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.

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 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 Expression Pattern of CD55 and CD59 on Red Blood Cells in Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4815-4815
Author(s):  
Salah A. Al Humood ◽  
Lama A. Al-Faris ◽  
Monera Al-Rukhayes
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Conflicts Of Interest ◽  
Flow Cytometric Analysis ◽  
Healthy Controls ◽  
Cell Disease ◽  
Altered Expression ◽  
Cd59 Expression

Abstract Background: Altered expression of glycosylphosphatidylinositol (GPI)-anchored proteins, might result in increased susceptibility of red blood cells (RBCs) to complement-mediated lysis. Limited information is available on the pattern of CD55 and CD59 expression on RBCs of sickle cell disease (SCD) patients. Methods: Flow cytometric analysis was performed on RBCs from 71 adult SCD patients and 53 healthy controls, using the commercial REDQUANT kit. Results: CD59 deficiency was significantly higher among SCD patients than among healthy controls. The proportions of CD55-deficient and CD59-deficient RBCs from SCD patients were significantly higher when compared with those from healthy controls (0.17 vs. 0.09 and 2.1 vs. 1.2, respectively). The MFI of CD55 and CD59 expression on RBCs in SCD was significantly reduced when compared to the expression healthy controls (5.2 vs. 6.4 and 19.4 vs 20.3, respectively). The pattern of CD55 and CD59 expression was not correlated with anemia, biomarkers of hemolysis, erythropoietin level or other pro-inflammatory markers. Conclusions: There is an altered pattern of CD55 and CD59 expression on RBCs of SCD Patients; however, it does not seem to play a causal role in the pathophysiology of anemia, and is unlikely to be influenced by the level of erythropoietin or other inflammatory mediators. Disclosures No relevant conflicts of interest to declare.

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.

Increased Reticulocytosis in Infants with Sickle Cell Disease May Be a Marker for Future Disease Severity

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2128-2128
Author(s):  
Emily R. Meier ◽  
Colleen Byrnes ◽  
Y.Terry Lee ◽  
Maxine Weissman ◽  
Pierre Noel ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Disease Severity ◽  
Sickle Cell ◽  
Blood Cells ◽  
Healthy Infant ◽  
Healthy Controls ◽  
Cell Disease ◽  
Splenic Sequestration ◽  
Healthy Infants

Abstract Abstract 2128 The first erythropoietic stress in term neonates occurs at the time of the erythrocyte nadir (around three months of age) and is associated with increased reticulocytosis. In infants with sickle cell disease (HbSS, SCD), this nadir generally precedes the onset of clinical signs and symptoms. The objective of this study was to determine if reticulocyte levels and properties during early infancy in SCD patients are useful in disease severity prediction. Peripheral blood from 111 children with SCD who were enrolled in this observational study was analyzed within 48 hours of collection and storage at 4°C. Reticulocytes were quantified by absolute reticulocyte count (ARC) as well as reticulocyte flow cytometry phenotyping and sorting using CD71 (CD71 Hi, CD71 Lo and CD71 Neg) and CD36 markers. Among the entire group, ARC is negatively correlated with HbF (r=−0.72, p<0.0001) and F-cells (r=−0.68, p<0.0001). Analysis of lysates from sorted reticulocytes and red blood cells revealed that the least mature reticulocytes (CD71 Hi) had the lowest HbF levels. CD71 Hi sickle reticulocytes also expressed the adhesion molecule CD36 on the cell surface. CD36 was barely detectable in reticulocytes from healthy infants and older children. The proportion of sickle red cells that expressed CD71 at Hi and Lo levels was compared to age-matched healthy controls. Although red blood cells with similar levels of CD71 Lo (mean healthy infant controls 0.71±0.36% vs. 0.92±0.30% in SCD infants, p=0.43) were present in both healthy infants and infants with SCD less than five months of age, CD71 Hi expression was significantly higher in infants with SCD (mean healthy infant controls 0.19±0.08% vs. 0.58±0.25% in SCD infants, p=0.02). Examination of the reticulocyte profiles of SCD patients older than 5 months of age revealed markedly increased CD71 Lo and Hi levels when compared to similarly aged healthy controls (mean CD71 Lo healthy controls 0.31±0.30% vs SCD patients 4.06±3.45%, p=0.0001; mean CD71 Hi healthy controls 0.01±0.01% vs. SCD patients 1.55±1.42%, p=0.0001). Clinically, increased reticulocytosis during this nadir period (2–5 months of age) was associated with a worse clinical course during infancy and childhood. The ARC at physiologic nadir was identified by retrospective chart review for 37 of the 111 enrolled subjects. Significantly higher ARCs were associated with hospitalization during the first three years of life. Of the twelve children who had not been hospitalized by 3 years of age, only one had an ARC greater than 200 K/uL during the nadir period (mean ARC for the no hospitalization group 151±54 K/uL). Among subjects who were first hospitalized before age 3 years for acute chest syndrome (ACS, n=6), there was no significant increase in ARC (mean ARC 174±95, p=0.53 vs. no hospitalization group). However, patients who were first hospitalized for splenic sequestration (n=8) and vaso-occlusive crisis (VOC, n=11) had significantly higher ARCs [splenic sequestration 223±66 K/uL (p=0.017), VOC 262±102 K/uL, (p=0.004) vs. the no hospitalization group]. Twelve of 37 (32%) patients received chronic therapy with either monthly transfusions or hydroxyurea before the age of 12 years (ARC range 123–384 K/uL, mean 250±82 K/uL). Nine of the twelve (75%) had a steady state ARC of greater than 200 K/uL between ages 2 and 5 months. These data support the hypothesis that completion of the fetal-to-adult hemoglobin switching phenomenon during infancy triggers the beginning of a pathologic cascade of increased sickle hemoglobin polymerization and hemolysis followed by increased release of immature reticulocytes that express adhesion molecules including CD36. Among SCD infants with lower expression of fetal hemoglobin, the magnitude of the reticulocyte response is predicted to be further driven by uncompensated tissue hypoxia. Overall, the data suggest that increased reticulocytosis is one of the earliest clinical features of SCD, and the level of reticulocytosis during the first five months of postnatal life may help predict disease severity later in life. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Impact of Selenium Deficiency on a Sickle Cell Disease Mouse Model

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3645-3645
Author(s):  
Ramasamy Jagadeeswaran ◽  
Hong Lenny ◽  
Helen Zhang ◽  
Jennifer Afranie-Sakyi ◽  
Robert E. Molokie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
African Americans ◽  
Sickle Cell Disease ◽  
Mouse Model ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Cell Disease ◽  
Anti Oxidant ◽  
The Impact

Abstract Sickle cell disease (SCD) is caused by a mutation in the β-globin gene resulting in a disease that affects more than 100,000 Americans and millions worldwide. Though pain is the hallmark of SCD, patients also suffer damage to most organ systems. Sickle cell hemoglobin (HbS) polymerization occurs when deoxygenated, rendering red blood cells rigid and fragile. Production of excessive reactive oxygen species (ROS) and intracellular hypoxia in RBCs further accelerates the pathology associated with SCD. Recently, vaso-occlusive crisis (VOC) and organ damage were established to be strongly associated with oxidative stress in RBCs. This occurs when there is an increase in oxidants that exceeds the cellular anti-oxidant defenses. Excessive ROS can trigger a cascade of oxidative reactions that damage membrane lipids, and essential enzymatic antioxidants such as GPx-1, ultimately leading to hemolysis and multi-organ dysfunction. ROS generation in RBCs of SCD patients is due to factors such as HbS auto-oxidation and potentially aberrant mitochondrial function. We recently determined that red blood cells obtained from SCD mice and SCD patients retain their mitochondria compared to control subjects. Mitochondria retained SCD RBCs are also associated with elevated levels of ROS and hemolysis. Oxidative stress in the RBCs of SCD patients may be elevated by lower levels of antioxidant proteins such as the selenium-dependent enzyme GPX1. GPX1 was first described as an enzyme capable of protecting hemoglobin from ROS and has been reported to be lower in the RBCs in SCD. Selenium levels are lower among African Americans in the Chicago area and elsewhere. In this regard, it is notable that in the United States, African Americans represent the majority of those with SCD. To investigate the relationship between selenium levels and SCD, we have utilized a mouse model of SCD to examine the impact of a reduced intake of selenium on parameters associated with SCD pathology. SCD mice on a selenium-deficient diet (<0.01 mg/kg diet) were compared to mice fed with a selenium-adequate diet (0.1mg/kg). SCD mice in the selenium-deficient group exhibited an increase in mitochondria retaining RBCs (Se deficient: 26%±6.9%, n=3 vs. Se adequate: 5 % ± 3.5%, n=3, p<0.01), reduced Hb levels (Se deficient 5.7± 0.17 g/dl, n=3 vs. Se adequate 7.0± 0.83 g/dl, n=4 p<0.05), and an increased RBC oxygen consumption rate (OCR). These results support the hypothesis that low selenium status likely results in reduced levels of anti-oxidant selenoproteins and enhanced SCD severity. Disclosures Lavelle: Global Blood therapeutics: Research Funding.

Increased Procoagulant Activity of Red Blood Cells from Patients with Homozygous Sickle Cell Disease and β-Thalassemia

1996 ◽  
Vol 76 (03) ◽  
pp. 322-327 ◽  
Author(s):  
Dominique Helley ◽  
Amiram Eldor ◽  
Robert Girot ◽  
Rolande Ducrocq ◽  
Marie-Claude Guillin ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Annexin V ◽  
Mean Value ◽  
Procoagulant Activity ◽  
Dependent Manner ◽  
Cell Disease ◽  
Homozygous Sickle Cell Disease

SummaryIt has recently been proved that, in vitro, red blood cells (RBCs) from patients with homozygous β-thalassemia behave as procoagulant cells. The procoagulant activity of β-thalassemia RBCs might be the result of an increased exposure of procoagulant phospholipids (i. e. phosphatidylserine) in the outer leaflet of the membrane. In order to test this hypothesis, we compared the catalytic properties of RBCs of patients with β-thalassemia and homozygous sickle cell disease (SS-RBCs) with that of controls. The catalytic parameters (Km, kcat) of prothrombin activation by factor Xa were determined both in the absence and in the presence of RBCs. The turn-over number (kcat) of the reaction was not modified by normal, SS- or (3-thalassemia RBCs. The Km was lower in the presence of normal RBCs (mean value: 9.1 µM) than in the absence of cells (26 µM). The Km measured in the presence of either SS-RBCs (mean value: 1.6 µM) or β-thalassemia RBCs (mean value: 1.5 pM) was significantly lower compared to normal RBCs (p <0.001). No significant difference was observed between SS-RBCs and p-thalassemia RBCs. Annexin V, a protein with high affinity and specificity for anionic phospholipids, inhibited the procoagulant activity of both SS-RBCs and (3-thalassemia RBCs, in a dose-dependent manner. More than 95% inhibition was achieved at nanomolar concentrations of annexin V. These results indicate that the procoagulant activity of both β-thalassemia RBCs and SS-RBCs may be fully ascribed to an abnormal exposure of phosphatidylserine at the outer surface of the red cells.

Microfluidic electrical impedance assessment of red blood cell mediated microvascular occlusion

Lab on a Chip ◽  
2021 ◽  
Author(s):  
Yuncheng Man ◽  
Debnath Maji ◽  
Ran An ◽  
Sanjay Ahuja ◽  
Jane A Little ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Blood Cell ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Blood Cells ◽  
Electrical Impedance ◽  
Cell Disease ◽  
Blood Disorders

Alterations in the deformability of red blood cells (RBCs), occurring in hemolytic blood disorders such as sickle cell disease (SCD), contributes to vaso-occlusion and disease pathophysiology. However, there are few...

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.

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