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Figure (A) shows normal red blood cells flowing freely through veins. The inset shows a cross section of a normal red blood cell with normal haemoglobin. Figure B shows abnormal, sickled red blood cells log jamming, sticking and accumulating at the branching point in a vein. The inset image shows a cross-section of a sickle cell with long polymerized HbS strands stretching and distorting the cell shape.
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Sickle-cell disease (SCD), or sickle-cell anaemia (SCA) or sometimes drepanocytosis, is a hereditary blood disorder, characterized by an abnormality in the oxygen-carrying haemoglobin molecule in red blood cells that leads to a propensity for the cells to assume an abnormal, rigid, sickle-like shape under certain circumstances. Sickle-cell disease is associated with a number of acute and chronic health problems, such as severe infections and attacks of severe pain ("sickle-cell crisis"), and an increased risk of death. Sickle-cell disease occurs when a person inherits two abnormal copies of the haemoglobin gene, one from each parent. Several subtypes exist, depending on the exact mutation in each haemoglobin gene. A person with a single abnormal copy does not experience symptoms and is said to have sickle cell trait.
The complications of sickle-cell disease can be prevented to a large extent with vaccination, preventative antibiotics, blood transfusion, and the drug hydroxyurea/hydroxycarbamide. A small proportion requires a transplant of bone marrow cells.
Almost 300,000 children are born with a form of sickle cell disease every year, mostly in sub-Sarahan Africa but also in other countries such as the West Indies, South Asia and in people of African origin elsewhere in the world. The condition was first described in the medical literature by the American physician James B. Herrick in 1910, and in the 1940s and 1950s contributions by Nobel prize winner Linus Pauling made it the first disease where the exact genetic and molecular defect was elucidated.
- 1 Signs and symptoms
- 2 Genetics
- 3 Pathophysiology
- 4 Diagnosis
- 5 Management
- 6 Prognosis
- 7 Epidemiology
- 8 History
- 9 See also
- 10 References
- 11 Further reading
- 12 External links
Signs and symptoms
Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortality rate.
The terms "sickle cell crisis" or "sickling crisis" may be used to describe several independent acute conditions occurring in patients with sickle-cell disease. Sickle cell disease results in anemia and crises that could be of many types including the vaso-occlusive crisis, aplastic crisis, sequestration crisis, haemolytic crisis and others. Most episodes of sickle-cell crises last between five and seven days. "Although infection, dehydration, and acidosis (all of which favor sickling) can act as triggers, in most instances no predisposing cause is identified."
The vaso-occlusive crisis is caused by 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 administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) 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, a technique to encourage deep breathing to minimise the development of atelectasis, is recommended.
Splenic sequestration crisis
Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected. It is usually infarcted before the end of childhood in individuals suffering from sickle-cell anemia. This autosplenectomy increases the risk of infection from encapsulated organisms; preventive antibiotics and vaccinations are recommended for those with such asplenia.
Splenic sequestration crises are acute, painful enlargements of the spleen, caused by intrasplenic trapping of red cells and resulting in a precipitous fall in hemoglobin levels with the potential for hypovolemic shock. Sequestration crises are considered an emergency. If not treated, patients may die within 1–2 hours due to circulatory failure. Management is supportive, sometimes with blood transfusion. These crises are transient, they continue for 3–4 hours and may last for one day.
Acute chest syndrome
Acute chest syndrome (ACS) is defined by new pulmonary infiltrate with a manifestation of pulmonary symptoms like tachypnea and dyspnea. It is the second most common complication and it accounts for about 25% of death in patients with SCD, majority of cases present with vaso occlusive crises then they develop ACS. Nevertheless, in Dessap et al., 2007 study they reported that about 80% of patients has vaso occlusive crises during ACS.
Aplastic crises are acute worsenings of the patient's baseline anaemia, producing pallor, tachycardia, 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 them and destroying them. Parvovirus infection nearly completely prevents red blood cell production for two to three days. In normal individuals, this is of little consequence, but the shortened red cell life of sickle-cell patients results in an abrupt, life-threatening situation. Reticulocyte counts drop dramatically during the disease (causing reticulocytopenia), and the rapid turnover of red cells leads to the drop in haemoglobin. This crisis takes 4 days to one week to disappear. Most patients can be managed supportively; some need blood transfusion.
Haemolytic crises are acute accelerated drops in haemoglobin level. The red blood cells break down at a faster rate. This is particularly common in patients with co-existent G6PD deficiency. Management is supportive, sometimes with blood transfusions.
One of the earliest clinical manifestations is dactylitis, presenting as early as six months of age, and may occur in children with sickle trait. The crisis can last up to a month. Another recognised type of sickle crisis is the acute chest syndrome, a condition characterised by fever, chest pain, difficulty breathing, and pulmonary infiltrate on a chest X-ray. Given that pneumonia and sickling in the lung can both produce these symptoms, the patient is treated for both conditions. It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery.
Sickle-cell anaemia can lead to various complications, including:
- Increased risk of severe bacterial infections due to loss of functioning spleen tissue (and comparable to the risk of infections after having the spleen removed surgically). These infections are typically caused by encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae. Daily penicillin prophylaxis is the most commonly used treatment during childhood, with some haematologists continuing treatment indefinitely. Patients benefit today from routine vaccination for S. pneumoniae.
- Stroke, which can result from a progressive narrowing of blood vessels, preventing oxygen from reaching the brain. Cerebral infarction occurs in children and cerebral haemorrhage in adults.
- Silent stroke is a stroke that causes no immediate symptoms but is associated with damage to the brain. Silent stroke is probably five times as common as symptomatic stroke. Approximately 10–15% of children with sickle-cell disease suffer strokes, with silent strokes predominating in the younger patients.
- Cholelithiasis (gallstones) and cholecystitis, which may result from excessive bilirubin production and precipitation due to prolonged haemolysis.
- Avascular necrosis (aseptic bone necrosis) of the hip and other major joints, which may occur as a result of ischaemia.
- Decreased immune reactions due to hyposplenism (malfunctioning of the spleen).
- Priapism and infarction of the penis.
- Osteomyelitis (bacterial bone infection); the most common cause of osteomyelitis in sickle-cell disease is Salmonella (especially the non-typical serotypes Salmonella typhimurium, Salmonella enteritidis, Salmonella choleraesuis and Salmonella paratyphi B), followed by Staphylococcus aureus and Gram-negative enteric bacilli perhaps because intravascular sickling of the bowel leads to patchy ischaemic infarction.
- Opioid tolerance, which can occur as a normal, physiologic response to the therapeutic use of opiates. Addiction to opiates occurs no more commonly among individuals with sickle-cell disease than among other individuals treated with opiates for other reasons.
- Acute papillary necrosis in the kidneys.
- Leg ulcers.
- In eyes, background retinopathy, proliferative retinopathy, vitreous haemorrhages and retinal detachments, resulting in blindness. Regular annual eye checks are recommended.
- During pregnancy, intrauterine growth retardation, spontaneous abortion, and pre-eclampsia.
- Chronic pain: Even in the absence of acute vaso-occlusive pain, many patients have chronic pain that is not reported.
- Pulmonary hypertension (increased pressure on the pulmonary artery), leading to strain on the right ventricle and a risk of heart failure; typical symptoms are shortness of breath, decreased exercise tolerance and episodes of syncope.
- Chronic renal failure due to sickle-cell nephropathy—manifests itself with hypertension (high blood pressure), proteinuria (protein loss in the urine), haematuria (loss of red blood cells in urine) and worsened anaemia. If it progresses to end-stage renal failure, it carries a poor prognosis.
Normally, humans have Haemoglobin A, which consists of two alpha and two beta chains, Haemoglobin A2, which consists of two alpha and two delta chains and Haemoglobin F, consisting of two alpha and two gamma chains in their bodies. Of these, Haemoglobin A makes up around 96-97% of the normal haemoglobin in humans.
Sickle-cell conditions have an autosomal recessive pattern of inheritance from parents. The types of haemoglobin a person makes in the red blood cells depend on what haemoglobin genes are inherited from her or his parents. If one parent has sickle-cell anaemia (SS) and the other has sickle-cell trait then there is a 50% chance of a child's having sickle-cell disease and a 50% chance of a child's having sickle-cell trait. When both parents have sickle-cell trait a child has a 25% chance of sickle-cell disease, 25% will not carry any sickle-cell alleles, and 50% will have the heterozygous condition, as shown in the diagram.
Sickle-cell gene mutation probably arose spontaneously in different geographic areas, as suggested by restriction endonuclease analysis. These variants are known as Cameroon, Senegal, Benin, Bantu and Saudi-Asian. Their clinical importance springs from the fact that some of them are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease.
In people heterozygous for HgbS (carriers of sickling haemoglobin), the polymerisation problems are minor, because the normal allele is able to produce over 50% of the haemoglobin. In people homozygous for HgbS, the presence of long-chain polymers of HbS distort the shape of the red blood cell from a smooth doughnut-like shape to ragged and full of spikes, making it fragile and susceptible to breaking within capillaries. Carriers have symptoms only if they are deprived of oxygen (for example, while climbing a mountain) or while severely dehydrated. The sickle-cell disease occurs when the sixth amino acid, glutamic acid, is replaced by valine to change its structure and function; as such, sickle-cell anemia is also known as E6V. Valine is hydrophobic, causing the haemoglobin to collapse in on itself occasionally. The structure is not changed otherwise. When enough haemoglobin collapses in on itself the red blood cells become sickle-shaped.
The gene defect is a known mutation of a single nucleotide (see single-nucleotide polymorphism - SNP) (A to T) of the β-globin gene, which results in glutamic acid being substituted by valine at position 6. Haemoglobin S with this mutation is referred to as HbS, as opposed to the normal adult HbA. The genetic disorder is due to the mutation of a single nucleotide, from a CTC to CAC codon on the coding strand, which is transcribed from the template strand into a GUG codon. This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structure of haemoglobin in conditions of normal oxygen concentration. What it does allow for, under conditions of low oxygen concentration, is the polymerization of the HbS itself. The deoxy form of haemoglobin exposes a hydrophobic patch on the protein between the E and F helices. The hydrophobic residues of the valine at position 6 of the beta chain in haemoglobin are able to associate with the hydrophobic patch, causing haemoglobin S molecules to aggregate and form fibrous precipitates.
The allele responsible for sickle-cell anaemia can be found on the short arm of chromosome 11. A person that receives the defective gene from both father and mother develops the disease; a person that receives one defective and one healthy allele remains healthy, but can pass on the disease and is known as a carrier. If two parents who are carriers have a child, there is a 1-in-4 chance of their child developing the disease and a 1-in-2 chance of their child being just a carrier. Heterozygotes are still able to contract malaria, but their symptoms are generally less severe.
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, 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 life cycle and spends part of it in red blood cells. In a carrier, the presence of the malaria parasite causes the red blood cells with defective haemoglobin to rupture prematurely, making the plasmodium unable to reproduce. Further, the polymerization of Hb affects the ability of the parasite to digest Hb in the first place. Therefore, in areas where malaria is a problem, people's chances of survival actually increase if they carry sickle-cell trait (selection for the heterozygote).
In the USA, where there is no endemic malaria, the prevalence of sickle-cell anaemia among blacks is lower (about 0.25%) than in West Africa (about 4.0%) and is falling. Without endemic malaria, the sickle-cell mutation is purely disadvantageous and will tend to be selected out of the affected population via natural selection. However, the African American community of the USA is known to be the result of significant admixture between several African and non-African ethnic groups, and also represents the descendants of survivors of the slavery and the slave trade. Thus, a lower degree of endogamy and, particularly, abnormally high health-selective pressure through slavery may be the most plausible explanations for the lower prevalence of sickle-cell anaemia (and, possibly, other genetic diseases) among African-Americans compared to Sub-Saharan Africans. Another factor limiting the spread of sickle-cell genes in North America is the absence of cultural proclivities to polygamy, which allows affected males to continue to seek unaffected children with multiple partners.
Sickle-cell anaemia is caused by a point mutation in the β-globin chain of haemoglobin, causing the hydrophilic amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the sixth position. The β-globin gene is found on chromosome 11. The association of two wild-type α-globin subunits with two mutant β-globin subunits forms haemoglobin S (HbS). Under low-oxygen conditions (being at high altitude, for example), the absence of a polar amino acid at position six of the β-globin chain promotes the non-covalent polymerisation (aggregation) of haemoglobin, which distorts red blood cells into a sickle shape and decreases their elasticity.
The loss of red blood cell elasticity is central to the pathophysiology of sickle-cell disease. Normal red blood cells are quite elastic, 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.
The actual anaemia of the illness is caused by haemolysis, the destruction of the red cells, because of their misshape. 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 live 90–120 days, but sickle-cells only survive 10–20 days.
In HbSS, the full blood count reveals haemoglobin levels in the range of 6–8 g/dL with a high reticulocyte count (as the bone marrow compensates for the destruction of sickle-cells by producing more red blood cells). In other forms of sickle-cell disease, Hb levels tend to be higher. A blood film may show features of hyposplenism (target cells and Howell-Jolly bodies).
Sickling of the red blood cells, on a blood film, can be induced by the addition of sodium metabisulfite. The presence of sickle haemoglobin can also be demonstrated with the "sickle solubility test". A mixture of haemoglobin S (Hb S) in a reducing solution (such as sodium dithionite) gives a turbid appearance, whereas normal Hb gives a clear solution.
Abnormal haemoglobin forms can be detected on haemoglobin electrophoresis, a form of gel electrophoresis on which the various types of haemoglobin move at varying speeds. Sickle-cell haemoglobin (HgbS) and haemoglobin C with sickling (HgbSC)—the two most common forms—can be identified from there. The diagnosis can be confirmed with high-performance liquid chromatography (HPLC). Genetic testing is rarely performed, as other investigations are highly specific for HbS and HbC.
An acute sickle-cell crisis is often precipitated by infection. Therefore, a urinalysis to detect an occult urinary tract infection, and chest X-ray to look for occult pneumonia should be routinely performed.
People who are known carriers of the disease often undergo genetic counseling before they have a child. A test to see if an unborn child has the disease takes either a blood sample from the fetus or a sample of amniotic fluid. Since taking a blood sample from a fetus has greater risks, the latter test is usually used. Neonatal screening provides not only a method of early detection for individuals with sickle-cell disease, but also allows for identification of the groups of people that carry the sickle cell trait.
Folic acid and penicillin
Children born with sickle-cell disease will undergo close observation by the pediatrician and will require management by a haematologist to assure they remain healthy. These patients will take a 1 mg dose of folic acid daily for life. From birth to five years of age, they will also have to take penicillin daily due to the immature immune system that makes them more prone to early childhood illnesses.
The protective effect of sickle-cell trait does not apply to people with sickle cell disease; in fact, they are uniquely vulnerable to malaria, since the most common cause of painful crises in malarial countries is infection with malaria. It has therefore been recommended that people with sickle-cell disease living in malarial countries should receive anti-malarial chemoprophylaxis for life.
Most people with sickle-cell disease have intensely painful episodes called vaso-occlusive crises. The frequency, severity, and duration of these crises, however, vary tremendously. Painful crises are treated symptomatically with analgesics; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) devices are commonly used in this setting. Diphenhydramine is also an effective agent that is frequently prescribed by doctors in order to help control any itching associated with the use of opioids.
Acute chest crisis
Management is similar to vaso-occlusive crisis, with 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. Should 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 patients red cell mass for normal red cells, which decreases the percent of haemoglobin S in the patient's blood.
The first approved drug for the causative treatment of sickle-cell anaemia, hydroxyurea, was shown to decrease the number and severity of attacks in a study in 1995 (Charache et al.) and shown to possibly increase survival time in a study in 2003 (Steinberg et al.). This is achieved, in part, by reactivating fetal haemoglobin production in place of the haemoglobin S that causes sickle-cell anaemia. Hydroxyurea had previously been used as a chemotherapy agent, and there is some concern that long-term use may be harmful, but this risk has been shown to be either absent or very small and it is likely that the benefits outweigh the risks.
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 (RBC) that can sickle by adding normal red blood cells. In children prophylactic chronic red blood cell (RBC) transfusion therapy has been shown to be efficacious to a certain extent in reducing the risk of first stroke or silent stroke when transcranial Doppler (TCD) ultrasonography shows abnormal increased cerebral blood flow velocities. In those who have sustained a prior stroke event it also reduces the risk of recurrent stroke and additional silent strokes.
Bone marrow transplants
Bone marrow transplants have proven to be effective in children. Bone marrow transplants are the only known cure for SCD. However, bone marrow transplants are difficult to obtain because of the specific HLA typing necessary. Ideally, a twin family member (syngeneic) or close relative (allogeneic) would donate the bone marrow necessary for transplantation.
About 90% of patients survive to age 20, and close to 50% survive beyond the fifth decade. In 2001, according to one study, the estimated mean survival for sickle-cell patients was 53 years old for men and 58 years old for women with homozygous SCD.
The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, India and the Middle-East. Migration of substantial populations from these high prevalence areas to low prevalence countries in Europe has dramatically increased in recent decades and in some European countries sickle-cell disease has now overtaken more familiar genetic conditions such as haemophilia and cystic fibrosis. In 2010, there were about 29,000 deaths attributed to sickle-cell disease globally.
Sickle-cell disease occurs more commonly among people whose ancestors lived in tropical and sub-tropical sub-Saharan regions where malaria is or was common. Where malaria is common, carrying a single sickle-cell allele (trait) confers a selective advantage—in other words, being a heterozygote is advantageous. Specifically, humans with one of the two alleles of sickle-cell disease show less severe symptoms when infected with malaria.
Three quarters of sickle-cell cases occur in Africa. A recent WHO report estimated that around 2% of newborns in Nigeria were affected by sickle cell anaemia, giving a total of 150,000 affected children born every year in Nigeria alone. The carrier frequency ranges between 10% and 40% across equatorial Africa, decreasing to 1–2% on the north African coast and <1% in South Africa.
The prevalence of the disease in the United States is approximately 1 in 5,000, mostly affecting Americans of Sub-Saharan African descent, according to the National Institutes of Health. In the United States, about 1 out of 500 African-American children and 1 in every 36,000 Hispanic-American children born will have sickle-cell anaemia. It is estimated that sickle-cell disease affects 90,000 Americans. Most infants with SCD born in the United States are now identified by routine neonatal screening. Forty-four states along with the District of Columbia, Puerto Rico and the Virgin Islands currently provide universal neonatal screening for SCD. Sickle cell trait occurs among about 1:12 African-Americans and 1:100 Hispanic-Americans. It is estimated that 2.5 million Americans are heterozygous carriers for the sickle-cell trait.
As a result of population growth in African-Caribbean regions of overseas France and immigration from North and sub-Saharan Africa to mainland France, sickle-cell disease has become a major health problem in France. SCD has become the most common genetic disease in the country, with an overall birth prevalence of 1/2,415 in mainland France, ahead of phenylketonuria (1/10,862), congenital hypothyroidism (1/3,132), congenital adrenal hyperplasia (1/19,008) and cystic fibrosis (1/5,014) for the same reference period. In 2010, 31.5% of all newborns in mainland France (253,466 out of 805,958) were screened for SCD (this percentage was 19% in 2000). 341 newborns with SCD and 8,744 heterozygous carriers were found representing 1.1% of all newborns in mainland France. The Paris metropolitan district (Île-de-France) is the region that accounts for the largest number of newborns screened for SCD (60% in 2010). The second largest number of at-risk is in Provence-Alpes-Côte d'Azur at nearly 43.2% and the lowest number is in Brittany at 5.5%.
In the United Kingdom, all babies receive a blood test to screen for this condition.
In Saudi Arabia about 4.2% of the population carry the sickle-cell trait and 0.26% have sickle-cell disease. The highest prevalence is in the Eastern province where approximately 17% of the population carry the gene and 1.2% have sickle-cell disease. In 2005 in Saudi Arabia a mandatory pre-marital test including HB electrophoresis was launched and aimed to decrease the incidence of SCD and thalassemia.
Sickle-cell disease is common in many parts of India, where the prevalence has ranged from 9.4 to 22.2% in endemic areas.
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In 1910 a Chicago physician, James B. Herrick, reported the presence of sickle-cells in the blood of an anaemic dental student, Walter Clement Noel. These cells had first been observed by his intern Ernest Irons while they were treating Noel in 1904.
An association with pigmented gall stones was noted in 1911 by Washborn. A genetic basis for this disease was proposed in 1915 by Cook and Meyer. The disease was named sickle-cell anaemia in 1922 by Verne Mason after several additional cases were reported. All the known cases had been reported in blacks and he concluded that this disease was confined to those of black African descent. The heterozygous condition was independently recognised in 1923 by Huck and Syndestrickler. Syndestrickler also was the first to note the splenic atrophy that occurs in this condition. It was recognised as a Mendelian autosomal characteristic by Taliaffero and Huck also in 1923. A predisposition to pneumonia was noted in 1924 by Graham. The concept of progressive splenic atrophy was proposed by Hahn and Gilespie in 1927. Pneumococcal meningitis in this condition was first reported in 1928 by Wollstein and Kriedel but it was not until 1966 that the association between splenic atrophy and infection was made by Robinson and Watson.
In 1927 Vernon Hahn and Elizabeth Biermann Gillespie showed that sickling of the red cells was related to low oxygen. In some individuals this change occurs at partial pressures of O
2 prevalent in the body, and produces anemia and other disorders, termed sickle-cell disease. In other persons sickling occurs only at very low O
2 partial pressures; these are asymptomatic sickle-cell trait carriers.
The association with kidney and lung infarcts was noted in 1931 by Yater and Mollari and Baird in 1934 respectively. The term sickle-cell trait was coined by Samuel Diggs in Memphis in 1933 to distinguish heterozygotes from those with sickle-cell anaemia. Diggs also reported the association with splenic fibrosis in 1935. The pathological mechanism of vaso-occlusion was proposed by Ham and Castle in 1940.
In 1946, E A Beet, a British medical officer stationed in Southern Rhodesia (Zimbabwe), observed that blood from malaria patients who had sickle-cell trait had fewer malarial parasites than blood from patients without the trait and suggested that this might be a protective feature. In 1947 Beet published that the incidence of enlarged spleens in sickle-cell patients was much lower than in non sickle-cell and suggested that this was due to recurrent thromboses which resulted in fibrosis and shrinkage of the spleen. In 1949 Lehmann and Raper published a map of Uganda and showed that the presence of sickle-cell anaemia correlated with the presence of malaria. In 1950 Singer et al. noted the abrupt cessation of marrow activity that may occur and coined the term aplastic crisis. The role of parvovirus in aetiology of this condition was not recognised until 1981. P. Brain also while working in Northern Rhodesia confirmed the lower incidence of splenomegaly and suggested that while homozygotes for the sickle-cell gene suffered from several problems heterozygotes might be protected against malaria.
The modern phase of research on this disorder was initiated by the famous chemist Linus Pauling in 1949. Pauling postulated that the hemoglobin (Hb) in sickle-cell disease is abnormal; when deoxygenated it polymerizes into long, thin, helical rods that distort the red cell into a sickle shape. In his laboratory, electrophoretic studies showed that sickle-cell Hb (S) is indeed abnormal, having at physiological pH a lower negative charge than normal adult human Hb (A). In sickle-cell trait carriers there is a nearly equal amount of HbA and HbS, whereas in persons with sickle-cell disease nearly all the Hb is of the S type, apart from a small amount of fetal Hb. These observations showed that most patients with sickle-cell disease are homozygous for the gene encoding HbS, while trait carriers are heterozygous for this gene. Persons inheriting a sickle-cell gene and another mutant at the same locus, e.g. a thalassemia gene, can also have a variant form of sickle-cell disease. Pauling also introduced the term "molecular disease", which, together with molecular medicine, has become widely used.
The next major advance was the discovery by Vernon Ingram in 1959 that HbS differs from HbA by only a single amino-acid substitution in the β-polypeptide chain (β6Glu → Val). It was later established that this results from a substitution of thymine for adenine in the DNA codon (GAG → GTG). This was the first example in any species of the effects of a mutation on a protein.
This collection of clinical findings was unknown until the explanation of the sickle-cells in 1910 by a Chicago cardiologist and professor of medicine James B. Herrick (1861–1954), whose intern Ernest Edward Irons (1877–1959) found "peculiar elongated and sickle-shaped" cells in the blood of Walter Clement Noel, a 20-year-old first-year dental student from Grenada, after Noel was admitted to the Chicago Presbyterian Hospital in December 1904 suffering from anaemia.
Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks". Noel completed his studies and returned to the capital of Grenada (St. George's) to practice dentistry. He died of pneumonia in 1916 and is buried in the Catholic cemetery at Sauteurs in the north of Grenada. Herrick's published account included illustrations, but the earliest available slide showing sickle-cells is that of a 1918 autopsy from a soldier with sickle trait, initially reviewed only 92 years later.
The disease was named "sickle-cell anemia" by Verne Mason in 1922, then a medical resident at Johns Hopkins Hospital. However, some elements of the disease had been recognized earlier: A paper in the Southern Journal of Medical Pharmacology in 1846 described the absence of a spleen in the autopsy of a runaway slave. The African medical literature reported this condition in the 1870s, when it was known locally as ogbanjes ("children who come and go") because of the very high infant mortality rate caused by this condition. A history of the condition tracked reports back to 1670 in one Ghanaian family.
Linus Pauling and colleagues were the first, in 1949, to demonstrate that sickle-cell disease occurs as a result of an abnormality in the haemoglobin molecule. This was the first time a genetic disease was linked to a mutation of a specific protein, a milestone in the history of molecular biology, and it was published in their paper "Sickle Cell Anemia, a Molecular Disease".
- Malowany JI, Butany J (February 2012). "Pathology of sickle cell disease". Seminars in Diagnostic Pathology 29 (1): 49–55. doi:10.1053/j.semdp.2011.07.005. PMID 22372205.
- "BestBets: How long should an average sickle cell crisis last?". Retrieved 2010-11-27.
- Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009-05-28). Robbins and Cotran Pathologic Basis of Disease, Professional Edition: Expert Consult - Online (Robbins Pathology) (Kindle Locations 33498-33499). Elsevier Health. Kindle Edition.
- Olujohungbe, A; Burnett, A. L. (2013). "How I manage priapism due to sickle cell disease". British Journal of Haematology 160 (6): 754–65. doi:10.1111/bjh.12199. PMID 23293942.
- Glassberg J (August 2011). "Evidence-based management of sickle cell disease in the emergency department". Emergency Medicine Practice 13 (8): 1–20; quiz 20. PMID 22164362.
- Anie KA, Green J (2012). "Psychological therapies for sickle cell disease and pain". In Anie, Kofi A. Cochrane Database of Systematic Reviews (Online) 2: CD001916. doi:10.1002/14651858.CD001916.pub2. PMID 22336781.
- Pearson HA (Aug 1977). "Sickle cell anemia and severe infections due to encapsulated bacteria" (Free full text). J Infect Dis. 136 Suppl: S25–30. doi:10.1093/infdis/136.Supplement.S25. ISSN 0022-1899. PMID 330779.
- Wong WY, Powars DR, Chan L, Hiti A, Johnson C, Overturf G (Mar 1992). "Polysaccharide encapsulated bacterial infection in sickle cell anaemia: a thirty year epidemiologic experience". Am J Hematol 39 (3): 176–82. doi:10.1002/ajh.2830390305. PMID 1546714.
- Khatib R, Rabah R, Sarnaik SA (January 2009). "The spleen in the sickling disorders: an update". Pediatric Radiology 39 (1): 17–22. doi:10.1007/s00247-008-1049-9. PMID 19002450.
- Dessap AM, Leon R, Habibi A, Nzouakou R, Roudot-Thoraval F, Adnot S, Godeau B, Galacteros F, Brun-Buisson C, Brochard L, Maitre B (2008). "Pulmonary hypertension and cor pulmonale during severe acute chest syndrome in sickle cell disease". Am. J. Respir. Crit. Care Med. 177 (6): 646–53. doi:10.1164/rccm.200710-1606OC. PMID 18174543.
- Paul RN, Castro OL, Aggarwal A, Oneal PA (2011). "Acute chest syndrome: sickle cell disease". Eur. J. Haematol. 87 (3): 191–207. doi:10.1111/j.1600-0609.2011.01647.x. PMID 21615795.
- Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009-05-28). Robbins and Cotran Pathologic Basis of Disease, Professional Edition: Expert Consult - Online (Robbins Pathology) (Kindle Location 33329). Elsevier Health. Kindle Edition.
- Slavov SN, Kashima S, Pinto AC, Covas DT (August 2011). "Human parvovirus B19: general considerations and impact on patients with sickle-cell disease and thalassemia and on blood transfusions". FEMS Immunology and Medical Microbiology 62 (3): 247–62. doi:10.1111/j.1574-695X.2011.00819.x. PMID 21585562.
- Balgir RS (March 2012). "Community expansion and gene geography of sickle cell trait and G6PD deficiency, and natural selection against malaria: experience from tribal land of India". Cardiovascular & Hematological Agents in Medicinal Chemistry 10 (1): 3–13. doi:10.2174/187152512799201190. PMID 22264009.
- Jadavji T, Prober CG (April 1985). "Dactylitis in a child with sickle cell trait". Can Med Assoc J 132 (7): 814–5. ISSN 0008-4409. PMC 1345873. PMID 3978504.
- Miller ST (May 2011). "How I treat acute chest syndrome in children with sickle cell disease". Blood 117 (20): 5297–305. doi:10.1182/blood-2010-11-261834. PMID 21406723.
- Kavanagh PL, Sprinz PG, Vinci SR, Bauchner H, Wang CJ (2011). "Management of children with sickle cell disease: a comprehensive review of the literature". Pediatrics 128 (6): e1552–74. doi:10.1542/peds.2010-3686. PMID 22123880.
- Adams RJ, Ohene-Frempong K, Wang W (2001). "Sickle cell and the brain". Hematology Am Soc Hematol Educ Program 2001 (1): 31–46. doi:10.1182/asheducation-2001.1.31. PMID 11722977.
- Adams RJ (November 2007). "Big strokes in small persons". Arch. Neurol. 64 (11): 1567–74. doi:10.1001/archneur.64.11.1567. PMID 17998439.
- Martí-Carvajal A, Dunlop R, Agreda-Perez L (Oct 2004). "Treatment for avascular necrosis of bone in people with sickle cell disease". In Martí-Carvajal, Arturo J. Cochrane database of systematic reviews (Online) (4): CD004344. doi:10.1002/14651858.CD004344.pub2. PMID 15495103.
- Kenny MW, George AJ, Stuart J (July 1980). "Platelet hyperactivity in sickle-cell disease: a consequence of hyposplenism". Journal of Clinical Pathology 33 (7): 622–5. doi:10.1136/jcp.33.7.622. PMC 1146172. PMID 7430367. Retrieved 2011-03-23.
- Chrouser KL, Ajiboye OB, Oyetunji TA, Chang DC (April 2011). "Priapism in the United States: the changing role of sickle cell disease". American Journal of Surgery 201 (4): 468–74. doi:10.1016/j.amjsurg.2010.03.017. PMID 21421100.
- Almeida A, Roberts I (May 2005). "Bone involvement in sickle cell disease". Br. J. Haematol. 129 (4): 482–90. doi:10.1111/j.1365-2141.2005.05476.x. PMID 15877730.
- Rudge FW (1991). "Hyperbaric oxygen therapy in the treatment of sickle cell leg ulcers". J. Hyperbaric Med 6 (1): 1–4. Retrieved 2011-03-23.
- Elagouz M, Jyothi S, Gupta B, Sivaprasad S (July 2010). "Sickle cell disease and the eye: old and new concepts". Survey of Ophthalmology 55 (4): 359–77. doi:10.1016/j.survophthal.2009.11.004. PMID 20452638. Retrieved 2011-03-23.
- Smith WR, Penberthy LT, Bovbjerg VE, McClish DK, Roberts JD, Dahman B, Aisiku IP, Levenson JL, Roseff SD (Jan 2008). "Daily assessment of pain in adults with sickle cell disease". Annals of Internal Medicine 148 (2): 94–101. doi:10.7326/0003-4819-148-2-200801150-00004. ISSN 0003-4819. PMID 18195334.
- Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder WC, Schechter AN, Rodgers GP, Castro O, Ognibene FP (February 2004). "Pulmonary hypertension as a risk factor for death in patients with sickle cell disease". N. Engl. J. Med. 350 (9): 886–95. doi:10.1056/NEJMoa035477. PMID 14985486.
- Powars DR, Elliott-Mills DD, Chan L, Niland J, Hiti AL, Opas LM, Johnson C (Oct 1991). "Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality". Annals of Internal Medicine 115 (8): 614–20. doi:10.7326/0003-4819-115-8-614. ISSN 0003-4819. PMID 1892333.
- Green NS, Fabry ME, Kaptue-Noche L, Nagel RL (Oct 1993). "Senegal haplotype is associated with higher HbF than Benin and Cameroon haplotypes in African children with sickle cell anemia". Am. J. Hematol. 44 (2): 145–6. doi:10.1002/ajh.2830440214. ISSN 0361-8609. PMID 7505527.
- Allison AC (October 2009). "Genetic control of resistance to human malaria". Current Opinion in Immunology 21 (5): 499–505. doi:10.1016/j.coi.2009.04.001. PMID 19442502.
- Kwiatkowski DP (Aug 2005). "How Malaria Has Affected the Human Genome and What Human Genetics Can Teach Us about Malaria". Am. J. Hum. Genet. 77 (2): 171–92. doi:10.1086/432519. ISSN 0002-9297. PMC 1224522. PMID 16001361.
- Ponçon N, Toty C, L'Ambert G, Le Goff G, Brengues C, Schaffner F, Fontenille D (2007). "Biology and dynamics of potential malaria vectors in Southern France". Malar. J. 6: 18. doi:10.1186/1475-2875-6-18. PMC 1808464. PMID 17313664.
- Lesi FE, Bassey EE (July 1972). "Family study in sickle cell disease in Nigeria". J Biosoc Sci 4 (3): 307–13. doi:10.1017/S0021932000008622. PMID 5041262.
- Lazarus, Hillard M.; Schmaier, Alvin H. (2011). Concise Guide to Hematology. Wiley-Blackwell. p. 18. ISBN 1-4051-9666-1.
- "How Does Sickle Cell Cause Disease?". Retrieved 2010-11-27.
- "Sickle Cell Anemia: eMedicine Emergency Medicine". Retrieved 2010-11-27.
- Clarke GM, Higgins TN (August 2000). "Laboratory investigation of hemoglobinopathies and thalassemias: review and update". Clin. Chem. 46 (8 Pt 2): 1284–90. PMID 10926923.
- "BestBets: Does routine urinalysis and chest radiography detect occult bacterial infection in sickle cell patients presenting to the accident and emergency department with painful crisis?". Retrieved 2010-11-27.
- Lee, C., Davies, S.,& Dezatoux, C.(2000). Neonatal Screening for sickle cell disease. The Cochrane Collaboration. John Wiley & Sons, Ltd.
- Oniyangi O, Omari AA (2006). "Malaria chemoprophylaxis in sickle cell disease". In Oniyangi, Oluseyi. Cochrane Database of Systematic Reviews 13 (4): CD003489. doi:10.1002/14651858.CD003489.pub2. PMID 17054173.
- Aldrich TK, Nagel RL. (1998). "Pulmonary Complications of Sickle Cell Disease.". In Reynolds HY, Bone RC, Dantzker DR, George RB, Matthay RA. Pulmonary and Critical Care Medicine (6th ed.). St. Louis: Mosby. pp. 1–10. ISBN 0-8151-1371-4.
- Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR (May 1995). "Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia". N. Engl. J. Med. 332 (20): 1317–22. doi:10.1056/NEJM199505183322001. ISSN 0028-4793. PMID 7715639.
- Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, Orringer E, Bellevue R, Olivieri N, Eckman J, Varma M, Ramirez G, Adler B, Smith W, Carlos T, Ataga K, DeCastro L, Bigelow C, Saunthararajah Y, Telfer M, Vichinsky E, Claster S, Shurin S, Bridges K, Waclawiw M, Bonds D, Terrin M (April 2003). "Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment". JAMA 289 (13): 1645–51. doi:10.1001/jama.289.13.1645. PMID 12672732.
- Platt OS (Mar 2008). "Hydroxyurea for the treatment of sickle cell anemia". N. Engl. J. Med. 358 (13): 1362–9. doi:10.1056/NEJMct0708272. PMID 18367739.
- Drasar E, Igbineweka N, Vasavda N, Free M, Awogbade M, Allman M, Mijovic A, Thein SL (March 2011). "Blood transfusion usage among adults with sickle cell disease - a single institution experience over ten years". Br. J. Haematol. 152 (6): 766–70. doi:10.1111/j.1365-2141.2010.08451.x. PMID 21275951.
- Gyang E, Yeom K, Hoppe C, Partap S, Jeng M (January 2011). "Effect of chronic red cell transfusion therapy on vasculopathies and silent infarcts in patients with sickle cell disease". Am. J. Hematol. 86 (1): 104–6. doi:10.1002/ajh.21901. PMID 21117059.
- Mirre E, Brousse V, Berteloot L, Lambot-Juhan K, Verlhac S, Boulat C, Dumont MD, Lenoir G, de Montalembert M (March 2010). "Feasibility and efficacy of chronic transfusion for stroke prevention in children with sickle cell disease". Eur. J. Haematol. 84 (3): 259–65. doi:10.1111/j.1600-0609.2009.01379.x. PMID 19912310.
- Walters MC, Patience M, Leisenring W, Eckman JR, Scott JP, Mentzer WC, Davies SC, Ohene-Frempong K, Bernaudin F, Matthews DC, Storb R, Sullivan KM (August 1996). "Bone marrow transplantation for sickle cell disease". N. Engl. J. Med. 335 (6): 369–76. doi:10.1056/NEJM199608083350601. PMID 8663884.
- Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009-05-28). Robbins and Cotran Pathologic Basis of Disease, Professional Edition: Expert Consult - Online (Robbins Pathology) (Kindle Locations 33530-33531). Elsevier Health. Kindle Edition.
- Wierenga KJ, Hambleton IR, Lewis NA (2001). "Survival estimates for patients with homozygous sickle-cell disease in Jamaica: A clinic-based population study". Lancet 357 (9257): 680–683. doi:10.1016/s0140-6736(00)04132-5. PMID 11247552.
- Weatherall DJ, Clegg JB (2001). "Inherited haemoglobin disorders: an increasing global health problem". Bull. World Health Organ. 79 (8): 704–12. PMC 2566499. PMID 11545326.
- Roberts I, de Montalembert M (July 2007). "Sickle cell disease as a paradigm of immigration hematology: new challenges for hematologists in Europe". Haematologica 92 (7): 865–71. doi:10.3324/haematol.11474. PMID 17606434.
- Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, et al. (Dec 15, 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604.
- Wellems TE, Hayton K, Fairhurst RM (September 2009). "The impact of malaria parasitism: from corpuscles to communities". J. Clin. Invest. 119 (9): 2496–505. doi:10.1172/JCI38307. PMC 2735907. PMID 19729847.
- WHO. "Sickle-cell anaemia - Report by the Secretariat" (PDF). Retrieved 2010-11-27.
- National Heart, Lung and Blood Institute. "Sickle cell anemia, key points". Retrieved 2010-11-27.
- "September is Sickle Cell Awareness Month". CDC. Retrieved 6 February 2011.
- "Sickle Cell Disease: Data & Statistics". Centers for Disease Control and Prevention. 16 September 2011. Retrieved 8 November 2011.
- American Academy of Pediatrics Section on Hematology/Oncology Committee on Genetics (2002). "Health Supervision for Children with Sickle Cell Disease". Pediatrics 109 (3): 526–535. doi:10.1542/peds.109.3.526. PMID 11875155.
- Pass KA, Lane PA, Fernhoff PM, Hinton CF, Panny SR, Parks JS, Pelias MZ, Rhead WJ, Ross SI, Wethers DL, Elsas LJ (2000). "US newborn screening system guidelines II: follow-up of children, diagnosis, management, and evaluation". J Pediatr 137 (37): S1–S46. doi:10.1067/mpd.2000.109437. PMID 11044838.
- "Sickle Cell Disease". March of Dimes®. February 2008. Retrieved 8 November 2011.
- Cinnchinsky EP, Mahoney DH, Landlaw SA (29 November 2011). "Uptodate: Sickle Cell Trait". Retrieved 8 November 2011.
- Bardakdjian J, Wajcman H (September 2004). "[Epidemiology of sickle cell anemia]". Rev Prat (in French) 54 (14): 1531–3. PMID 15558961.
- Bardakdjian-Michau J, Bahuau M, Hurtrel D, Godart C, Riou J, Mathis M, Goossens M, Badens C, Ducrocq R, Elion J, Perini JM (January 2009). "Neonatal screening for sickle cell disease in France". J. Clin. Pathol. 62 (1): 31–3. doi:10.1136/jcp.2008.058867. PMID 19103855.
- Le dépistage néonatal de la drépanocytose en France. Numéro thématique. La drépanocytose en France : des données épidémiologiques pour améliorer la prise en charge, Bardakdjian-Michau J, INVS, July 2012
- Jastaniah W (2011). "Epidemiology of sickle cell disease in Saudi Arabia". Annals of Saudi Medicine 31 (3): 289–93. doi:10.4103/0256-4947.81540. PMC 3119971. PMID 21623060.
- Memish ZA, Saeedi MY (2011). "Six-year outcome of the national premarital screening and genetic counseling program for sickle cell disease and β-thalassemia in Saudi Arabia". Annals of Saudi Medicine 31 (3): 229–35. doi:10.4103/0256-4947.81527. PMC 3119961. PMID 21623050.
- Awasthy N, Aggarwal KC, Goyal PC, Prasad MS, Saluja S, Sharma M (2008). "Sickle cell disease: Experience of a tertiary care center in a nonendemic area". Annals of Tropical Medicine and Public Health 1 (1): 1–4. doi:10.4103/1755-6783.43069.
- Asnani MR, McCaw-Binns AM, Reid ME (2011). "Excess Risk of Maternal Death from Sickle Cell Disease in Jamaica: 1998–2007". PLoS ONE 6 (10): e26281. doi:10.1371/journal.pone.0026281. PMID 22039456.
- Lebby R (1846) Case of absence of the spleen. Southern J of Med Pharmacol 1: 481-483
- Herrick JB (1910). "Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia.". Arch Intern Med 5: 517–521.; Reprinted in Herrick JB (2001). "Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. 1910". Yale J Biol Med 74 (3): 179–84. PMC 2588723. PMID 11501714.
- Taliaferro WH, Huck JG (1923). "The Inheritance of Sickle-Cell Anaemia in Man". Genetics 8 (6): 594–598. PMC 1200767. PMID 17246028.
- Hahn EV, Gillespie EB (1927). "Sickle cell anemia. Report of a case greatly improved by splenectomy. Experimental study of sickle cell formation". Arch Intern Med 39 (2): 233–254. doi:10.1001/archinte.1927.00130020072006.
- Lehmann H, Raper AB; Raper (1949). "Distribution of sickle cell trait in Uganda, and its ethnological significance". Nature 164 (4168): 494–495. Bibcode:1949Natur.164..494L. doi:10.1038/164494a0. PMID 18140460.
- Brain P (1952). "Sickle-cell Anaemia in Africa". Br Med J 2: 880. doi:10.1136/bmj.2.4789.880. PMC 2021738.
- Pauling L, Itano HA (1949). "Sickle cell anemia, a molecular disease". Science 110 (2865): 543–548. Bibcode:1949Sci...110..543P. doi:10.1126/science.110.2865.543. PMID 15395398.
- Ingram VM (1959). "Abnormal human haemoglobins. III. The chemical difference between normal and sickle cell haemoglobins". Biochim Biophys Acta 36 (2): 402–411. doi:10.1016/0006-3002(59)90183-0. PMID 13852872.
- Herrick JB (1910). "Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia". Arch. Intern. Med. 6 (5): 517–521. doi:10.1001/archinte.1910.00050330050003.; reprinted as Herrick JB (2001). "Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. 1910". The Yale journal of biology and medicine 74 (3): 179–84. PMC 2588723. PMID 11501714.
- Savitt TL, Goldberg MF (Jan 1989). "Herrick's 1910 case report of sickle cell anemia. The rest of the story". JAMA 261 (2): 266–71. doi:10.1001/jama.261.2.266. PMID 2642320.
- McKenna, Maryn (2010-11-15). "From 1918 Autopsy, A First Glimpse of Sickle Cell — and a Warning". Wired. Retrieved 2010-11-28.
- Mason VR (1922). "Sickle cell anemia". JAMA 79 (14): 1318–1320. doi:10.1001/jama.254.14.1955. PMID 3900438.
- Konotey-Ahulu FID. Effect of environment on sickle cell disease in West Africa: epidemiologic and clinical considerations. In: Sickle Cell Disease, Diagnosis, Management, Education and Research. Abramson H, Bertles JF, Wethers DL, eds. CV Mosby Co, St. Louis. 1973; 20; cited in Desai, D. V.; Hiren Dhanani (2004). "Sickle Cell Disease: History And Origin". The Internet Journal of Haematology 1 (2). ISSN 1540-2649.
|Library resources about
- Brown, Robert T., ed. (2006). Comprehensive handbook of childhood cancer and sickle cell disease: a biopsychosocial approach. Oxford University Press. ISBN 978-0-19-516985-0.
- Hill, Shirley A. (2003). Managing Sickle Cell Disease in Low-Income Families. Temple University Press. ISBN 978-1-59213-195-2.
- Serjeant, Graham R. & Beryl E. (2001). Sickle Cell Disease. Oxford University Press. ISBN 978-0-19-263036-0.
- Tapper, Melbourne (1999). In the blood: sickle cell anemia and the politics of race. University of Pennsylvania Press. ISBN 978-0-8122-3471-8.
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