scholarly journals Influence of Haptoglobin Polymorphism on Stroke in Sickle Cell Disease Patients

Genes ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 144
Author(s):  
Olivia Edwards ◽  
Alicia Burris ◽  
Josh Lua ◽  
Diana J. Wilkie ◽  
Miriam O. Ezenwa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Cells ◽  
Cell Disease ◽  
Free Hemoglobin ◽  
Cerebral Tissue ◽  
Sickle Hemoglobin ◽  
Haptoglobin Polymorphism

This review outlines the current clinical research investigating how the haptoglobin (Hp) genetic polymorphism and stroke occurrence are implicated in sickle cell disease (SCD) pathophysiology. Hp is a blood serum glycoprotein responsible for binding and removing toxic free hemoglobin from the vasculature. The role of Hp in patients with SCD is critical in combating blood toxicity, inflammation, oxidative stress, and even stroke. Ischemic stroke occurs when a blocked vessel decreases oxygen delivery in the blood to cerebral tissue and is commonly associated with SCD. Due to the malformed red blood cells of sickle hemoglobin S, blockage of blood flow is much more prevalent in patients with SCD. This review is the first to evaluate the role of the Hp polymorphism in the incidence of stroke in patients with SCD. Overall, the data compiled in this review suggest that further studies should be conducted to reveal and evaluate potential clinical advancements for gene therapy and Hp infusions.

scholarly journals Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 296
Author(s):  
Rosa Vona ◽  
Nadia Maria Sposi ◽  
Lorenza Mattia ◽  
Lucrezia Gambardella ◽  
Elisabetta Straface ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Organ Damage ◽  
Cell Disease ◽  
Vessel Occlusion ◽  
Antioxidant Agents ◽  
Oxidant Status

Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

Role of Adhesion Molecules and Vascular Endothelium in the Pathogenesis of Sickle Cell Disease

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 84-90 ◽  
Author(s):  
Marilyn J. Telen
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Adhesion Molecules ◽  
Sickle Cell ◽  
Vascular Endothelium ◽  
Blood Cells ◽  
Cell Disease ◽  
Adhesive Interactions ◽  
Lines Of Evidence

AbstractA number of lines of evidence now support the hypothesis that vaso-occlusion and several of the sequelae of sickle cell disease (SCD) arise, at least in part, from adhesive interactions of sickle red blood cells, leukocytes, and the endothelium. Both experimental and genetic evidence provide support for the importance of these interactions. It is likely that future therapies for SCD might target one or more of these interactions.

scholarly journals Metabolomic and molecular insights into sickle cell disease and innovative therapies

2019 ◽  
Vol 3 (8) ◽  
pp. 1347-1355 ◽  
Author(s):  
Morayo G. Adebiyi ◽  
Jeanne M. Manalo ◽  
Yang Xia
Keyword(s):  
Sickle Cell Disease ◽  
Disease Progression ◽  
Sickle Cell ◽  
Intracellular Signaling ◽  
Metabolic Reprogramming ◽  
Flux Analysis ◽  
High Morbidity ◽  
Cell Disease ◽  
Sickle Hemoglobin

Abstract Sickle cell disease (SCD) is an autosomal-recessive hemolytic disorder with high morbidity and mortality. The pathophysiology of SCD is characterized by the polymerization of deoxygenated intracellular sickle hemoglobin, which causes the sickling of erythrocytes. The recent development of metabolomics, the newest member of the “omics” family, has provided a powerful new research strategy to accurately measure functional phenotypes that are the net result of genomic, transcriptomic, and proteomic changes. Metabolomics changes respond faster to external stimuli than any other “ome” and are especially appropriate for surveilling the metabolic profile of erythrocytes. In this review, we summarize recent pioneering research that exploited cutting-edge metabolomics and state-of-the-art isotopically labeled nutrient flux analysis to monitor and trace intracellular metabolism in SCD mice and humans. Genetic, structural, biochemical, and molecular studies in mice and humans demonstrate unrecognized intracellular signaling pathways, including purinergic and sphingolipid signaling networks that promote hypoxic metabolic reprogramming by channeling glucose metabolism to glycolysis via the pentose phosphate pathway. In turn, this hypoxic metabolic reprogramming induces 2,3-bisphosphoglycerate production, deoxygenation of sickle hemoglobin, polymerization, and sickling. Additionally, we review the detrimental role of an impaired Lands’ cycle, which contributes to sickling, inflammation, and disease progression. Thus, metabolomic profiling allows us to identify the pathological role of adenosine signaling and S1P-mediated erythrocyte hypoxic metabolic reprogramming and hypoxia-induced impaired Lands' cycle in SCD. These findings further reveal that the inhibition of adenosine and S1P signaling cascade and the restoration of an imbalanced Lands' cycle have potent preclinical efficacy in counteracting sickling, inflammation, and disease progression.

scholarly journals Persistence of Chronic Inflammation Despite Years of Transfusion Program in SCD Patients: Changing Red Blood Cells Is Not Sufficient to Treat Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 764-764
Author(s):  
Abdoul Karim Dembele ◽  
Patricia Hermand-Tournamille ◽  
Florence Missud ◽  
Emmanuelle Lesprit ◽  
Malika Benkerrou ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Chronic Inflammation ◽  
Sickle Cell ◽  
Blood Cells ◽  
Healthy Controls ◽  
Cell Disease ◽  
The Impact

Abstract Sickle cell disease (SCD) is a severe hemoglobinopathy due to abnormal hemoglobin S (HbS). Although red blood cell dysfunction is at the core of the SCD pathophysiology, several studies have highlighted the important role of inflammatory cells like neutrophils. One of the most serious complications of SCD is cerebral vasculopathy (CV), due to the occlusion of one or more intracranial or cervical arteries. In 1998, the STOP study demonstrated that monthly blood transfusions could reduce the risk of stroke by 90% in children with CV. However, there is large heterogeneity in the evolution of CV under chronic transfusion, sometimes requiring exchange transfusion (ET) program for years without succeeding in healing the CV. The aim of the study is to investigate the impact of long-term transfusion program on neutrophil dysfunction, in order to understand if persistent inflammation could contribute to the non-healing of CV despite HbS permanently below 40%. In SCD children undergoing ET program for at least 1 year, we analysed i)the phenotype of neutrophils with 8 markers of activation/adhesion/ageing, ii)the plasmatic levels of elastase, witnessing the NETose activity of neutrophils, and iii)the ex-vivo adhesion of neutrophils on activated endothelial cells. One hundred and two SCD children with an ET transfusion program for at least 6 months because of CV were included in the study. ET session, carried out every 5 weeks and most of the time by erythrapheresis, reached their biological objectives with a mean HbS rate after ET session of 14.1%, and 35.4% before the next ET session, which means that these patients globally live at an average HbS level of 24% for at least 1 year. We managed to limit iron overload with a mean ferritinemia of 207 µg/L in the whole cohort. Despite these satisfactory results in terms of HbS reduction, the efficiency in curing the CV was modest in accordance with the previously described efficiency of ET program in SCD children: after a mean ET program duration of 4.4 years only 22% of them had an improvement of their CV since the beginning of the ET program, while 60% of them had a stagnation of their CV, and 18% of them worsened their vascular lesions. Considering inflammatory parameters, the patients had persistence of high leukocytosis and high neutrophils count (respective mean of 9810 G/L and 5742 G/L), significantly not different of neutrophils count before inclusion in the ET program. In a random subgroup of 20 patients, we analysed neutrophils phenotype, NETose and endothelial adhesion and compared them to healthy controls and SCD children without ET, treated or not with Hydroxyurea (HU). Overall, we observed as expected an activated, aged and adherent profile of neutrophils from untreated SCD children compared to healthy controls, characterized by an overexpression of CD18/CD11b (p=0,03), CD18/CD11a (p=0,02), CD162 (p=0,01), CD66a (p=0,01) and the ageing markers CD184 high/CD62Llow (p=0,04) as well as a higher plasmatic level of elastase (p=0. 01) and higher adhesion of neutrophils to endothelial cells. All these parameters were alleviated in SCD patients treated with HU. In SCD patient undergoing ET program, we found a similar profile of activated neutrophils to that of untreated SCD patients with a similar expression of activation molecules, high level of elastase and the same increase of neutrophils adhesion to endothelial cells compared to controls, witnessing a persistence of chronic inflammation despites years of ET. Overall, our study highlights that the replacement of sickle red blood cells, even for years, is not sufficient to reverse the deleterious inflammatory phenotype of neutrophils. Given the major role of inflammation in endothelial dysfunction, these could contribute to the persistence of CV in a majority of patients despite efficient ET programs. This raises the question of systematically combining ET program with anti-inflammatory treatment such as HU or P-selectin inhibitors in children with CV. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Evolving treatment paradigms in sickle cell disease

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 440-446 ◽  
Author(s):  
Ramasamy Jagadeeswaran ◽  
Angela Rivers
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Cellular Adhesion ◽  
Ros Generation ◽  
Cell Disease ◽  
Therapeutic Approaches ◽  
Chronic Hemolytic Anemia

AbstractSickle cell disease (SCD) is an inheritable hemoglobinopathy characterized by polymerization of hemoglobin S in red blood cells resulting in chronic hemolytic anemia, vaso-occlusive painful crisis, and multiorgan damage. In SCD, an increased reactive oxygen species (ROS) generation occurs both inside the red blood cells and inside the vascular lumen, which augment hemolysis and cellular adhesion. This review discusses the evolving body of literature on the role of ROS in the pathophysiology of SCD as well as some emerging therapeutic approaches to SCD with a focus on the reduction of ROS.

scholarly journals The Role of RBC Oxidative Stress in Sickle Cell Disease: From the Molecular Basis to Pathologic Implications

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1608
Author(s):  
Qinhong Wang ◽  
Rahima Zennadi
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Redox State ◽  
Continuous Production ◽  
Globin Gene ◽  
Critical Role ◽  
Cell Disease ◽  
Membrane Structure And Function

Sickle cell disease (SCD) is an inherited monogenic disorder and the most common severe hemoglobinopathy in the world. SCD is characterized by a point mutation in the β-globin gene, which results in hemoglobin (Hb) S production, leading to a variety of mechanistic and phenotypic changes within the sickle red blood cell (RBC). In SCD, the sickle RBCs are the root cause of the disease and they are a primary source of oxidative stress since sickle RBC redox state is compromised due to an imbalance between prooxidants and antioxidants. This imbalance in redox state is a result of a continuous production of reactive oxygen species (ROS) within the sickle RBC caused by the constant endogenous Hb autoxidation and NADPH oxidase activation, as well as by a deficiency in the antioxidant defense system. Accumulation of non-neutralized ROS within the sickle RBCs affects RBC membrane structure and function, leading to membrane integrity deficiency, low deformability, phosphatidylserine exposure, and release of micro-vesicles. These oxidative stress-associated RBC phenotypic modifications consequently evoke a myriad of physiological changes involved in multi-system manifestations. Thus, RBC oxidative stress in SCD can ultimately instigate major processes involved in organ damage. The critical role of the sickle RBC ROS production and its regulation in SCD pathophysiology are discussed here.

scholarly journals Vaso-Occlusion in Sickle Cell Disease: Is Autonomic Dysregulation of the Microvasculature the Trigger?

2019 ◽  
Vol 8 (10) ◽  
pp. 1690 ◽  
Author(s):  
Saranya Veluswamy ◽  
Payal Shah ◽  
Christopher Denton ◽  
Patjanaporn Chalacheva ◽  
Michael Khoo ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Critical Role ◽  
Microvascular Blood Flow ◽  
Cell Disease ◽  
Hemoglobin S

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity.

A Novel Hemoglobin Binding Peptide Increases Intracellular Heme and Potentiates Hemoglobin-Induced HO-1 Levels in Endothelial Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1065-1065
Author(s):  
Madelyn S. Hanson ◽  
Timothy C. Flewelen ◽  
Hao Xu ◽  
Kirkwood A Pritchard ◽  
Nancy J Wandersee ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vascular Dysfunction ◽  
Murine Models ◽  
Cell Disease ◽  
Intravascular Hemolysis ◽  
Free Hemoglobin ◽  
Hemoglobin Binding

Abstract Abstract 1065 The hemolysis that occurs in many forms of hereditary and acquired hemolytic anemia, including sickle cell disease, saturates the hemoglobin/heme scavenging system resulting in increased levels of cell-free hemoglobin circulating in the plasma. Several recent studies have suggested a central role for intravascular hemolysis and cell-free hemoglobin in the development of vascular dysfunction, including pulmonary hypertension, in affected humans potentially by imposing oxidative and inflammatory stress. In agreement, mouse models of sickle cell disease and severe hereditary spherocytosis also develop vascular dysfunction and pulmonary hypertension. However, the role of intravascular hemolysis and cell-free hemoglobin in vascular dysfunction has proved controversial and a resolution of this important issue requires new experimental tools. This controversy highlights the importance of understanding if cell-free hemoglobin does indeed contribute to vascular complications associated with sickle cell disease. To address the role of cell-free hemoglobin in vascular pathology, we have synthesized a novel hemoglobin-binding peptide, hE-Hb-B10. This peptide is linked to a small fragment of apolipoprotein-E (apoE) to facilitate the endocytic clearance of cell-free hemoglobin through the ubiquitous heparin sulfate proteoglycan (HSPG)-associated lipoprotein pathway versus hemoglobin/heme scavenging system. We have shown previously that hE-Hb-B10 reduces cell-free hemoglobin levels and restores NO-dependent vascular function in murine models of hemolytic anemia. In the current studies, we investigate the cellular response of endothelial cells to hemoglobin uptake facilitated by hE-Hb-B10. We show that treatment of bovine aortic endothelial cells (BAECs) with oxyhemoglobin in the presence of hE-Hb-B10 augments intracellular heme concentration compared to oxyhemoglobin alone. Additionally, incubation of BAECs with methemoglobin increases heme oxygenase-1 (HO-1) protein levels and this induction is potentiated by hE-Hb-B10. hE-Hb-B10 also augments HO-1 induction by oxyhemoglobin, suggesting that hemoglobin uptake facilitated by hE-Hb-B10 is not dependent on the oxidation state of hemoglobin. In contrast, both Hb-B10, a peptide lacking the apoE fragment, and the scrambled hE-Hb-sB10 peptide in which the hemoglobin-binding sequence is scrambled, inhibit HO-1 induction caused by hemoglobin. Taken together, these data suggest that hE-Hb-B10 facilitates hemoglobin uptake into endothelial cells, augmenting both intracellular heme concentration and the induction of HO-1 by hemoglobin. While HO-1 expression is indicative of oxidative stress, enzymatic products of HO-1 can provide important protective functions against oxidative stress and iron overload. Therefore, altering HO-1 expression in SCD could potentially improve or worsen the severity of this disease. Indeed, potentiating HO-1 levels in models of SCD has been shown to be protective in murine models of SCD. Overall, our findings demonstrate that hE-Hb-B10 is a useful tool in determining the role of Cell-free hemoglobin in SCD pathology and suggests a mechanism by which this novel peptide could impact disease outcome. Disclosures: No relevant conflicts of interest to declare.

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