Vasculopathy in Sickle Cell Disease: From Red Blood Cell Sickling to Vascular Dysfunction

Nader, Élie; Conran, Nicola; Romana, Marc; Connes, Philippe

doi:10.1002/cphy.c200024

Cited by 18 publications

(20 citation statements)

References 183 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Through its effects on inflammation and oxidative stress, hemolysis plays a central role in the pathophysiology of SCD and participates to the development of progressive vasculopathy and organ damages (Kato et al, 2018;Nader et al, 2021). Coagulation markers were not increased in patients with nocturnal hypoxemia but the greater monocytes and neutrophils count suggest that inflammation could be slightly increased in comparison with the non-hypoxemic group.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, a recent study performed in SCD children failed to find an association between OSA or low nocturnal oxyhemoglobin saturation (SpO2) and the frequency of vaso-occlusive like events (Willen et al, 2018). Low nocturnal oxyhemoglobin saturation has been associated with biomarkers of hemolysis and endothelial activation in SCD (Setty et al, 2003;Rotz et al, 2016), and enhanced hemolysis plays a central role in the pathophysiology of SCD (Nader et al, 2021). However, the associations between complications related to chronic hemolysis and low oxyhemoglobin saturation have not been investigated.…”

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

Nocturnal Hypoxemia Rather Than Obstructive Sleep Apnea Is Associated With Decreased Red Blood Cell Deformability and Enhanced Hemolysis in Patients With Sickle Cell Disease

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background: Although obstructive sleep apnea (OSA) could act as a modulator of clinical severity in sickle cell disease (SCD), few studies focused on the associations between the two diseases.Research Question: The aims of this study were: (1) to explore the associations between OSA, nocturnal oxyhemoglobin saturation (SpO2) and the history of several acute/chronic complications, (2) to investigate the impact of OSA and nocturnal SpO2 on several biomarkers (hematological, blood rheological, and coagulation) in patients with SCD.Study Design and Methods: Forty-three homozygous SCD patients underwent a complete polysomnography recording followed by blood sampling.Results: The proportion of patients suffering from nocturnal hypoxemia did not differ between those with and those without OSA. No association between OSA and clinical severity was found. Nocturnal hypoxemia was associated with a higher proportion of patients with hemolytic complications (glomerulopathy, leg ulcer, priapism, or pulmonary hypertension). In addition, nocturnal hypoxemia was accompanied by a decrease in RBC deformability, enhanced hemolysis and more severe anemia.Interpretation: Nocturnal hypoxemia in SCD patients could be responsible for changes in RBC deformability resulting in enhanced hemolysis leading to the development of complications such as leg ulcers, priapism, pulmonary hypertension or glomerulopathy.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03753854.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Nocturnal Hypoxemia Rather Than Obstructive Sleep Apnea Is Associated With Decreased Red Blood Cell Deformability and Enhanced Hemolysis in Patients With Sickle Cell Disease

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Traditionally, the pathophysiology of SCD was thought to result exclusively from the polymerization of HbS under hypoxic conditions, causing erythrocytes to become deformed, sludge, and occlude blood vessels, along with oxidative stress, inflammation, and hemolytic anemia ( 8 ). More recent studies show that SCD is also characterized by a chronic deficiency of the endogenous vasodilator nitric oxide (NO) and vascular dysfunction ( 8 , 9 ). As a consequence, SCD leads to progressive multi-organ failure resulting in pulmonary hypertension, leg ulcers, renal failure, stroke, infarct, retinopathy, neurocognitive impairment, bone loss, and priapism ( 2 , 9 , 10 ).…”

Section: Sickle Cell Diseasementioning

confidence: 99%

“…More recent studies show that SCD is also characterized by a chronic deficiency of the endogenous vasodilator nitric oxide (NO) and vascular dysfunction ( 8 , 9 ). As a consequence, SCD leads to progressive multi-organ failure resulting in pulmonary hypertension, leg ulcers, renal failure, stroke, infarct, retinopathy, neurocognitive impairment, bone loss, and priapism ( 2 , 9 , 10 ).…”

Section: Sickle Cell Diseasementioning

confidence: 99%

Testosterone Deficiency in Sickle Cell Disease: Recognition and Remediation

Musicki¹,

Burnett²

2022

Front. Endocrinol.

View full text Add to dashboard Cite

Hypogonadism is common in men with sickle cell disease (SCD) with prevalence rates as high as 25%. Testicular failure (primary hypogonadism) is established as the principal cause for this hormonal abnormality, although secondary hypogonadism and compensated hypogonadism have also been observed. The underlying mechanism for primary hypogonadism was elucidated in a mouse model of SCD, and involves increased NADPH oxidase-derived oxidative stress in the testis, which reduces protein expression of a steroidogenic acute regulatory protein and cholesterol transport to the mitochondria in Leydig cells. In all men including those with SCD, hypogonadism affects physical growth and development, cognition and mental health, sexual function, as well as fertility. However, it is not understood whether declines in physical, psychological, and social domains of health in SCD patients are related to low testosterone, or are consequences of other abnormalities of SCD. Priapism is one of only a few complications of SCD that has been studied in the context of hypogonadism. In this pathologic condition of prolonged penile erection in the absence of sexual excitement or stimulation, hypogonadism exacerbates already impaired endothelial nitric oxide synthase/cGMP/phosphodiesterase-5 molecular signaling in the penis. While exogenous testosterone alleviates priapism, it disadvantageously decreases intratesticular testosterone production. In contrast to treatment with exogenous testosterone, a novel approach is to target the mechanisms of testosterone deficiency in the SCD testis to drive endogenous testosterone production, which potentially decreases further oxidative stress and damage in the testis, and preserves sperm quality. Stimulation of translocator protein within the transduceosome of the testis of SCD mice reverses both hypogonadism and priapism, without affecting intratesticular testosterone production and consequently fertility. Ongoing research is needed to define and develop therapies that restore endogenous testosterone production in a physiologic, mechanism-specific fashion without affecting fertility in SCD men.

show abstract

“…Although conflicting results on antioxidant levels in SCD patients have been reported ( 43 – 45 ), the antioxidant capacity is insufficient to neutralize the excess of ROS, resulting in chronic oxidative stress ( 32 ). Enhanced oxidative stress may lead to endothelial damages through peroxidation of the lipid membrane and/or DNA fragmentation and ultimately cellular apoptosis ( 33 ) and has been linked to vascular alterations in SCD patients ( 34 ). In addition to these deleterious effects, ROS may promote vascular inflammation and NF-κB endothelial activation through the activation of redox-sensitive transcription factors such as ( 35 ).…”

Section: Scd Pathophysiology: a Complex Schema And Interrelated Pathwaysmentioning

confidence: 99%

Extracellular Vesicles in Sickle Cell Disease: Plasma Concentration, Blood Cell Types Origin Distribution and Biological Properties

et al. 2021

Self Cite

View full text Add to dashboard Cite

Prototype of monogenic disorder, sickle cell disease (SCD) is caused by a unique single mutation in the β-globin gene, leading to the production of the abnormal hemoglobin S (HbS). HbS polymerization in deoxygenated condition induces the sickling of red blood cells (RBCs), which become less deformable and more fragile, and thus prone to lysis. In addition to anemia, SCD patients may exhibit a plethora of clinical manifestations ranging from acute complications such as the frequent and debilitating painful vaso-occlusive crisis to chronic end organ damages. Several interrelated pathophysiological processes have been described, including impaired blood rheology, increased blood cell adhesion, coagulation, inflammation and enhanced oxidative stress among others. During the last two decades, it has been shown that extracellular vesicles (EVs), defined as cell-derived anucleated particles delimited by a lipid bilayer, and comprising small EVs (sEVs) and medium/large EVs (m/lEVs); are not only biomarkers but also subcellular actors in SCD pathophysiology. Plasma concentration of m/lEVs, originated mainly from RBCs and platelets (PLTs) but also from the other blood cell types, is higher in SCD patients than in healthy controls. The concentration and the density of externalized phosphatidylserine of those released from RBCs may vary according to clinical status (crisis vs. steady state) and treatment (hydroxyurea). Besides their procoagulant properties initially described, RBC-m/lEVs may promote inflammation through their effects on monocytes/macrophages and endothelial cells. Although less intensely studied, sEVs plasma concentration is increased in SCD and these EVs may cause endothelial damages. In addition, sEVs released from activated PLTs trigger PLT-neutrophil aggregation involved in lung vaso-occlusion in sickle mice. Altogether, these data clearly indicate that EVs are both biomarkers and bio-effectors in SCD, which deserve further studies.

show abstract

Vasculopathy in Sickle Cell Disease: From Red Blood Cell Sickling to Vascular Dysfunction

Cited by 18 publications

References 183 publications

Nocturnal Hypoxemia Rather Than Obstructive Sleep Apnea Is Associated With Decreased Red Blood Cell Deformability and Enhanced Hemolysis in Patients With Sickle Cell Disease

Nocturnal Hypoxemia Rather Than Obstructive Sleep Apnea Is Associated With Decreased Red Blood Cell Deformability and Enhanced Hemolysis in Patients With Sickle Cell Disease

Testosterone Deficiency in Sickle Cell Disease: Recognition and Remediation

Extracellular Vesicles in Sickle Cell Disease: Plasma Concentration, Blood Cell Types Origin Distribution and Biological Properties

Contact Info

Product

Resources

About