Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events

Jang, Tim; Poplawska, Maria; Cimpeanu, Emanuela; Mo, George; Dutta, Dibyendu; Lim, Seah H.

doi:10.1186/s12967-021-03074-z

Cited by 32 publications

(38 citation statements)

References 79 publications

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“…These deformed (“sickle shaped”) RBCs become very adhesive and upon interaction with white blood cells (WBCs) and the endothelium cause chronic hemolysis and occasional microvascular occlusion in multiple body organs ( 4 ). These processes can result in serious clinical complications that include acute pain (also called as vaso-occlusive crisis or VOC), tissue ischemia, multi-organ damage, stroke, acute chest syndrome (ACS) ( 5 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

Real-World data on efficacy of L-glutamine in preventing sickle cell disease-related complications in pediatric and adult patients

Elenga¹,

Loko

Etienne-Julan³

et al. 2022

Front. Med.

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BackgroundL-glutamine has been shown to play an important role in the regulation of oxidative stress which is one of the key contributors to the pathophysiology of sickle cell disease (SCD). In a Phase 3 clinical trial, L-glutamine demonstrated a significant reduction in SCD-related complications including vaso-occlusive crises (VOCs), hospitalizations, and acute chest syndrome (ACS) compared to placebo in patients with SCD.ObjectiveThe primary objective was to confirm the efficacy of L-glutamine (Endari®) therapy in pediatric and adult patients with SCD at follow-up time points of 24, 48 and 72 weeks.MethodsIn the observational study, nineteen patients with SCD were treated orally with L-glutamine twice daily for 72 weeks. Clinical and laboratory parameters were measured at baseline and follow-up time points. Patients with severe VOC and ACS were hospitalized. Blood transfusion was given in case of ACS and uncontrolled pain associated with VOC despite administration of the highest dose of intravenous (IV) narcotic.ResultsCompared to baseline, patients had significantly fewer pain crises (median change from 3.0 to 0.0; P < 0.00001), hospitalizations (median change from 3.0 to 0.0; P < 0.00001), days of hospitalization (median change from 15.0 to 0.0; P < 0.00001), and blood transfusions (median change from 3.0 to 0.0; P < 0.00001) at 24, 48, and 72 weeks following L-glutamine therapy. Moreover, there was a drastic decrease in the number of ACS events during this time. A significant increase was observed in mean hemoglobin levels and hematocrit proportions from baseline to 72 weeks (P < 0.001). Conversely, compared to baseline, mean reticulocyte counts and lactate dehydrogenase (LDH) levels were considerably lower at follow-up time points (P = 0.003 and P < 0.001, respectively). No patient reported treatment-related adverse events.ConclusionAlthough the sample size was small, our data clearly demonstrated that L-glutamine therapy was safe and significantly improved clinical outcomes and hemolysis parameters in patients with SCD.

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Section: Introductionmentioning

confidence: 99%

Real-World data on efficacy of L-glutamine in preventing sickle cell disease-related complications in pediatric and adult patients

Elenga¹,

Loko

Etienne-Julan³

et al. 2022

Front. Med.

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“…For people living with SCD experiencing vaso-occlusive crises, current treatment options are generally supportive, with pain relief dominated by opioids, which in themselves have significant side effects and may lead to longer-term issues with hyperalgesia, tolerance and dependence [26]. Little progress has been made to date in developing effective treatments for the acute vaso-occlusive crisis itself that addresses the underlying disease process [27]. Hemopexin treatment has the potential to reverse the downstream pathophysiological effects of heme on the development of vaso-occlusion, with the effect of reducing the extent and duration of the pain, and potentially reducing healthcare utilization, such as hospital admission.…”

Section: Discussionmentioning

confidence: 99%

Plasma-Derived Hemopexin as a Candidate Therapeutic Agent for Acute Vaso-Occlusion in Sickle Cell Disease: Preclinical Evidence

Gentinetta

Belcher

Brügger-Verdon

et al. 2022

JCM

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People living with sickle cell disease (SCD) face intermittent acute pain episodes due to vaso-occlusion primarily treated palliatively with opioids. Hemolysis of sickle erythrocytes promotes release of heme, which activates inflammatory cell adhesion proteins on endothelial cells and circulating cells, promoting vaso-occlusion. In this study, plasma-derived hemopexin inhibited heme-mediated cellular externalization of P-selectin and von Willebrand factor, and expression of IL-8, VCAM-1, and heme oxygenase-1 in cultured endothelial cells in a dose-responsive manner. In the Townes SCD mouse model, intravenous injection of free hemoglobin induced vascular stasis (vaso-occlusion) in nearly 40% of subcutaneous blood vessels visualized in a dorsal skin-fold chamber. Hemopexin administered intravenously prevented or relieved stasis in a dose-dependent manner. Hemopexin showed parallel activity in relieving vascular stasis induced by hypoxia-reoxygenation. Repeated IV administration of hemopexin was well tolerated in rats and non-human primates with no adverse findings that could be attributed to human hemopexin. Hemopexin had a half-life in wild-type mice, rats, and non-human primates of 80–102 h, whereas a reduced half-life of hemopexin in Townes SCD mice was observed due to ongoing hemolysis. These data have led to a Phase 1 clinical trial of hemopexin in adults with SCD, which is currently ongoing.

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“…Vaso-occlusion arises when sickled red blood cells obstruct blood flow to the extent that tissues are oxygen-deprived [ 14 ]. In response, an inflammatory reaction is triggered, which may lead to the narrowing of vessels, including intracranial and extracranial arteries ( Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

Neuroimaging and Cognitive Function in Sickle Cell Disease: A Systematic Review

2023

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Sickle cell disease (SCD) is the most common inherited single-gene disease. Complications include chronic anaemia, reduced oxygen-carrying capability, and cerebral vasculopathy, resulting in silent cerebral infarction, stroke, and cognitive dysfunction with impairments in measures of executive function, attention, reasoning, language, memory, and IQ. This systematic review aims to investigate the association between neuroimaging findings and cognition in children with SCD. Searches of PubMed and Embase were conducted in March 2022. Studies were included if participants were <18 years, if original data were published in English between 1960 and 2022, if any genotype of SCD was included, and if the relationship between cognition and neuroimaging was examined. Exclusion criteria included case studies, editorials, and reviews. Quality was assessed using the Critical Appraisal Skills Programme Case Control Checklist. A total of 303 articles were retrieved; 33 met the eligibility criteria. The presence of overt or silent strokes, elevated blood flow velocities, abnormal functional connectivity, and decreased fMRI activation were associated with neuropsychological deficits in children with SCD when compared to controls. There is a critical need to address the disease manifestations of SCD early, as damage appears to begin at a young age. Most studies were cross-sectional, restricting the interpretation of the directionality of relationships. Future research employing longitudinal neuroimaging and neuropsychological assessments could improve our understanding of the cumulative consequences of SCD on the developing brain.

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Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events

Cited by 32 publications

References 79 publications

Real-World data on efficacy of L-glutamine in preventing sickle cell disease-related complications in pediatric and adult patients

Real-World data on efficacy of L-glutamine in preventing sickle cell disease-related complications in pediatric and adult patients

Plasma-Derived Hemopexin as a Candidate Therapeutic Agent for Acute Vaso-Occlusion in Sickle Cell Disease: Preclinical Evidence

Neuroimaging and Cognitive Function in Sickle Cell Disease: A Systematic Review

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