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Annual Review of Genomics and Human... Aug 2018In the 100 years since sickle cell anemia (SCA) was first described in the medical literature, studies of its molecular and pathophysiological basis have been at the... (Review)
Review
In the 100 years since sickle cell anemia (SCA) was first described in the medical literature, studies of its molecular and pathophysiological basis have been at the vanguard of scientific discovery. By contrast, the translation of such knowledge into treatments that improve the lives of those affected has been much too slow. Recent years, however, have seen major advances on several fronts. A more detailed understanding of the switch from fetal to adult hemoglobin and the identification of regulators such as BCL11A provide hope that these findings will be translated into genomic-based approaches to the therapeutic reactivation of hemoglobin F production in patients with SCA. Meanwhile, an unprecedented number of new drugs aimed at both the treatment and prevention of end-organ damage are now in the pipeline, outcomes from potentially curative treatments such as allogeneic hematopoietic stem cell transplantation are improving, and great strides are being made in gene therapy, where methods employing both antisickling β-globin lentiviral vectors and gene editing are now entering clinical trials. Encouragingly, after a century of neglect, the profile of the vast majority of those with SCA in Africa and India is also finally improving.
Topics: Anemia, Sickle Cell; Carrier Proteins; Genetic Therapy; Hemoglobins; Humans; Nuclear Proteins; Phenotype; Repressor Proteins; Treatment Outcome
PubMed: 29641911
DOI: 10.1146/annurev-genom-083117-021320 -
Journal of Hematology & Oncology Mar 2022Sickle cell disease (SCD), which affects approximately 100,000 individuals in the USA and more than 3 million worldwide, is caused by mutations in the βb globin gene... (Review)
Review
Sickle cell disease (SCD), which affects approximately 100,000 individuals in the USA and more than 3 million worldwide, is caused by mutations in the βb globin gene that result in sickle hemoglobin production. Sickle hemoglobin polymerization leads to red blood cell sickling, chronic hemolysis and vaso-occlusion. Acute and chronic pain as well as end-organ damage occur throughout the lifespan of individuals living with SCD resulting in significant disease morbidity and a median life expectancy of 43 years in the USA. In this review, we discuss advances in the diagnosis and management of four major complications: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. We also discuss advances in disease-modifying and curative therapeutic options for SCD. The recent availability of L-glutamine, crizanlizumab and voxelotor provides an alternative or supplement to hydroxyurea, which remains the mainstay for disease-modifying therapy. Five-year event-free and overall survival rates remain high for individuals with SCD undergoing allogeneic hematopoietic stem cell transplant using matched sibling donors. However, newer approaches to graft-versus-host (GVHD) prophylaxis and the incorporation of post-transplant cyclophosphamide have improved engraftment rates, reduced GVHD and have allowed for alternative donors for individuals without an HLA-matched sibling. Despite progress in the field, additional longitudinal studies, clinical trials as well as dissemination and implementation studies are needed to optimize outcomes in SCD.
Topics: Anemia, Sickle Cell; Chronic Pain; Graft vs Host Disease; Hemoglobin, Sickle; Humans; Hydroxyurea
PubMed: 35241123
DOI: 10.1186/s13045-022-01237-z -
TheScientificWorldJournal Dec 2008The root cause of sickle cell disease is a single beta-globin gene mutation coding for the sickle beta-hemoglobin chain. Sickle hemoglobin tetramers polymerize when... (Review)
Review
The root cause of sickle cell disease is a single beta-globin gene mutation coding for the sickle beta-hemoglobin chain. Sickle hemoglobin tetramers polymerize when deoxygenated, damaging the sickle erythrocyte. A multifaceted pathophysiology, triggered by erythrocyte injury induced by the sickle hemoglobin polymer, and encompassing more general cellular and tissue damage caused by hypoxia, oxidant damage, inflammation, abnormal intracellular interactions, and reduced nitric oxide bioavailability, sets off the events recognized clinically as sickle cell disease. This disease is a group of related disorders where sickle hemoglobin is the principal hemoglobin species. All have varying degrees of chronic hemolytic anemia, vasculopathy, vasoocclusive disease, acute and chronic organ damage, and shortened life span. Its complex pathophysiology, of which we have a reasonable understanding, provides multiple loci for potential therapeutic intervention.
Topics: Anemia, Sickle Cell; Erythrocyte Membrane; Female; Hemoglobin, Sickle; Humans; Hydroxyurea; Hypoxia; Inflammation; Male; Mutation; Nitric Oxide; Oxidants; Polymers; alpha-Thalassemia
PubMed: 19112541
DOI: 10.1100/tsw.2008.157 -
Annual Review of Pathology Jan 2019Since 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... (Review)
Review
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.
Topics: Anemia, Sickle Cell; Hemolysis; Humans; Inflammation; Oxidative Stress; Reperfusion Injury; Toll-Like Receptor 4
PubMed: 30332562
DOI: 10.1146/annurev-pathmechdis-012418-012838 -
The New England Journal of Medicine Apr 2017
Review
Topics: Air Pollution; Anemia, Sickle Cell; Fetal Hemoglobin; Humans; Infant, Newborn; Infections; Phenotype; alpha-Thalassemia
PubMed: 28423290
DOI: 10.1056/NEJMra1510865 -
Revista Medica de Chile Sep 2021Sickle cell anemia is a type of hemoglobinopathy characterized by a specific mutation in the beta globin gene with the consequent generation of an unstable hemoglobin...
Sickle cell anemia is a type of hemoglobinopathy characterized by a specific mutation in the beta globin gene with the consequent generation of an unstable hemoglobin that crystallizes in a state of hypoxia. This causes a change in the structure of the red blood cell, which ends up producing vaso-occlusion with the corresponding clinical complications for the patient. Worldwide, various diagnostic tests have been developed that allow the appropriate approach to the affected patient. These include techniques for the determination of hemoglobin and the use of molecular markers, among others. There are new therapeutic alternatives to the use of hydroxyurea and L-glutamine, such as the use of gene therapy tools. The most recent experimental trials are exploring gene editing techniques.
Topics: Anemia, Sickle Cell; Haplotypes; Humans; Hydroxyurea; Hypoxia
PubMed: 35319686
DOI: 10.4067/S0034-98872021000901322 -
Hematology. American Society of... 2015The sickle hemoglobin (HbS) point mutation has independently undergone evolutionary selection at least five times in the world because of its overwhelming malarial... (Review)
Review
The sickle hemoglobin (HbS) point mutation has independently undergone evolutionary selection at least five times in the world because of its overwhelming malarial protective effects in the heterozygous state. In 1949, homozygous Hb S or sickle cell disease (SCD) became the first inherited condition identified at the molecular level; however, since then, both SCD and heterozygous Hb S, sickle cell trait (SCT), have endured a long and complicated history. Hasty adoption of early mass screening programs for SCD, recent implementation of targeted screening mandates for SCT in athletics, and concerns about stigmatization have evoked considerable controversy regarding research and policy decisions for SCT. Although SCT is a largely protective condition in the context of malaria, clinical sequelae, such as exercise-related injury, renal complications, and venous thromboembolism can occur in affected carriers. The historical background of SCD and SCT has provided lessons about how research should be conducted in the modern era to minimize stigmatization, optimize study conclusions, and inform genetic counseling and policy decisions for SCT.
Topics: Anemia, Sickle Cell; Athletes; Electrophoresis; Exercise; Female; Hemoglobin, Sickle; Heterozygote; Homozygote; Humans; Kidney Diseases; Male; Mass Screening; Pregnancy; Sickle Cell Trait; Venous Thromboembolism; Wounds and Injuries
PubMed: 26637716
DOI: 10.1182/asheducation-2015.1.160 -
Cleveland Clinic Journal of Medicine Jan 2020Sickle cell disease (SCD) is the most common hemoglobinopathy in the United States and causes significant disease-related morbidity including multiorgan damage, chronic... (Review)
Review
Sickle cell disease (SCD) is the most common hemoglobinopathy in the United States and causes significant disease-related morbidity including multiorgan damage, chronic anemia, and debilitating pain crises. Primary care physicians play a key role in the medical home model of care for adults with SCD. This review focuses on current recommendations for health maintenance and provides a brief summary of disease complications and current updates.
Topics: Adolescent; Adult; Anemia, Sickle Cell; Female; Humans; Male; Patient-Centered Care; Primary Health Care; United States; Young Adult
PubMed: 31990651
DOI: 10.3949/ccjm.87a.18051 -
Medicine Sep 2023Sickle cell disease (SCD) is a hereditary blood disorder characterized by the production of abnormal hemoglobin molecules that cause red blood cells to take on a... (Review)
Review
Sickle cell disease (SCD) is a hereditary blood disorder characterized by the production of abnormal hemoglobin molecules that cause red blood cells to take on a crescent or sickle shape. This condition affects millions of people worldwide, particularly those of African, Mediterranean, Middle Eastern, and South Asian descent. This paper aims to provide an overview of SCD by exploring its causes, symptoms, and available treatment options. The primary cause of SCD is a mutation in the gene responsible for producing hemoglobin, the protein that carries oxygen in red blood cells. This mutation has abnormal hemoglobin called hemoglobin S, which causes red blood cells to become stiff and sticky, leading to various health complications. Patients with SCD may experience recurrent pain, fatigue, anemia, and increased infection susceptibility. Treatment options for SCD focus on managing symptoms and preventing complications. This includes pain management with analgesics, hydration, and blood transfusions to improve oxygen delivery. Hydroxyurea, a medication that increases the production of fetal hemoglobin, is commonly used to reduce the frequency and severity of pain crises. Additionally, bone marrow or stem cell transplants can cure select individuals with severe SCD. Finally, understanding the causes, symptoms, and treatment options for SCD is crucial for healthcare professionals, patients, and their families. It enables early diagnosis, effective symptom management, and improved quality of life for individuals with this chronic condition.
Topics: Humans; Anemia, Sickle Cell; Causality; Erythrocytes; Quality of Life
PubMed: 37746969
DOI: 10.1097/MD.0000000000035237 -
British Journal of Haematology Jul 2021Dr. John Herrick described the first clinical case of sickle cell anaemia (SCA) in the United States in 1910. Subsequently, four decades later, Ingram and colleagues... (Review)
Review
Dr. John Herrick described the first clinical case of sickle cell anaemia (SCA) in the United States in 1910. Subsequently, four decades later, Ingram and colleagues characterized the A to T substitution in DNA producing the GAG to GTG codon and replacement of glutamic acid with valine in the sixth position of the β -globin chain. The establishment of Comprehensive Sickle Cell Centers in the United States in the 1970s was an important milestone in the development of treatment strategies and describing the natural history of sickle cell disease (SCD) comprised of genotypes including homozygous haemoglobin SS (HbSS), HbSβ thalassaemia, HbSC and HbSβ thalassaemia, among others. Early drug studies demonstrating effective treatments of HbSS and HbSβ thalassaemia, stimulated clinical trials to develop disease-specific therapies to induce fetal haemoglobin due to its ability to block HbS polymerization. Subsequently, hydroxycarbamide proved efficacious in adults with SCA and was Food and Drug Administration (FDA)-approved in 1998. After two decades of hydroxycarbamide use for SCD, there continues to be limited clinical acceptance of this chemotherapy drug, providing the impetus for investigators and pharmaceutical companies to develop non-chemotherapy agents. Investigative efforts to determine the role of events downstream of deoxy-HbS polymerization, such as endothelial cell activation, cellular adhesion, chronic inflammation, intravascular haemolysis and nitric oxide scavenging, have expanded drug targets which reverse the pathophysiology of SCD. After two decades of slow progress in the field, since 2018 three new drugs were FDA-approved for SCA, but research efforts to develop treatments continue. Currently over 30 treatment intervention trials are in progress to investigate a wide range of agents acting by complementary mechanisms, providing the rationale for ushering in the age of effective and safe combination drug therapy for SCD. Parallel efforts to develop curative therapies using haematopoietic stem cell transplant and gene therapy provide individuals with SCD multiple treatment options. We will discuss progress made towards drug development and potential combination drug therapy for SCD with the standard of care hydroxycarbamide.
Topics: Anemia, Sickle Cell; Animals; Antisickling Agents; Drug Development; Drug Therapy, Combination; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Hydroxyurea; Molecular Targeted Therapy
PubMed: 33471938
DOI: 10.1111/bjh.17312