Sickle-cell disease

From Wikipedia, the free encyclopedia
  (Redirected from Sickle Cell Anemia)
Jump to: navigation, search
Sickle-cell disease
Classification and external resources
Sickle cell 01.jpg
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.
ICD-10 D57
ICD-9 282.6
OMIM 603903
DiseasesDB 12069
MedlinePlus 000527
eMedicine med/2126 oph/490 ped/2096 emerg/26 emerg/406
MeSH C15.378.071.141.150.150
GeneReviews

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. This 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, attacks of severe pain ("sickle-cell crisis"), and stroke, and there is 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-Saharan Africa, but also in other countries such as the West Indies and 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.

Signs and symptoms[edit]

Sickle-cells in human blood: both normal red blood cells and sickle-shaped cells are present.
Normal blood cells next to a sickle-blood cell, colored scanning electron microscope image

Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortality rate.[1]

Sickle-cell crisis[edit]

The terms "sickle-cell crisis" or "sickling crisis" may be used to describe several independent acute conditions occurring in patients with SCD. SCD 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.[2] "Although infection, dehydration, and acidosis (all of which favor sickling) can act as triggers, in most instances, no predisposing cause is identified."[3]

Vaso-occlusive crisis[edit]

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 devices are commonly used in this setting. Vaso-occlusive crisis involving organs such as the penis [4] 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.[5]

Splenic sequestration crisis[edit]

Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected.[6] 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;[7][8] 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.[9]

Acute chest syndrome[edit]

Acute chest syndrome (ACS) is defined by new pulmonary infiltrate with a manifestation of pulmonary symptoms such as tachypnea and dyspnea.[10] It is the second-most common complication and it accounts for about 25% of deaths in patients with SCD, majority of cases present with vaso-occlusive crises then they develop ACS.[10][11] Nevertheless, about 80% of patients have vaso-occlusive crises during ACS.

Aplastic crisis[edit]

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 and destroying them.[12] 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 SCD 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.[13]

Haemolytic crisis[edit]

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 coexistent G6PD deficiency.[14] Management is supportive, sometimes with blood transfusions.[5]

Other[edit]

One of the earliest clinical manifestations is dactylitis, presenting as early as six months of age, and may occur in children with sickle-cell trait.[15] The crisis can last up to a month.[16] Another recognised type of sickle crisis, acute chest syndrome, is 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.[17] It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery.

Complications[edit]

Sickle-cell anaemia can lead to various complications, including:

Genetics[edit]

Distribution of the sickle-cell trait shown in pink and purple
Historical distribution of malaria (no longer endemic in Europe) shown in green
Modern distribution of malaria

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 F dominates until about 6 weeks of age then A dominates throughout life.

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 and the other has sickle-cell trait, then the child has a 50% chance of having sickle-cell disease and a 50% chance of 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.

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 is because some are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease.[30]

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 on itself occasionally. The structure is not changed otherwise. When enough haemoglobin collapses 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 structures 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, more specifically 11p15. A person who receives the defective gene from both father and mother develops the disease; a person who receives one defective and one healthy allele remains healthy, but can pass on the disease and is known as a carrier or heterozygote. Heterozygotes are still able to contract malaria, but their symptoms are generally less severe.[31]

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.[32] Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases.[33]

The malaria parasite has a complex lifecycle 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 parasite 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, with 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 by 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 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.[34]

Sickle-cell disease is inherited in the autosomal recessive pattern.

Pathophysiology[edit]

Scanning electron micrograph showing a mixture of red blood cells, some with round normal morphology, some with mild sickling showing elongation and bending

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 shape. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction.[35] Healthy red blood cells typically function for 90–120 days, but sickled cells only last 10–20 days.[36]

Diagnosis[edit]

In HbSS, the complete 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 sickled 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. Genetic testing is rarely performed, as other investigations are highly specific for HbS and HbC.[37]

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.[38]

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.[39]

Management[edit]

Folic acid and penicillin[edit]

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.

Malaria chemoprophylaxis[edit]

The protective effect of sickle-cell trait does not apply to people with sickle cell disease; in fact, they are more 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.[40]

Vaso-occlusive crisis[edit]

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[edit]

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),[41] 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.

Hydroxyurea[edit]

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.)[42] and shown to possibly increase survival time in a study in 2003 (Steinberg et al.).[43] 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.[44]

Transfusion therapy[edit]

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.[45] 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.[46][47]

Bone marrow transplants[edit]

Bone marrow transplants have proven to be effective in children. Bone marrow transplants are the only known cure for SCD.[48] 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.

Prognosis[edit]

About 90% of patients survive to age 20, and close to 50% survive beyond the fifth decade.[49] In 2001, according to one study performed in Jamaica, the estimated mean survival for sickle-cell patients was 53 years old for men and 58 years old for women with homozygous SCD.[50]

Epidemiology[edit]

The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, India and the Middle-East.[51] 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.[52] In 2010, there were about 29,000 deaths attributed to sickle-cell disease globally.[53]

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.[54]

Africa[edit]

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.[55] There have been studies in Africa that show a significant decrease in infant mortality rate, ages 2–16 months, because of the sickle-cell trait. This happened in areas that were known to be predominant areas of malarial cases.[56]

United States[edit]

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.[57] 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.[58] It is estimated that sickle-cell disease affects 90,000 Americans.[59] 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.[60][61] Sickle cell trait occurs among about 1:12 African-Americans and 1:100 Hispanic-Americans.[62] It is estimated that 2.5 million Americans are heterozygous carriers for the sickle-cell trait.[63]

France[edit]

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.[64] 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%.[65][66]

United Kingdom[edit]

In the United Kingdom, all babies receive a blood test to screen for this condition.[67]

Middle East[edit]

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.[68] 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.[69]

India[edit]

Sickle-cell disease is common in many parts of India, where the prevalence has ranged from 9.4 to 22.2% in endemic areas.[70]

Caribbean Islands[edit]

In Jamaica, 10% of the population carries the sickle-cell gene, making it the most prevalent genetic disorder in the country.[71]

History[edit]

The first modern report of sickle-cell disease may have been in 1846, where the autopsy of an executed runaway slave was discussed; the key findings was the absence of the spleen.[72][73] There were also reports amongst African slaves in the United States exhibiting resistance to malaria but being prone to leg ulcers.[73] The abnormal characteristics of the red blood cells, which later lent their name to the condition, was first described by Ernest Edward Irons (1877–1959), intern to the Chicago cardiologist and professor of medicine James B. Herrick (1861–1954), in 1910. Irons saw "peculiar elongated and sickle-shaped" cells in the blood of a man named Walter Clement Noel, a 20-year-old first-year dental student from Grenada. Noel had been admitted to the Chicago Presbyterian Hospital in December 1904 suffering from anaemia.[74][75] Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks" but 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.[75][76] Shortly after the report by Herrick, several other cases appeared in the medical literature. In the description by Verne Mason in 1922, the name "sickle cell anemia" is first used.[76][77] Childhood problems related to sickle cells disease were not reported until the 1930s, despite the fact that this cannot have been uncommon in African-American populations.[73]

The Memphis physician Lemuel Diggs, a prolific researcher into sickle cell disease, first introduced the distinction between sickle cell disease and trait in 1933, although it took until 1949 until the genetic characteristics were elucidated by James V. Neel and E.A. Beet.[76] 1949 was the year when Linus Pauling described the unusual chemical behaviour of haemoglobin S, and attributed this to an abnormality in the molecule itself.[76][78] The actual molecular change in HbS was described in the late 1950s BY Vernon Ingram.[76] The late 1940s and early 1950s saw further understanding in the link between malaria and sickle cell disease. In 1954, the introduction of haemoglobin electrophoresis allowed the discovery of particular subtypes, such as HbSC disease.[76]

Large scale natural history studies and further intervention studies were introduced in the 1970s and 1980s, leading to the more widespread use of prophylaxis against pneumococcal infections amongst other interventions. The 1990s saw the development of hydroxycarbamide, and reports of cure through bone marrow transplantation appeared in 2007.[76]

Research[edit]

Gene therapy[edit]

In 2001 it was reported that sickle-cell disease had been successfully treated in mice using gene therapy.[79][80] The mice – which have essentially the same defect that causes sickle cell disease in humans – through the use a viral vector, were made to express the production of fetal hemoglobin (HbF), which normally ceases to be produced by an individual shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF has been known to temporarily alleviate the symptoms of sickle cell disease. The researchers demonstrated this method of gene therapy to be a more permanent means to increase the production of the therapeutic HbF.[81]

Phase 1 clinical trials of gene therapy for sickle cell disease in humans were started in 2014[82][83] although one review failed to find them. [84]

See also[edit]

References[edit]

  1. ^ Yawn, BP; Buchanan, GR; Afenyi-Annan, AN; Ballas, SK; Hassell, KL; James, AH; Jordan, L; Lanzkron, SM; Lottenberg, R; Savage, WJ; Tanabe, PJ; Ware, RE; Murad, MH; Goldsmith, JC; Ortiz, E; Fulwood, R; Horton, A; John-Sowah, J (Sep 10, 2014). "Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members.". JAMA 312 (10): 1033–48. doi:10.1001/jama.2014.10517. PMID 25203083. 
  2. ^ "BestBets: How long should an average sickle cell crisis last?". Retrieved 2010-11-27. 
  3. ^ 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.
  4. ^ Olujohungbe A, Burnett AL (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. 
  5. ^ a b 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. 
  6. ^ Anie KA, Green J (2012). Anie, Kofi A, ed. "Psychological therapies for sickle cell disease and pain". Cochrane Database of Systematic Reviews (Online) 2: CD001916. doi:10.1002/14651858.CD001916.pub2. PMID 22336781. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ a b 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. 
  11. ^ 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. 
  12. ^ 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.
  13. ^ 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. 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ http://www.ejbjs.org/cgi/content/abstract/58/8/1161
  17. ^ 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. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ Adams RJ (November 2007). "Big strokes in small persons". Arch. Neurol. 64 (11): 1567–74. doi:10.1001/archneur.64.11.1567. PMID 17998439. 
  21. ^ Martí-Carvajal A, Dunlop R, Agreda-Perez L (Oct 2004). Martí-Carvajal, Arturo J, ed. "Treatment for avascular necrosis of bone in people with sickle cell disease". Cochrane database of systematic reviews (Online) (4): CD004344. doi:10.1002/14651858.CD004344.pub2. PMID 15495103. 
  22. ^ 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. 
  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. 
  24. ^ 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. 
  25. ^ 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. 
  26. ^ 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. 
  27. ^ 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. 
  28. ^ 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. 
  29. ^ 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. 
  30. ^ 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. 
  31. ^ 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. 
  32. ^ 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. 
  33. ^ 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. 
  34. ^ 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. 
  35. ^ "How Does Sickle Cell Cause Disease?". Retrieved 2010-11-27. 
  36. ^ "Sickle Cell Anemia: eMedicine Emergency Medicine". Retrieved 2010-11-27. 
  37. ^ 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. 
  38. ^ "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. 
  39. ^ Lee, C., Davies, S.,& Dezatoux, C. (2000). Neonatal Screening for sickle cell disease. The Cochrane Collaboration. John Wiley & Sons, Ltd.
  40. ^ Oniyangi O, Omari AA (2006). Oniyangi, Oluseyi, ed. "Malaria chemoprophylaxis in sickle cell disease". Cochrane Database of Systematic Reviews 13 (4): CD003489. doi:10.1002/14651858.CD003489.pub2. PMID 17054173. 
  41. ^ 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. 
  42. ^ 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. 
  43. ^ 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. 
  44. ^ 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. 
  45. ^ 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. 
  46. ^ 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. 
  47. ^ 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. 
  48. ^ 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. 
  49. ^ 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.
  50. ^ 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. 
  51. ^ 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. 
  52. ^ 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. 
  53. ^ 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. 
  54. ^ 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. 
  55. ^ WHO. "Sickle-cell anaemia - Report by the Secretariat" (PDF). Retrieved 2010-11-27. 
  56. ^ Aidoo, Michael, Dianne J Terlouw, Margarette S Kolczak, Peter D McElroy, Feiko O ter Kuile, Simon Kariuki, Bernard L Nahlen, Altaf A Lal, and Venkatachalam Udhayakumar. "Protective Effects of the Sickle-cell Gene Against Malaria Morbidity and Mortality." The Lancet. 359.9314 (2002): 1311-1312.
  57. ^ National Heart, Lung and Blood Institute. "Sickle cell anemia, key points". Retrieved 2010-11-27. 
  58. ^ "September is Sickle Cell Awareness Month". CDC. Retrieved 6 February 2011. 
  59. ^ "Sickle Cell Disease: Data & Statistics". Centers for Disease Control and Prevention. 16 September 2011. Retrieved 8 November 2011. 
  60. ^ 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. 
  61. ^ 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. 
  62. ^ "Sickle Cell Disease and Your Baby". March of Dimes®. February 2008. Retrieved 11 November 2014. 
  63. ^ Cinnchinsky EP, Mahoney DH, Landlaw SA (29 November 2011). "Uptodate: Sickle Cell Trait". Retrieved 8 November 2011. 
  64. ^ Bardakdjian J, Wajcman H (September 2004). "[Epidemiology of sickle cell anemia]". Rev Prat (in French) 54 (14): 1531–3. PMID 15558961. 
  65. ^ 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. 
  66. ^ 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
  67. ^ http://www.nhs.uk/conditions/sickle-cell-anaemia/Pages/Introduction.aspx
  68. ^ 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. 
  69. ^ 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. 
  70. ^ 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. 
  71. ^ 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. PMC 3200316. PMID 22039456. 
  72. ^ Lebby R (1846). "Case of absence of the spleen". Southern J of Med Pharmacol 1: 481–3. 
  73. ^ a b c Ballas, SK; Gupta, K; Adams-Graves, P (Nov 1, 2012). "Sickle cell pain: a critical reappraisal.". Blood 120 (18): 3647–56. doi:10.1182/blood-2012-04-383430. PMID 22923496. 
  74. ^ 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. 
  75. ^ a b 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. 
  76. ^ a b c d e f g Serjeant, GR (Dec 2010). "One hundred years of sickle cell disease.". British journal of haematology 151 (5): 425–9. doi:10.1111/j.1365-2141.2010.08419.x. PMID 20955412. 
  77. ^ Mason VR (1922). "Sickle cell anemia". JAMA 79 (14): 1318–1320. doi:10.1001/jama.254.14.1955. PMID 3900438. 
  78. ^ Pauling L, Itano HA, Singer SJ, Wells IC (1949). "Sickle cell anemia, a molecular disease". Science 110 (2865): 543–548. doi:10.1126/science.110.2865.543. PMID 15395398. 
  79. ^ Pawliuk, R.; et al (2001). "Correction of Sickle Cell Disease in Transgenic Mouse Models by Gene Therapy". Science 294 (5550): 2368. doi:10.1126/science.1065806.  edit
  80. ^ Wilson, Jennifer Fisher (18 March 2002). "Murine Gene Therapy Corrects Symptoms of Sickle Cell Disease". The Scientist – Magazine of the Life Sciences. Retrieved 17 December 2014. 
  81. ^ St. Jude Children's Research Hospital (4 December 2008). "Gene Therapy Corrects Sickle Cell Disease In Laboratory Study". ScienceDaily. Retrieved 17 December 2014. 
  82. ^ (15 December 2014) Stem Cell Gene Therapy for Sickle Cell Disease, ClinicalTrials.gov Identifier: NCT02247843 ClinicalTrials.gov, U.S. National Institutes of Health, Retrieved 17 December 2014
  83. ^ (15 December 2014) Collection and Storage of Umbilical Cord Stem Cells for Treatment of Sickle Cell Disease; ClinicalTrials.gov Identifier: NCT00012545 ClinicalTrials.gov, U.S. National Institutes of Health, Retrieved 17 December 2014
  84. ^ Olowoyeye, A (October 2015). "Gene therapy for sickle cell disease". Cochrane Database of Systematic Reviews 11 (10): CD007652. doi:10.1002/14651858.CD007652.pub3. PMID 23152248. Retrieved 27 October 2014. 

Further reading[edit]

External links[edit]