hypercoagulability in hemoglobinopathies: Decoding the thrombotic threat.
The Neuropeptide Substance P is Elevated in Sickle Cell Disease and is a Marker of Severity of Vaso-occlusive Crisis.
Secretory Phospholipase A2 as a Promising Biomarker for Predicting Acute Chest Syndrome in Children With Sickle Cell Disease: A Systematic Review and Meta-Analysis.
Changes in indicators of cerebral metabolic stress following treatment with voxelotor in children and adolescents with sickle cell anemia.
Clinical Outcomes of Sickle Cell Disease Patients With Myocardial Infarction Undergoing Percutaneous Coronary Intervention: A Nationwide Analysis.

Sci Rep. 2024 10 16. 14(1): 24298

Zinc finger nuclease-mediated gene editing in hematopoietic stem cells results in reactivation of fetal hemoglobin in sickle cell disease.

Samuel Lessard, Pauline Rimmelé, Hui Ling, Kevin Moran, Benjamin Vieira, Yi-Dong Lin, Gaurav Manohar Rajani, Vu Hong, Andreas Reik, Richard Boismenu, Ben Hsu, Michael Chen, Bettina M Cockroft, Naoya Uchida, John Tisdale, Asif Alavi, Lakshmanan Krishnamurti, Mehrdad Abedi, Isobelle Galeon, David Reiner, Lin Wang, Anne Ramezi, Pablo Rendo, Mark C Walters, Dana Levasseur, Robert Peters, Timothy Harris, Alexandra Hicks.

BIVV003 is a gene-edited autologous cell therapy in clinical development for the potential treatment of sickle cell disease (SCD). Hematopoietic stem cells (HSC) are genetically modified with mRNA encoding zinc finger nucleases (ZFN) that target and disrupt a specific regulatory GATAA motif in the BCL11A erythroid enhancer to reactivate fetal hemoglobin (HbF). We characterized ZFN-edited HSC from healthy donors and donors with SCD. Results of preclinical studies show that ZFN-mediated editing is highly efficient, with enriched biallelic editing and high frequency of on-target indels, producing HSC capable of long-term multilineage engraftment in vivo, and express HbF in erythroid progeny. Interim results from the Phase 1/2 PRECIZN-1 study demonstrated that BIVV003 was well-tolerated in seven participants with SCD, of whom five of the six with more than 3 months of follow-up displayed increased total hemoglobin and HbF, and no severe vaso-occlusive crises. Our data suggest BIVV003 represents a compelling and novel cell therapy for the potential treatment of SCD.

DOI: https://doi.org/10.1038/s41598-024-74716-7
Hemoglobin. 2024 Oct 18. 1-13

Venous Thromboembolism in Individuals with Sickle Cell Disease: A Narrative Review.

Ismail A Raslan, Ziad Solh, Kevin H M Kuo, Jameel Abdulrehman.

  Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by vaso-occlusion, hemolysis of red blood cells (RBC), and a predisposition for venous thromboembolism (VTE). The sickling and hemolysis of RBC culminate in coagulation system abnormalities, platelet activation, endothelial dysfunction, and impaired blood flow manifesting as a prothrombotic state. In addition, individuals with SCD are often exposed to extrinsic risk factors for VTE including recurrent hospitalizations, central venous catheters, and acute medical illnesses. The diagnosis is often challenging as symptoms may mimic other complications of SCD, and there is little data to guide diagnostic algorithms involving probability scoring in the SCD population. Non-anticoagulant strategies aimed at reducing disease severity may aid in lowering the risk of VTE, but data is limited. Furthermore, high quality evidence regarding anticoagulation in prevention and treatment of SCD is severely lacking, resulting in heterogeneity in clinical practice. In this narrative review we aim to review the prothrombotic pathophysiology of SCD, to describe the risk factors, high risk of mortality, and types of VTE in SCD, to develop an approach to the diagnosis of VTE in SCD, and to understand the limited available evidence for the prevention and treatment of VTE in SCD.

Keywords:  DOAC; Sickle cell disease; deep vein thrombosis; pulmonary embolism; thrombosis

DOI:  https://doi.org/10.1080/03630269.2024.2371884
Transfusion. 2024 Oct 15.

Post-exchange neutrophil count, but not post-hematocrit, predicts endogenous erythropoiesis in patients with sickle cell disease undergoing chronic red cell exchange.

Nalan Yurtsever, Nicholas Tong, Saroja Geetha, Vijay Nandi, Patricia A Shi.

   BACKGROUND: With chronic transfusion in sickle cell disease (SCD), equipoise exists regarding whether increasing the post-procedure hematocrit (Hct) suppresses endogenous erythropoiesis. Reticulocytosis predicts SCD morbidity and mortality, so this study's objective was to clarify the role of the post-procedure Hct in suppressing reticulocytosis and to identify other potential red cell exchange (RCE) parameters predictive of reticulocytosis.
STUDY DESIGN AND METHODS: This retrospective analysis of 17 patients who underwent chronic RCE at a single institution between 2014 and 2022 examined both standard red cell exchanges (SRCE) and exchanges preceded by isovolemic hemodilution (IVH-RCE). Post-procedure parameters with biologic plausibility to influence the subsequent procedure's absolute reticulocyte count (sPre-ARC) were examined using regression modeling.
RESULTS: Neither post-hematocrit, nor post-hemoglobin (Hb), nor ΔHb/day was associated with sPre-ARC or the change in HbS% per day (ΔHbS%/day). Concurrent Hb was predictive for SRCE but not IVH-RCE, where ARC trended lower than with SRCE. Male gender and post-procedure neutrophil and white cell counts were predictors of sPre-ARC, consistent with their associations with SCD morbidity and mortality. IVH-RCE had a stronger correlation than standard RCE between pre-Hct and neutrophil or white cell depletion.
DISCUSSION: Although targeting a post-procedure Hct maintains a higher subsequent pre-procedure Hb and a lower sPre-HbS%, it does not lead to sustained suppression of reticulocytosis as measured by the sPre-ARC or the ΔHbS%/day. IVH-RCE or the addition of hydroxyurea could be considered in those patients with high reticulocyte, white blood cell, or neutrophil counts.

Keywords:  chronic transfusion; endogenous erythropoiesis; leukocytosis; neutrophilia; red cell exchange; reticulocytosis; sickle cell disease

DOI:  https://doi.org/10.1111/trf.18044
Am J Hematol. 2024 Oct 14.

Hypercoagulability in hemoglobinopathies: Decoding the thrombotic threat.

Rayan Bou-Fakhredin, Maria Domenica Cappellini, Ali T Taher, Lucia De Franceschi.

Beta (β)-thalassemia and sickle cell disease (SCD) are characterized by a hypercoagulable state, which can significantly influence organ complication and disease severity. While red blood cells (RBCs) and erythroblasts continue to play a central role in the pathogenesis of thrombosis in β-thalassemia and SCD, additional factors such as free heme, inflammatory vasculopathy, splenectomy, among other factors further contribute to the complexity of thrombotic risk. Thus, understanding the role of the numerous factors driving this hypercoagulable state will enable healthcare practitioners to enhance preventive and treatment strategies and develop novel therapies for the future. We herein describe the pathogenesis of thrombosis in patients with β-thalassemia and SCD. We also identify common mechanisms underlying the procoagulant profile of hemoglobinopathies translating into thrombotic events. Finally, we review the currently available prevention and clinical management of thrombosis in these patient populations.

DOI: https://doi.org/10.1002/ajh.27500
Niger Med J. 2024 Jul-Aug;65(4):65(4): 398-402

The Neuropeptide Substance P is Elevated in Sickle Cell Disease and is a Marker of Severity of Vaso-occlusive Crisis.

Olutoyin Adenike Olawuyi, Lateef Salawu, Mutiu Ademayowa Adeyemo, Rahman A Bolarinwa, Victor Olatunji Mabayoje, Olalekan Isaac Akerele.

   Background: Acute episode of pain is the most frequent symptom for which patients with sickle cell disease (SCD) seek medical attention. The neuropeptide Substance P (SP) has been suggested as a possible aetiologic factor. This study compared the serum levels of SP in SCD subjects in painful vaso-occlusive crisis with those in steady state and normal HbAA subjects.
Methodology: This case-controlled study investigated eighteen SCD patients in vaso-occlusive crisis (VOC) and eighteen in steady state, while fourteen HbAA subjects were recruited as controls. Blood was collected in plain bottles and subsequently, the serum was separated for SP assay using the ELISA technique. Each sample was run, and results were confirmed in duplicate. Optical density was read at an absorbance of 450nm.
Results: The study showed that SP was significantly higher in SCD patients in steady state (184.79±18.67ng/L versus 104.17±19.24ng/L) compared to the controls (t=2.97, p=0.006); while the values obtained in those in VOC (375.78±76.21ng/L) were also significantly higher (t=2.433, p=0.02) than those in steady state (184.79±18.67ng/L). The SP value in the SCD patients in VOC was almost twice as much as those in steady state and about three times as much as the value in the controls and the differences were statistically significant (t=7.72, p=0.001).
Conclusion: The study showed significantly higher SP levels in VOC compared to steady state or HbAA subjects suggesting that SP may be a marker for pain sensitisation.

Keywords:   Neuropeptide Substance P; Severity; Sickle Cell Disease; Vaso-occlusive Crisis

DOI:  https://doi.org/10.60787/nmj-v65i3-419
Cureus. 2024 Sep;16(9): e69053

Secretory Phospholipase A2 as a Promising Biomarker for Predicting Acute Chest Syndrome in Children With Sickle Cell Disease: A Systematic Review and Meta-Analysis.

Mohammed Alsabri, Ahmed B Elsnhory, Omar Alattar, Noha Ahmed, Sarah Ashraf, Riffa Alassri.

  Acute chest syndrome (ACS) is a severe and potentially life-threatening complication of sickle cell disease (SCD). Early identification of patients at risk for ACS is crucial for timely intervention. There is a potential association between ACS and elevated levels of secretory phospholipase A2 (sPLA2), an enzyme involved in the breakdown of phospholipids. sPLA2 has emerged as a promising biomarker for predicting ACS. This systematic review and meta-analysis aimed to assess the diagnostic value of PLA2 in predicting ACS among children with SCD. A comprehensive search was conducted across multiple databases, including MEDLINE, Embase, Cochrane Library, PubMed, and Web of Science. Studies assessing the relationship between sPLA2 levels and ACS in SCD patients were included. Pooled sensitivity, specificity, likelihood ratios, and the area under the receiver operating characteristic curve (AUC) were calculated to assess sPLA2's diagnostic accuracy. There is a potential association between significant association between elevated sPLA2 levels and increased ACS risk in SCD patients. The pooled sensitivity of sPLA2 for predicting ACS was 0.766 (95% CI: 0.620-0.877), with a pooled specificity of 0.736 (95% CI: 0.680-0.787). The AUC of the summary receiver operating characteristic (SROC) curve was 0.84, indicating good discriminatory ability. sPLA2 emerges as a promising biomarker for predicting ACS in SCD patients, potentially guiding risk stratification and early intervention strategies to enhance patient outcomes. Nonetheless, further prospective studies are warranted to validate its clinical utility and standardize sPLA2 assay protocols.

Keywords:  acs; acute chest syndrome; biomarker; phospholipase a2; sickle cell disease

DOI:  https://doi.org/10.7759/cureus.69053
EJHaem. 2024 Oct;5(5): 976-980

Changes in indicators of cerebral metabolic stress following treatment with voxelotor in children and adolescents with sickle cell anemia.

Andrew M Heitzer, Ping Zou, Jason Hodges, Clark Brown, Mark Davis, Sandy Dixon, Robert J Ogg, Jeremie Estepp, Jane S Hankins, Ranganatha Sitaram, Clifford M Takemoto.

  Voxelotor is a small molecule that reduces the polymerization of sickle hemoglobin by increasing its affinity for oxygen. In patients with sickle cell anemia, it has been postulated that increasing hemoglobin-oxygen affinity could limit oxygen offloading from hemoglobin, causing an increase in cerebral metabolic stress. To investigate this hypothetical concern, we used multimodal brain imaging to define the effects of voxelotor on cerebral blood flow and oxygen extraction. We followed four patients for 2-5 months during and/or after voxelotor therapy. This study showed no observable increase in cerebral blood flow or oxygen extraction fraction during treatment.

Keywords:  cerebral blood flow; cerebrovascular; oxygen extraction fraction; sickle cell anemia; voxelotor

DOI:  https://doi.org/10.1002/jha2.1001
Cureus. 2024 Sep;16(9): e69465

Clinical Outcomes of Sickle Cell Disease Patients With Myocardial Infarction Undergoing Percutaneous Coronary Intervention: A Nationwide Analysis.

Oluwasegun M Akinti, Jamal C Perry, Temi Ediale, Muzammil Rehman, Henry O Aiwuyo.

  Sickle cell disease (SCD) patients are predisposed to various cardiovascular complications due to the nature and progression of the disease; the clinical outcomes of SCD patients experiencing myocardial infarction (MI) and undergoing percutaneous coronary intervention (PCI) are not well known. This study aims to explore a comprehensive nationwide analysis of the clinical outcomes in SCD patients who have suffered an MI and subsequently undergone PCI. It also identifies potential complications and compares their outcomes with non-SCD counterparts with the same interventions. We conducted a retrospective analysis of SCD patients who have suffered an MI and subsequently undergone PCI using the National Inpatient Sample (NIS) database from 2016 to 2020. The primary outcome was mortality, while the secondary outcomes were the average length of stay, comorbid conditions, and cardiovascular outcomes. Logistic, linear, and Poisson regression model analysis applied for outcomes and adjusting co-founders. P-value <0.05 was considered significant. A total of 775 patients were analyzed for MI who had PCI with SCD, with a mean age of 58±1.06 years. SCD patients exhibited higher rates of comorbidities, including diabetes mellitus (45.81% vs. 37.84%), obesity (23.87% vs. 20.85%), and chronic kidney disease (CKD) (29.03% vs. 17.36%). Heart failure was more common among SCD patients with 34.19% vs. 26.02% in non-SCD patients (OR 1.5, CI 1.1-2.1, p-value=0.02). Other cardiovascular complications such as stroke, ventricular arrhythmias, atrial fibrillation, pulmonary edema, cardiogenic shock, cardiac arrest, and mortality did not significantly differ between SCD and non-SCD (P-values >0.05). The study observed that SCD patients experienced a significantly higher incidence of heart failure than non-SCD patients. This implies that SCD patients undergoing PCI for MI exhibit distinct clinical outcomes compared to their non-SCD counterparts.

Keywords:  clinical outcomes; heart failure; myocardial infarction; national inpatient sample; nationwide analysis; percutaneous coronary intervention; sickle cell disease

DOI:  https://doi.org/10.7759/cureus.69465