scholarly journals New insights into the pathophysiology and development of novel therapies for sickle cell disease

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 493-506 ◽  
Author(s):  
Scott Moerdler ◽  
Deepa Manwani
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cell Disease ◽  
Oxidant Damage ◽  
Emerging Treatments ◽  
Heterotypic Interactions ◽  
Abnormal Hemoglobin ◽  
Selection Of

Abstract Although the seminal event in sickle cell disease is the polymerization of abnormal hemoglobin, the downstream pathophysiology of vasoocclusion results from heterotypic interactions between the altered, adhesive sickle cell red blood cells, neutrophils, endothelium, and platelets. Ischemia reperfusion injury, hemolysis, and oxidant damage all contribute to heightened inflammation and activation of the hemostatic system. These various pathways are the focus of emerging treatments with potential to ameliorate disease manifestations. This review summarizes the considerable progress in development of these agents despite challenges in selection of study end points and complex pathophysiology.

scholarly journals Pathophysiology of Sickle Cell Disease

2019 ◽  
Vol 14 (1) ◽  
pp. 263-292 ◽  
Author(s):  
Prithu Sundd ◽  
Mark T. Gladwin ◽  
Enrico M. Novelli
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Sterile Inflammation ◽  
Organ Injury ◽  
Single Amino Acid ◽  
Current Evidence ◽  
Cell Disease ◽  
Hemoglobin S

Since the discovery of sickle cell disease (SCD) in 1910, enormous strides have been made in the elucidation of the pathogenesis of its protean complications, which has inspired recent advances in targeted molecular therapies. In SCD, a single amino acid substitution in the β-globin chain leads to polymerization of mutant hemoglobin S, impairing erythrocyte rheology and survival. Clinically, erythrocyte abnormalities in SCD manifest in hemolytic anemia and cycles of microvascular vaso-occlusion leading to end-organ ischemia-reperfusion injury and infarction. Vaso-occlusive events and intravascular hemolysis promote inflammation and redox instability that lead to progressive small- and large-vessel vasculopathy. Based on current evidence, the pathobiology of SCD is considered to be a vicious cycle of four major processes, all the subject of active study and novel therapeutic targeting: ( a) hemoglobin S polymerization, ( b) impaired biorheology and increased adhesion-mediated vaso-occlusion, ( c) hemolysis-mediated endothelial dysfunction, and ( d) concerted activation of sterile inflammation (Toll-like receptor 4– and inflammasome-dependent innate immune pathways). These molecular, cellular, and biophysical processes synergize to promote acute and chronic pain and end-organ injury and failure in SCD. This review provides an exhaustive overview of the current understanding of the molecular pathophysiology of SCD, how this pathophysiology contributes to complications of the central nervous and cardiopulmonary systems, and how this knowledge is being harnessed to develop current and potential therapies.

scholarly journals Thromboinflammatory mechanisms in sickle cell disease - challenging the hemostatic balance

Haematologica ◽  
2020 ◽  
Vol 105 (10) ◽  
pp. 2380-2390 ◽  
Author(s):  
Nicola Conran ◽  
Erich V. De Paula
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Ischemia Reperfusion ◽  
Organ Damage ◽  
Acute Chest Syndrome ◽  
Cellular Interactions ◽  
Innate Immune Responses ◽  
Cell Disease ◽  
Inflammatory Processes ◽  
Abnormal Hemoglobin

Sickle cell disease (SCD) is an inherited hemoglobinopathy that is caused by the presence of abnormal hemoglobin S (HbS) in red blood cells, leading to alterations in red cell properties and shape, as the result of HbS dexoygenation and subsequent polymerization. SCD pathophysiology is characterized by chronic inflammatory processes, triggered by hemolytic and vaso-occlusive events, which lead to the varied complications, organ damage and elevated mortality seen in individuals with the disease. In association with activation of the endothelium and leukocytes, hemostatic alterations and thrombotic events are well-documented in SCD. Here we discuss the role for inflammatory pathways in modulating coagulation and inducing platelet activation in SCD, due to tissue factor activation, adhesion molecule expression, inflammatory mediator production and the induction of innate immune responses, amongst other mechanisms. Thromboinflammatory pathways may play a significant role in some of the major complications of SCD, such as stroke, venous thromboembolism and possibly acute chest syndrome, besides exacerbating the chronic inflammation and cellular interactions that trigger vaso-occlusion, ischemia-reperfusion processes, and eventually organ damage.

scholarly journals Targeting novel mechanisms of pain in sickle cell disease

Blood ◽  
2017 ◽  
Vol 130 (22) ◽  
pp. 2377-2385 ◽  
Author(s):  
Huy Tran ◽  
Mihir Gupta ◽  
Kalpna Gupta
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Acute Pain ◽  
Pain Perception ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Poor Quality ◽  
Current Treatment ◽  
Future Research ◽  
Cell Disease

Abstract Patients with sickle cell disease (SCD) suffer from intense pain that can start during infancy and increase in severity throughout life, leading to hospitalization and poor quality of life. A unique feature of SCD is vaso-occlusive crises (VOCs) characterized by episodic, recurrent, and unpredictable episodes of acute pain. Microvascular obstruction during a VOC leads to impaired oxygen supply to the periphery and ischemia reperfusion injury, inflammation, oxidative stress, and endothelial dysfunction, all of which may perpetuate a noxious microenvironment leading to pain. In addition to episodic acute pain, patients with SCD also report chronic pain. Current treatment of moderate to severe pain in SCD is mostly reliant upon opioids; however, long-term use of opioids is associated with multiple side effects. This review presents up-to-date developments in our understanding of the pathobiology of pain in SCD. To help focus future research efforts, major gaps in knowledge are identified regarding how sickle pathobiology evokes pain, pathways specific to chronic and acute sickle pain, perception-based targets of “top-down” mechanisms originating from the brain and neuromodulation, and how pain affects the sickle microenvironment and pathophysiology. This review also describes mechanism-based targets that may help develop novel therapeutic and/or preventive strategies to ameliorate pain in SCD.

scholarly journals Targeting novel mechanisms of pain in sickle cell disease

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 546-555 ◽  
Author(s):  
Huy Tran ◽  
Mihir Gupta ◽  
Kalpna Gupta
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Acute Pain ◽  
Pain Perception ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Poor Quality ◽  
Current Treatment ◽  
Future Research ◽  
Cell Disease

Abstract Patients with sickle cell disease (SCD) suffer from intense pain that can start during infancy and increase in severity throughout life, leading to hospitalization and poor quality of life. A unique feature of SCD is vaso-occlusive crises (VOCs) characterized by episodic, recurrent, and unpredictable episodes of acute pain. Microvascular obstruction during a VOC leads to impaired oxygen supply to the periphery and ischemia reperfusion injury, inflammation, oxidative stress, and endothelial dysfunction, all of which may perpetuate a noxious microenvironment leading to pain. In addition to episodic acute pain, patients with SCD also report chronic pain. Current treatment of moderate to severe pain in SCD is mostly reliant upon opioids; however, long-term use of opioids is associated with multiple side effects. This review presents up-to-date developments in our understanding of the pathobiology of pain in SCD. To help focus future research efforts, major gaps in knowledge are identified regarding how sickle pathobiology evokes pain, pathways specific to chronic and acute sickle pain, perception-based targets of “top-down” mechanisms originating from the brain and neuromodulation, and how pain affects the sickle microenvironment and pathophysiology. This review also describes mechanism-based targets that may help develop novel therapeutic and/or preventive strategies to ameliorate pain in SCD.

Hydroxyurea can be used in children with sickle cell disease and cerebral vasculopathy for the prevention of chronic complications? A meta-analysis

2019 ◽  
Vol 24 (1) ◽  
pp. 64-77
Author(s):  
Ramiro Manzano Núñez ◽  
Carlos Andrés Portilla Figueroa ◽  
Herney Andrés García-Perdomo
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Lower Risk ◽  
Meta Analysis ◽  
Risk Difference ◽  
Cell Disease ◽  
High Quality Research ◽  
Abnormal Hemoglobin ◽  
High Concentrations ◽  
The Impact

We conducted a systematic review for evaluating the impact of hydroxyurea and chronic blood transfusion in children with sickle cell disease (SCD). A search was done in four databases from inception to 2017. Trials enrolling pediatric patients with SCD and cerebral vasculopathy with or without previous episode of stroke and that reported outcomes of occurrence of stroke and other events were included. Trained reviewers determined eligibility, risk of bias, and abstracted data. Random-effects meta-analysis was conducted. We found that the primary outcome was the occurrence of stroke. We found two trials that recruited 254 patients. No difference was found for confirmed stroke occurrence (risk difference 0.04 [95% CI: −0.03 to 0.03]) and for new-onset neurological deficit (risk difference 0.11 [95% CI: −0.00 to 0.21]). Transfusions provided a significant lower risk of vaso-occlussive crisis (risk difference 0.10 [95% CI: 0.001 to 0.20]). Finally, transfusions provided a lower risk of having high concentrations of abnormal hemoglobin S (mean difference 37.94 [95% CI: 27.55 to 48.32]). As a conclusion, transfusions plus chelation therapy might be used instead of hydroxyurea in children with SCD. There is a lack of high-quality research in the care of children with SCD, and therefore a call for action is needed.

scholarly journals Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease

2020 ◽  
Vol 11 ◽  
pp. 204062072095500
Author(s):  
Ifeyinwa Osunkwo ◽  
Deepa Manwani ◽  
Julie Kanter
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Severe Pain ◽  
Management Strategies ◽  
Organ Damage ◽  
Care Utilization ◽  
Cell Disease ◽  
High Resource ◽  
Emerging Treatments

Individuals with sickle cell disease (SCD) are living further into adulthood in high-resource countries. However, despite increased quantity of life, recurrent, acute painful episodes cause significant morbidity for affected individuals. These SCD-related painful episodes, also referred to as vaso-occlusive crises (VOCs), have multifactorial causes, and they often occur as a result of multicellular aggregation and vascular adherence of red blood cells, neutrophils, and platelets, leading to recurrent and unpredictable occlusion of the microcirculation. In addition to severe pain, long-term complications of vaso-occlusion may include damage to muscle and/or bone, in addition to vital organs such as the liver, spleen, kidneys, and brain. Severe pain associated with VOCs also has a substantial detrimental impact on quality of life for individuals with SCD, and is associated with increased health care utilization, financial hardship, and impairments in education and vocation attainment. Previous treatments have targeted primarily SCD symptom management, or were broad nontargeted therapies, and include oral or parenteral hydration, analgesics (including opioids), nonsteroidal anti-inflammatory agents, and various other types of nonpharmacologic pain management strategies to treat the pain associated with VOC. With increased understanding of the pathophysiology of VOCs, there are several new potential therapies that specifically target the pathologic process of vaso-occlusion. These new therapies may reduce cell adhesion and inflammation, leading to decreased incidence of VOCs and prevention of end-organ damage. In this review, we consider the benefits and limitations of current treatments to reduce the occurrence of VOCs in individuals with SCD and the potential impact of emerging treatments on future disease management.

Sickle cell disease resulting from uniparental disomy in a child who inherited sickle cell trait

Blood ◽  
2010 ◽  
Vol 116 (15) ◽  
pp. 2822-2825 ◽  
Author(s):  
Jeffrey J. Swensen ◽  
Archana M. Agarwal ◽  
Jose M. Esquilin ◽  
Sabina Swierczek ◽  
Ajay Perumbeti ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Trait ◽  
Uniparental Disomy ◽  
Mendelian Inheritance ◽  
Cell Disease ◽  
Erythroid Progenitors ◽  
Mendelian Genetics ◽  
Abnormal Hemoglobin ◽  
Hb S

Abstract Sickle cell disease (SCD) is a classic example of a disorder with recessive Mendelian inheritance, in which each parent contributes one mutant allele to an affected offspring. However, there are exceptions to that rule. We describe here the first reported case of conversion of inherited sickle cell trait to SCD by uniparental disomy (UPD) resulting in mosaicism for SS and AS erythrocytes. A 14-year-old boy presented with splenomegaly and hemolysis. Although his father has sickle cell trait, his mother has no abnormal hemoglobin (Hb). DNA sequencing, performed to rule out Hb S/β-thalassemia, detected homozygous Hb SS. Further studies revealed mosaic UPD of the β-globin locus, more SS erythroid progenitors than AS, but a reverse ratio of erythrocytes resulting from the survival advantage of AS erythrocytes. This report exemplifies non-Mendelian genetics wherein a patient who inherited sickle cell trait has mild SCD resulting from postzygotic mitotic recombination leading to UPD.

scholarly journals Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease

Blood ◽  
2004 ◽  
Vol 104 (1) ◽  
pp. 270-280 ◽  
Author(s):  
Maria L. Jison ◽  
Peter J. Munson ◽  
Jennifer J. Barb ◽  
Anthony F. Suffredini ◽  
Shefali Talwar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Expression Profiles ◽  
Ischemia Reperfusion ◽  
Transcriptional Analysis ◽  
Heme Oxygenase 1 ◽  
Specific Gene ◽  
Cell Disease

Abstract In sickle cell disease, deoxygenation of intra-erythrocytic hemoglobin S leads to hemoglobin polymerization, erythrocyte rigidity, hemolysis, and microvascular occlusion. Ischemia-reperfusion injury, plasma hemoglobin-mediated nitric oxide consumption, and free radical generation activate systemic inflammatory responses. To characterize the role of circulating leukocytes in sickle cell pathogenesis we performed global transcriptional analysis of blood mononuclear cells from 27 patients in steady-state sickle cell disease (10 patients treated and 17 patients untreated with hydroxyurea) compared with 13 control subjects. We used gender-specific gene expression to validate human microarray experiments. Patients with sickle cell disease demonstrated differential gene expression of 112 genes involved in heme metabolism, cell-cycle regulation, antioxidant and stress responses, inflammation, and angiogenesis. Inducible heme oxygenase-1 and downstream proteins biliverdin reductase and p21, a cyclin-dependent kinase, were up-regulated, potentially contributing to phenotypic heterogeneity and absence of atherosclerosis in patients with sickle cell disease despite endothelial dysfunction and vascular inflammation. Hydroxyurea therapy did not significantly affect leukocyte gene expression, suggesting that such therapy has limited direct anti-inflammatory activity beyond leukoreduction. Global transcriptional analysis of circulating leukocytes highlights the intense oxidant and inflammatory nature of steady-state sickle cell disease and provides insight into the broad compensatory responses to vascular injury.

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