We searched Medline and EmBase from 1960 to May, 2010, with the search term “sickle” in combination with the search terms “stroke”, “pain”, “infection”, “malaria”, “chest”, “kidney”, “vaso-occlusion”, “haemolysis”, “nitric oxide”, “epidemiology”, “screening”, “diagnosis”, “hydroxyurea”, “hydroxycarbamide”, “blood transfusion”, “iron chelation”, “gene therapy”, “transplantation”, “neurology”, “vasculopathy”, “pulmonary hypertension”, “cardiac”, and “treatment”. We mostly selected publications
SeminarSickle-cell disease
Introduction
Sickle-cell disease is a multisystem disease, associated with episodes of acute illness and progressive organ damage, and is one of the most common severe monogenic disorders worldwide.1 Herrick2 first described the characteristic sickle-shaped erythrocytes in 1910 (figure 1), and understanding has gradually increased since then (table 1). Pauling and colleagues5 identified electrophoretic abnormalities in sickle haemoglobin (HbS) and coined the term “molecular disease” in 1949. The haemoglobin biophysics and genetics underlying the disease have been extensively studied and have helped the understanding of other molecular diseases. However, clinical management of sickle-cell disease is still basic and, although some evidence lends support to the use of blood transfusion and hydroxycarbamide in some circumstances, no drugs have been developed that specifically target the pathophysiology of this disease.
Section snippets
Classification
The term sickle-cell disease is used to refer to all the different genotypes that cause the characteristic clinical syndrome, whereas sickle-cell anaemia, the most common form of sickle-cell disease, refers specifically to homozygosity for the βS allele. In this Seminar, we mostly discuss sickle-cell anaemia, because there is little evidence for the management of other types of sickle-cell disease. In populations of African ethnic origin, sickle-cell anaemia typically accounts for 70% of cases
Pathophysiology
HbS is caused by a mutation in the β-globin gene in which the 17th nucleotide is changed from thymine to adenine and the sixth aminoacid in the β-globin chain becomes valine instead of glutamic acid.21 This mutation produces a hydrophobic motif in the deoxygenated HbS tetramer that results in binding between β1 and β2 chains of two haemoglobin molecules. This crystallisation produces a polymer nucleus, which grows and fills the erythrocyte, disrupting its architecture and flexibility and
Epidemiology
The global distribution of HbS is indicative of two factors: selection for carriers through their survival advantage in malaria-endemic regions and subsequent migration. Four region-specific African haplotypes (the Senegal, Benin, Bantu, and Cameroon haplotypes) and one Asian haplotype (the Arab-India haplotype) have been defined, providing support for the hypothesis that the mutation causing HbS has occurred, and been locally amplified, on at least two, and possibly several, separate occasions.
Phenotypic heterogeneity
The presentation and clinical course of sickle-cell disease shows substantial variation. For example, in the Cooperative Study of Sickle Cell Disease in the USA,68 39% of 3578 patients with sickle-cell anaemia had no episodes of pain but 1% had more than six per year. Such variability is characteristic of the disease and many of its complications, including cerebrovascular disease, acute chest syndrome, and premature death.
The two best established genetic modifiers are determinants of fetal
Diagnosis and screening
Diagnosis of sickle-cell disease is based on analysis of haemoglobin. Typically, this analysis involves protein electrophoresis or chromatography, which are cheap techniques and widely available worldwide, although haemoglobin mass spectrometry and DNA analysis are being increasingly used because these techniques enable high-throughput testing.89 Antenatal screening is available to women in some countries to help to identify couples who are at risk of having a baby with sickle-cell disease, and
Acute pain
Acute pain is the most common reason for admission to hospital for both adults and children, although it is more common in teenagers and young adults than in young children. Although acute vaso-occlusive pain is typically self-limiting and does not result in permanent organ damage, it is the most important complication from the patient's perspective, and increased frequency of pain is associated with early death in patients with sickle-cell anaemia who are older than 20 years.68 Frequent
Future developments
Stem-cell transplantation and gene therapy seem likely to become more widely applicable as new techniques develop, with the use of induced pluripotent stem cells offering the most promise.112 Data from genetic association studies should help to identify more unlinked and epigenetic factors to explain phenotypic diversity and to enable better prognosis, which might lead to the treatment of specific complications. Many drugs have given in-vitro or early benefit in sickle-cell disease without
Search strategy and selection criteria
References (150)
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The global distribution and population at risk of malaria: past, present, and future
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Effect of a comprehensive clinical care program on disease course in severely ill children with sickle cell anemia in a sub-Saharan African setting
Blood
Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case-control study
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Invasive pneumococcal infections in children with sickle cell disease in the era of penicillin prophylaxis, antibiotic resistance, and 23-valent pneumococcal polysaccharide vaccination
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Malaria in patients with sickle cell anemia: burden, risk factors, and outcome at the outpatient clinic and during hospitalization
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Gene interactions and stroke risk in children with sickle cell anemia
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Erythroid adhesion molecules in sickle cell disease: effect of hydroxyurea
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Exposure to hydroxyurea and pregnancy outcomes in sickle cell anemia
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The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS)
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Arch Intern Med
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The significance of the paucity of sickle cells in newborn negro infants
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Prevention of pneumococcal infection in children with homozygous sickle cell disease
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Prophylaxis with oral penicillin in children with sickle cell anemia
N Engl J Med
Bone-marrow transplantation in a patient with sickle-cell anemia
N Engl J Med
Effect of hydroxyurea on frequency of painful crises in sickle cell anemia
N Engl J Med
Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography
N Engl J Med
Sickle cell disease
Hemoglobin S Antilles: a variant with lower solubility than hemoglobin S and producing sickle cell disease in heterozygotes
Proc Natl Acad Sci USA
Sickle cell disease in a patient with sickle cell trait and compound heterozygosity for hemoglobin S and hemoglobin Quebec-Chori
N Engl J Med
Hemoglobin SE disease—a concise review
Am J Haematol
Hemoglobin Jamaica Plain—a sickling hemoglobin with reduced oxygen affinity
N Engl J Med
Pathogenesis and treatment of sickle cell disease
N Engl J Med
Levels of fetal hemoglobin necessary for treatment of sickle cell disease
N Engl J Med
Sickle cell vaso-occlusion: multistep and multicellular paradigm
Curr Opin Hematol
Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm
Proc Natl Acad Sci USA
Endothelial cell NADPH oxidase mediates the cerebral microvascular dysfunction in sickle cell transgenic mice
Faseb J
Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice
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Mortality in sickle cell disease. Life expectancy and risk factors for early death
N Engl J Med
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