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61-675: Sickle cell disease ( SCD ), also simply called sickle cell , is a group of hemoglobin-related blood disorders that are typically inherited . The most common type is known as sickle cell anemia . Sickle cell anemia results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells . This leads to the red blood cells adopting an abnormal sickle -like shape under certain circumstances; with this shape, they are unable to deform as they pass through capillaries , causing blockages. Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain (known as

122-492: A sickle cell crisis ) in joints, anemia , swelling in the hands and feet, bacterial infections , dizziness and stroke . The probability of severe symptoms, including long-term pain, increases with age. Without treatment, people with SCD rarely reach adulthood but with good healthcare, median life expectancy is between 58 and 66 years. All the major organs are affected by sickle cell disease. The liver, heart, kidneys, gallbladder, eyes, bones, and joints also can suffer damage from

183-519: A VOC which affects the lungs, possibly triggered by infection or by emboli which have circulated from other organs. Symptoms include wheezing, chest pain, fever, pulmonary infiltrate (visible on x-ray), and hypoxemia . After sickling crisis (see above) it is the second-most common cause of hospitalization and it accounts for about 25% of deaths in patients with SCD. Most cases present with vaso-occlusive crises, and then develop acute chest syndrome. Aplastic crises are instances of an acute worsening of

244-558: A biconcave disc shape, which allows the cells to deform to pass through capillaries. In sickle cell disease, low oxygen tension promotes red blood cell sickling and repeated episodes of sickling damage the cell membrane and decrease the cell's elasticity. These cells fail to return to normal shape when normal oxygen tension is restored. As a consequence, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion and ischaemia . Cells which have become sickled are detected as they pass through

305-511: A blood transfusion. Sickle cell anaemia can lead to various complications including: Hemoglobin is an oxygen-binding protein, found in erythrocytes , which transports oxygen from the lungs (or in the fetus, from the placenta) to the tissues. Each molecule of hemoglobin comprises 4 protein subunits, referred to as globins . Normally, humans have:- β-globin is encoded by the HBB gene on human chromosome 11 ; mutations in this gene produce variants of

366-461: A carrier's red blood cells; another is that a carrier's red cells show signs of damage when infected, and are detected and destroyed as they pass through the spleen. Under conditions of low oxygen concentration, HBS polymerises to form long strands within the red blood cell (RBC). These strands distort the shape of the cell and after a few seconds cause it to adopt an abnormal, inflexible sickle-like shape. This process reverses when oxygen concentration

427-483: A lack of medical evidence. Hydroxyurea was the first approved drug for the treatment of SCD, which has been shown to decrease the number and severity of attacks and possibly increase survival time. This is achieved, in part, by reactivating fetal haemoglobin production in place of the haemoglobin S that causes sickling. Hydroxyurea had previously been used as a chemotherapy agent, and some concern exists that long-term use may be harmful. A Cochrane review in 2022 found

488-404: A lesser degree in parts of India , Southern Europe , West Asia , North Africa and among people of African origin (sub-Saharan) living in other parts of the world. The condition was first described in the medical literature by American physician James B. Herrick in 1910. In 1949, its genetic transmission was determined by E. A. Beet and J. V. Neel. In 1954, it was established that carriers of

549-432: A prenatal screening questionnaire which includes, among other things, a consideration of health issues in the child's parents and close relatives. During pregnancy, genetic testing can be done on either a blood sample from the fetus or a sample of amniotic fluid . During the first trimester of pregnancy, chorionic villus sampling (CVS) is also a technique used for SCD prenatal diagnosis. A routine heel prick test , in which

610-443: A prior stroke event, it also reduces the risk of recurrent stroke and additional silent strokes. Transcranial Doppler ultrasound (TCD) can detect children with sickle cell that have a high risk for stroke. The ultrasound test detects blood vessels partially obstructed by sickle cells by measuring the rate of blood into the brain, as blood flow velocity is inversely related to arterial diameter, and consequently, high blood-flow velocity

671-458: A routine part of treatment of vaso-occlusive crises but the evidence about the most effective route, amount and type of fluid replacement remains uncertain. In 2019, Crizanlizumab , a monoclonal antibody target towards p-selectin was approved in the United States to reduce the frequency of vaso-occlusive crisis in those 16 years and older. Management is similar to vaso-occlusive crisis, with

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732-571: A sickle cell crisis, so relaxation techniques like breathing exercises can help. Pneumococcal infection is a leading cause of death among children with SCD; penicillin is recommended daily during the first 5 years of life in order to minimise the risk of infection. Dietary supplementation of folic acid is sometimes recommended, on the basis that it facilitates the creation of new red blood cells and may reduce anemia. A Cochrane review of its use in 2016 found "the effect of supplementation on anaemia and any symptoms of anaemia remains unclear" due to

793-720: A sickling test is performed on abnormal hemoglobins migrating in the S location to see if the hemoglobin precipitates in solution of sodium bisulfite . In general on acid electrophoresis in order of increasing mobility are hemoglobins F, A=D=G=E=O=Lepore, S, and C. This is how abnormal hemoglobin variants are isolated and identified using these two methods. For example, a Hgb G-Philadelphia would migrate with S on alkaline electrophoresis and would migrate with A on acid electrophoresis, respectively Some hemoglobinopathies (and also related diseases like glucose-6-phosphate dehydrogenase deficiency ) seem to have given an evolutionary benefit, especially to heterozygotes , in areas where malaria

854-520: A single abnormal copy does not usually have symptoms and is said to have sickle cell trait . Such people are also referred to as carriers . Diagnosis is by a blood test , and some countries test all babies at birth for the disease. Diagnosis is also possible during pregnancy. The care of people with sickle cell disease may include infection prevention with vaccination and antibiotics , high fluid intake, folic acid supplementation, and pain medication . Other measures may include blood transfusion and

915-460: A small sample of blood is collected a few days after birth, is used to check conclusively for SCD as well as other inherited conditions. Where SCD is suspected, a number of tests can be used. Often a simpler, cheaper test is applied first with a more complex test such as DNA analysis used to confirm a positive result. Two tests which are specific for SCD: Tests which can be used for SCD as well as for other hemoglobinopathies: Genetic counselling

976-450: A technique to encourage deep breathing to minimise the development of atelectasis , is recommended. Although it is not always clear what sets off a VOC, anything which causes blood vessels to constrict is a potential trigger. This includes physical or mental stress , cold, and dehydration . " After HbS deoxygenates in the capillaries, it takes some time (seconds) for HbS polymerization and the subsequent flexible-to-rigid transformation. If

1037-574: A weak evidence base for its use in SCD. Voxelotor was received accelerated approval as a treatment for SCD in the United States in 2019, and was approved by the European Medicines Agency (EMA) in 2021. In trials, it had been shown to have disease-modifying potential by increasing hemoglobin levels and decreasing hemolysis indicators However, following an increased risk of vaso-occlusive seizures and death observed in registries and clinical trials,

1098-405: Is 1.4 years. By the age of 5 years repeated instances of sequestration cause scarring and eventual atrophy of the spleen . Treatment is supportive, with blood transfusion if hemoglobin levels fall too low. Full or partial splenectomy may be necessary. Long term consequences of a loss of spleen function are increased susceptibility to bacterial infections . Acute chest syndrome is caused by

1159-417: Is a single nucleotide mutation of the β-globin gene, which results in glutamate being substituted by valine at position 6 of the β-globin chain. Hemoglobin S with this mutation is referred to as HbS, as opposed to the normal adult HbA. Under conditions of normal oxygen concentration this causes no apparent effects on the structure of haemoglobin or its ability to transport oxygen around the body. However,

1220-459: Is a common painful complication of sickle cell anemia in adolescents and adults. It is a form of sickle cell crisis. Sickle cell anemia – most common in those of African, Hispanic, and Mediterranean origin – leads to sickle cell crisis when the circulation of blood vessels is obstructed by sickled red blood cells , causing ischemic injuries. The most common complaint is of pain, and recurrent episodes may cause irreversible organ damage. One of

1281-665: Is abnormal; erythropoiesis generates a mixture of normal HbA and sickle HbS. The person has very few if any symptoms of sickle cell disease but carries the gene and can pass it on to their children. Sickle cell disease has an autosomal recessive pattern of inheritance from parents. Both copies of the affected gene must carry the same mutation ( homozygous condition) for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry one mutated gene and one normal gene ( heterozygous condition) and are referred to as genetic carriers ; they may not have any symptoms. When both parents have

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1342-617: Is also a common genetic cause of Hb disorders, and complex rearrangements and globin gene fusions can also occur. Haemoglobin variant are not necessarily pathological. For example, haemoglobin Valletta and haemoglobin Marseille are two haemoglobin variants which are non-pathological Hemoglobin variants can be detected by gel electrophoresis . In general on alkaline electrophoresis in order of increasing mobility are hemoglobins A2, E=O=C, G=D=S=Lepore, F, A, K, J, Bart's, N, I, and H. In general

1403-548: Is an episode of pain and swelling in the child's hands and feet, known as dactylitis or "hand-foot syndrome." Pallor , jaundice , and fatigue can also be early signs due to anaemia resulting from sickle cell disease. Among children older than 2 years, the most frequent initial presentation is a painful event of generalized or variable type, and a slightly less common version appears as an event of acute chest pain. Dactylitis rarely or never occurs in children older than 2 years. Also termed "sickle cell crisis" or "sickling crisis",

1464-462: Is associated with an iron-containing heme moiety . Throughout life, the synthesis of the α and the β chains is balanced so that their ratio is relatively constant and there is no excess of either type. The specific α and β chains that are incorporated into Hb are highly regulated during development: Hb variants: Hb structural variants are qualitative defects that cause a change in the structure (primary, secondary, tertiary, and/or quaternary) of

1525-708: Is correlated with narrowing of the arteries. In 2002, the National Institute of Health (NIH) issued a statement recommending that children with sickle cell get the Transcranial Doppler ultrasound screen annually, and in 2014, a panel of experts convened by the NIH issued guidelines reiterating the same recommendation. One review of medical records, by hematologist Dr. Julie Kanter at the University of Alabama at Birmingham, showed that on average only 48.4 per cent of children in

1586-481: Is endemic. Malaria parasites live inside red blood cells, but subtly disturb normal cellular function. In patients predisposed for rapid clearance of red blood cells, this may lead to early destruction of cells infected with the parasite and increased chance of survival for the carrier of the trait. Hemoglobin functions : Pathology and organic structural abnormalities may lead to any of the following disease processes: Hematopoietic stem cell transplantation (HSCT)

1647-430: Is most prevalent in areas which have historically been associated with endemic malaria . The sickle cell trait provides a carrier with a survival advantage against malaria fatality over people with normal hemoglobin in regions where malaria is endemic. Infection with the malaria parasite affects asymptomatic carriers of the abnormal hemoglobin gene differently from patients with full SCD. Carriers (heterozygous for

1708-425: Is of little consequence, but the shortened red cell life of SCD patients results in an abrupt, life-threatening situation. Reticulocyte count drops dramatically during the disease (causing reticulocytopenia ), red cell production lapses, and the rapid destruction of existing red cells leads to acute and severe anemia. This crisis takes four to seven days to resolve. Most patients can be managed supportively; some need

1769-538: Is raised and the cells resume their normal biconcave disc shape. If sickling takes place in the venous system, after blood has passed through the capillaries, it has no effect on the organs and the RBCs can unsickle when they become oxygenated in the lungs. Repeated switching between sickle and normal shapes damages the membrane of the RBC so that it eventually becomes permanently sickled. Normal red blood cells are quite elastic and have

1830-431: Is the process by which people with a hereditary disorder are advised of the probability of transmitting it and the ways in which this may be prevented or ameliorated. People who are known carriers of the disease or at risk of having a child with sickle cell anemia may undergo genetic counseling . Genetic counselors work with families to discuss the benefits, limitations, and logistics of genetic testing options as well as

1891-427: Is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood , or umbilical cord blood to replicate inside a patient and to produce normal blood cells. It may be autologous (the patient's own stem cells are used), allogeneic (the stem cells come from a donor) or syngeneic (from an identical twin). Vaso-occlusive crisis A vaso-occlusive crisis

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1952-546: The Mediterranean , India , and the Middle East . Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases. The malaria parasite has a complex lifecycle and spends part of it in red blood cells. There are two mechanisms which protect sickle cell carriers from malaria. One is that the parasite is hindered from growing and reproducing in

2013-551: The vaso-occlusive crisis (VOC) manifests principally as extreme pain, most often affecting the chest, back, legs and/or arms. The underlying cause is sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ, resulting in ischaemia , pain , necrosis , and often organ damage. The frequency, severity, and duration of these crises vary considerably. Painful crises are treated with hydration, analgesics , and blood transfusion ; pain management requires opioid drug administration at regular intervals until

2074-501: The Hb molecule. The majority of Hb variants do not cause disease and are most commonly discovered either incidentally or through newborn screening. A subset of Hb variants can cause severe disease when inherited in the homozygous or compound heterozygous state in combination with another structural variant or a thalassemia mutation. When clinical consequences occur, they may include anemia due to hemolysis or polycythemia due to alterations in

2135-526: The US with sickle cell get the recommended ultrasound test. A 1994 NIH study showed that children at risk for strokes who received blood transfusions had an annual stroke rate of less than 1 per cent, whereas those children who did not receive blood transfusions had a 10 per cent stroke rate per year. (Also see 1998 study in the New England Journal of Medicine .) In addition to ultrasounds and blood transfusions,

2196-444: The abnormal functions of the sickle cells, and their inability to flow through the small blood vessels correctly. Sickle cell disease occurs when a person inherits two abnormal copies of the β-globin gene that makes haemoglobin, one from each parent. Several subtypes exist, depending on the exact mutation in each haemoglobin gene. An attack can be set off by temperature changes, stress, dehydration , and high altitude. A person with

2257-418: The abnormal gene are some degree protected against malaria . Signs of sickle cell disease usually begin in early childhood. The severity of symptoms can vary from person to person, as can the frequency of crisis events. Sickle cell disease may lead to various acute and chronic complications , several of which have a high mortality rate. When SCD presents within the first year of life, the most common problem

2318-422: The addition of antibiotics (usually a quinolone or macrolide, since cell wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome), oxygen supplementation for hypoxia , and close observation. In the absence of high quality evidence regarding the effectiveness of antibiotics for acute chest syndrome in people with sickle cell disease, there is no standard antibiotic treatment as of 2019. Should

2379-481: The crisis has settled. For milder crises, a subgroup of patients manages on nonsteroidal anti-inflammatory drugs such as diclofenac or naproxen . For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia devices are commonly used in this setting. Vaso-occlusive crisis involving organs such as the penis or lungs are considered an emergency and treated with red blood cell transfusions. Incentive spirometry ,

2440-416: The deoxy form of HbS has an exposed hydrophobic patch which causes HbS molecules to join to form long inflexible chains. Under conditions of low oxygen concentration in the bloodstream, such as exercise, stress, altitude or dehydration, HbS polymerization forms fibrous precipitates within the red blood cell. In people homozygous for the sickle cell mutation, the presence of long-chain polymers of HbS distort

2501-500: The frequency, severity, and duration of these crises vary tremendously. Painful crises are treated symptomatically with pain medications ; pain management requires opioid drug administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manages on NSAIDs (such as diclofenac or naproxen ). For more severe crises, most patients require inpatient management for intravenous opioids. Extra fluids, administered either orally or intravenously, are

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2562-451: The gene) who catch malaria are less likely to suffer from severe symptoms than people with normal hemogolobin. SCD patients (homozygous for the gene) are similarly less likely to become infected with malaria; however once infected they are more likely to develop severe and life-threatening anemia. The impact of sickle cell anemia on malaria immunity illustrates some evolutionary trade-offs that have occurred because of endemic malaria. Although

2623-700: The hemoglobin genes, and the thalassemias , which are caused by an underproduction of otherwise normal hemoglobin molecules. The main structural hemoglobin variants are HbS, HbE and HbC. The main types of thalassemia are alpha-thalassemia and beta thalassemia . The two conditions may overlap because some conditions which cause abnormalities in hemoglobin proteins also affect their production. Some hemoglobin variants do not cause pathology or anemia , and thus are often not classed as hemoglobinopathies. Normal human hemoglobins are tetrameric proteins composed of two pairs of globin chains, each of which contains one α (alpha) chain and one β (beta) chain. Each globin chain

2684-400: The inexpensive generic drug hydroxyurea can reduce the risk of irreversible organ and brain damage. Guidelines from NIH published in 2014, state that all children and adolescents should take hydroxyurea, as should adults with serious complications or three or more pain crises in a year. Most people with sickle cell disease have intensely painful episodes called vaso-occlusive crises. However,

2745-517: The manufacturer, Pfizer , withdrew it from the market worldwide. Blood transfusions are often used in the management of sickle cell disease in acute cases and to prevent complications by decreasing the number of red blood cells (RBCs) that can sickle by adding normal red blood cells. In children, preventive RBC transfusion therapy has been shown to reduce the risk of first stroke or silent stroke when transcranial Doppler ultrasonography shows abnormal cerebral blood flow. In those who have sustained

2806-527: The medication hydroxycarbamide (hydroxyurea). In 2023, new gene therapies were approved involving the genetic modification and replacement of blood forming stem cells in the bone marrow. As of 2021, SCD is estimated to affect about 7.7 million people worldwide, directly causing 34,000 annual deaths and a contributory factor to a further 376,000 deaths. About 80% of sickle cell disease cases are believed to occur in Sub-Saharan Africa . It also occurs to

2867-742: The most severe forms is the acute chest syndrome which occurs as a result of infarction of the lung parenchyma. This can rapidly result in death. Other types of vaso-occlusive crisis in sickle cell anemia include dactylitis , priapism , abdominal pain , and jaundice . Diagnosis of vaso-occlusive crisis is based on clinical manifestations, complete blood count with white blood cell differential , platelet count, reticulocyte count, and comprehensive metabolic panel with liver and kidney function tests . Typical lab findings include acute drop in hemoglobin concentration, increased platelet count, increased reticulocyte count, and elevated serum urea . The management of an acute event of vaso-occlusive crisis

2928-483: The oxygen affinity of the abnormal Hb. Common examples of hemoglobin variants associated with hemolysis include sickle Hb (HbS) and HbC . Hb variants can usually be detected by protein-based assay methods; however, DNA-based methods may be required for variants with ambiguous or unusual results from protein analysis. The major functional consequences of Hb structural variants can be classified as follows: Copy number variation (e.g., deletion, duplication, insertion)

2989-423: The patient's baseline anaemia, producing pale appearance , fast heart rate , and fatigue. This crisis is normally triggered by parvovirus B19 , which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them. Parvovirus infection almost completely prevents red blood cell production for two to three days (red cell aplasia). In normal individuals, this

3050-415: The potential impact of testing and test results on the individual. Counselling is best given before a child is conceived, and a number of possible courses could be suggested. These include adoption, the use of eggs or sperm from a healthy donor, and in-vitro fertilisation (IVF) when combined with pre-implantation genetic diagnosis of the embryos. There are a number of precautions which can help reduce

3111-439: The protein which are implicated with abnormal hemoglobins . The mutation which causes sickle cell disease results in an abnormal hemoglobin known as hemoglobin S (HbS), which replaces HbA in adults. The human genome contains a pair of genes for β-globin; in people with sickle cell disease, both genes are affected and the erythropoietic cells in the bone marrow will only create HbS. In people with sickle cell trait , only one gene

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3172-597: The pulmonary infiltrate worsen or the oxygen requirements increase, simple blood transfusion or exchange transfusion is indicated. The latter involves the exchange of a significant portion of the person's red cell mass for normal red cells, which decreases the level of haemoglobin S in the patient's blood. However, there is currently uncertain evidence about the possible benefits or harms of blood transfusion for acute chest syndrome in people with sickle cell disease. Hemoglobinopathy There are two main groups: abnormal structural hemoglobin variants caused by mutations in

3233-437: The release of free heme into the bloodstream exceeding the capacity of the body's protective mechanisms. Although heme is an essential component of hemoglobin, it is also a potent oxidative molecule. Free heme is also an alarmin - a signal of tissue damage or infection, which triggers defensive responses in the body and increases the risk of inflammation and vaso-occlusive events. Checking for SCD begins during pregnancy, with

3294-452: The risk of developing a sickling crisis. Lifestyle behaviours include maintaining good hydration and avoiding physical stress or exhaustion. Since sickling can be triggered by low oxygen levels, people with SCD should avoid high altitudes such as high mountains or flying in unpressurised aircraft. People with SCD should avoid alcohol and smoking, as alcohol can cause dehydration and smoking can trigger acute chest syndrome. Stress can also trigger

3355-480: The shape of the red blood cell from a smooth, doughnut -like shape to the sickle shape, making it fragile and susceptible to blocking or breaking within capillaries . In people heterozygous for HbS ( carriers of sickle cell disease), the polymerisation problems are minor because the normal allele can produce half of the haemoglobin. Sickle cell carriers have symptoms only if they are deprived of oxygen (for example, at altitude) or while severely dehydrated . SCD

3416-430: The shorter life expectancy for those with the homozygous condition would tend to disfavour the trait's survival, the trait is preserved in malaria-prone regions because of the benefits provided by the heterozygous form; an example of natural selection. Due to the adaptive advantage of the heterozygote, the disease is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such as Africa ,

3477-587: The sickle cell trait, any given child has a 25% chance of sickle cell disease; a 25% chance of no sickle cell alleles, and a 50% chance of the heterozygous condition (see diagram). There are several different haplotypes of the sickle cell gene mutation, indicating that it probably arose spontaneously in different geographic areas. The variants are known as Cameroon, Senegal, Benin, Bantu, and Saudi-Asian. These are clinically important because some are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease. The gene defect

3538-406: The spleen and are destroyed. In young children with SCD, the accumulation of sickled cells in the spleen can result in splenic sequestration crisis. In this, the spleen becomes engorged with blood, depriving the general circulation of blood cells and leading to severe anemia. The spleen initially becomes noticeably swollen but the lack of a healthy blood flow through the organ culminates in scarring of

3599-480: The spleen tissues and eventually death of the organ, generally before the age of 5 years. The actual anaemia of the illness is caused by haemolysis , the destruction of the red cells, because of their shape. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction. Healthy red blood cells typically function for 90–120 days, but sickled cells only last 10–20 days. The rapid breakdown of RBC's in SCD results in

3660-419: The spleen to swell and fill with blood. The accumulation of red blood cells in the spleen results in a sudden drop in circulating hemoglobin and potentially life-threatening anemia. Symptoms include pain on the left side, swollen spleen (which can be detected by palpation ), fatigue, dizziness, irritability, rapid heartbeat, or pale skin. It most commonly affects young children, the median age of first occurrence

3721-403: The transit time of RBC through the microvasculature is longer than the polymerization time, sickled RBC will lodge in the microvasculature. " The spleen is especially prone to damage in SCD due to its role as a blood filter. A splenic sequestration crisis, also known as a spleen crisis, is a medical emergency that occurs when sickled red blood cells block the spleen's filter mechanism , causing

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