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Methodist Comprehensive Sickle Cell Center Opens

Published On 09/28/2012
Methodist Comprehensive Sickle Cell CenterOn September 5, a dedication and consecration service was held for the opening of the long awaited Methodist Healthcare Comprehensive Sickle Cell Center. Public funding for the Center was launched in 2010 with a $250,000 gift from local mortgage banker Jim McGehee.  In April 2011 the Methodist Healthcare Foundation received a $1 million challenge grant from the Plough Foundation to establish an endowed chair in hematology.  That challenge grant was recently met by the Foundation and a total of $3 million has been raised to date.
The goal of the Sickle Cell Center is to enhance quality of life and reduce admission rates for sickle cell patients. Sickle cell disease, a genetic disorder that leads to the formation of irregularly-shaped red blood cells, affects about 1 in every 350 African-Americans. Right here in Memphis, we have one of the largest populations of sickle cell disease patients in the country.
The Center is located on the Methodist University Hospital campus and will operate as an outpatient clinic to provide preventative health maintenance specific to sickle cell disease in a primary care setting. It will also offer a specially designed 9-chair infusion unit for sickle cell pain crisis management.  The clinic is the only one of its type within a 300-mile radius and one of only a small handful of centers like this in the United States.
The Sickle Cell Center will provide comprehensive preventative outpatient disease management weekdays from 8 am- 5 pm for adults and will partner with existing resources such as the Sickle Cell Foundation of Tennessee. The Center will also partner with St. Jude Children’s Research Hospital to provide care to teens transitioning from pediatric care.
Daily life for sickle cell patients is often interrupted by unpredictable bouts of pain that last a few hours to many weeks — threatening their family life, career, education and social life. The Methodist Healthcare Sickle Cell Center is committed to helping to enhance the quality of life for these patients by providing continuity of care that wasn’t available before. To find out more about the Center and how you can help, visit www.methodisthealth.org/sicklecell or call 901-516-0508.
Photo:(l-r) Kevin M. Spiegel, FACHE, CEO of Methodist University Hospital; Gary Shorb, president and CEO, Methodist Le Bonheur Healthcare; Mark Yancy, manager of Operations, Comprehensive Sickle Cell Center of Memphis and Luke Yancy, MLH Board Chair and president Mid-South Minority Business Council Continuum, at the opening of the Methodist Healthcare Comprehensive Sickle Cell Center

Sickle-cell disease

From Wikipedia, the free encyclopedia
 
Jump to: navigation, search
Sickle-cell disease
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.
Classification and external resources
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), also known as sickle-cell anaemia (SCA) and 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. Such people are also referred to as carriers.
The complications of sickle-cell disease can be prevented to a large extent with vaccination, preventive 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 parts of the world such as the West Indies and in people of African origin elsewhere in the world. In 2013 it resulted in 176,000 deaths up from 113,000 deaths in 1990.[1] 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.[2]

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.[3] "Although infection, dehydration, and acidosis (all of which favor sickling) can act as triggers, in most instances, no predisposing cause is identified."[4]

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[5] 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.[6]

Splenic sequestration crisis[edit]

Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected.[7] It is usually infarcted before the end of childhood in individuals suffering from sickle-cell anemia. This spleen damage increases the risk of infection from encapsulated organisms;[8][9] preventive antibiotics and vaccinations are recommended for those lacking proper spleen function.
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.[10]

Acute chest syndrome[edit]

Acute chest syndrome (ACS) is defined by at least two of the following signs or symptoms: chest pain, fever, pulmonary infiltrate or focal abnormality, respiratory symptoms, or hypoxemia.[11] 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.[12][13] 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 pale appearance, fast heart rate, and fatigue. This crisis is normally triggered by parvovirus B19, which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them.[14] Parvovirus infection almost 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.[15]

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.[16] Management is supportive, sometimes with blood transfusions.[6]

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.[17] The crisis can last up to a month.[18] 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.[19] It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery.

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% do not carry any sickle-cell alleles, and 50% 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.[20]
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. Note, historic numbering put this glutamic acid residue at position 6 due to skipping the methionine start codon in protein amino acid position numbering. Current nomenclature calls for counting the methionine as the first amino acid, resulting in the glutamic acid residue falling at position 7. Many references still refer to position 6 and both should likely be referenced for clarity. 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 GAG to GTG 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 side chain of the valine residue at position 6 of the beta chain in haemoglobin is 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.[21]
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.[22] Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases.[23]
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 tends to decline in the affected population by natural selection, and now artificially through prenatal genetic screening. However, the African American community descends from a significant admixture of 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 that limits 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.[24]
 
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.[25] Healthy red blood cells typically function for 90–120 days, but sickled cells only last 10–20 days.[26]

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.[27]
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.[28]
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.[29]

Management[edit]

Folic acid and penicillin[edit]

Children born with sickle-cell disease undergo close observation by the pediatrician and require management by a haematologist to assure they remain healthy. These patients take a 1 mg dose of folic acid daily for life. From birth to five years of age, they 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.[30]

Vaso-occlusive crisis[edit]

Most people with sickle-cell disease have intensely painful episodes called vaso-occlusive crises. However, the frequency, severity, and duration of these crises vary tremendously. Painful crises are treated symptomatically with pain medications; 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 doctors frequently prescribe to help control 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),[31] 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 patient with suspected acute chest syndrome should be admitted to the hospital with worsening A-a gradient an indication for ICU admission [11]

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.)[32] and shown to possibly increase survival time in a study in 2003 (Steinberg et al.).[33] 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.[2][34]

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.[35] 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.[36][37]

Bone marrow transplants[edit]

Bone marrow transplants have proven effective in children. Bone marrow transplants are the only known cure for SCD.[38] 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.[39] 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.[40]

Complications[edit]Methodist Comprehensive Sickle Cell Center Opens

Published On 09/28/2012
Methodist Comprehensive Sickle Cell CenterOn September 5, a dedication and consecration service was held for the opening of the long awaited Methodist Healthcare Comprehensive Sickle Cell Center. Public funding for the Center was launched in 2010 with a $250,000 gift from local mortgage banker Jim McGehee.  In April 2011 the Methodist Healthcare Foundation received a $1 million challenge grant from the Plough Foundation to establish an endowed chair in hematology.  That challenge grant was recently met by the Foundation and a total of $3 million has been raised to date.
The goal of the Sickle Cell Center is to enhance quality of life and reduce admission rates for sickle cell patients. Sickle cell disease, a genetic disorder that leads to the formation of irregularly-shaped red blood cells, affects about 1 in every 350 African-Americans. Right here in Memphis, we have one of the largest populations of sickle cell disease patients in the country.
The Center is located on the Methodist University Hospital campus and will operate as an outpatient clinic to provide preventative health maintenance specific to sickle cell disease in a primary care setting. It will also offer a specially designed 9-chair infusion unit for sickle cell pain crisis management.  The clinic is the only one of its type within a 300-mile radius and one of only a small handful of centers like this in the United States.
The Sickle Cell Center will provide comprehensive preventative outpatient disease management weekdays from 8 am- 5 pm for adults and will partner with existing resources such as the Sickle Cell Foundation of Tennessee. The Center will also partner with St. Jude Children’s Research Hospital to provide care to teens transitioning from pediatric care.
Daily life for sickle cell patients is often interrupted by unpredictable bouts of pain that last a few hours to many weeks — threatening their family life, career, education and social life. The Methodist Healthcare Sickle Cell Center is committed to helping to enhance the quality of life for these patients by providing continuity of care that wasn’t available before. To find out more about the Center and how you can help, visit www.methodisthealth.org/sicklecell or call 901-516-0508.
Photo:(l-r) Kevin M. Spiegel, FACHE, CEO of Methodist University Hospital; Gary Shorb, president and CEO, Methodist Le Bonheur Healthcare; Mark Yancy, manager of Operations, Comprehensive Sickle Cell Center of Memphis and Luke Yancy, MLH Board Chair and president Mid-South Minority Business Council Continuum, at the opening of the Methodist Healthcare Comprehensive Sickle Cell Center

Sickle-cell disease

From Wikipedia, the free encyclopedia
 
Jump to: navigation, search
Sickle-cell disease
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.
Classification and external resources
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), also known as sickle-cell anaemia (SCA) and 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. Such people are also referred to as carriers.
The complications of sickle-cell disease can be prevented to a large extent with vaccination, preventive 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 parts of the world such as the West Indies and in people of African origin elsewhere in the world. In 2013 it resulted in 176,000 deaths up from 113,000 deaths in 1990.[1] 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.[2]

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.[3] "Although infection, dehydration, and acidosis (all of which favor sickling) can act as triggers, in most instances, no predisposing cause is identified."[4]

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[5] 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.[6]

Splenic sequestration crisis[edit]

Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected.[7] It is usually infarcted before the end of childhood in individuals suffering from sickle-cell anemia. This spleen damage increases the risk of infection from encapsulated organisms;[8][9] preventive antibiotics and vaccinations are recommended for those lacking proper spleen function.
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.[10]

Acute chest syndrome[edit]

Acute chest syndrome (ACS) is defined by at least two of the following signs or symptoms: chest pain, fever, pulmonary infiltrate or focal abnormality, respiratory symptoms, or hypoxemia.[11] 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.[12][13] 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 pale appearance, fast heart rate, and fatigue. This crisis is normally triggered by parvovirus B19, which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them.[14] Parvovirus infection almost 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.[15]

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.[16] Management is supportive, sometimes with blood transfusions.[6]

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.[17] The crisis can last up to a month.[18] 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.[19] It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery.

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% do not carry any sickle-cell alleles, and 50% 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.[20]
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. Note, historic numbering put this glutamic acid residue at position 6 due to skipping the methionine start codon in protein amino acid position numbering. Current nomenclature calls for counting the methionine as the first amino acid, resulting in the glutamic acid residue falling at position 7. Many references still refer to position 6 and both should likely be referenced for clarity. 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 GAG to GTG 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 side chain of the valine residue at position 6 of the beta chain in haemoglobin is 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.[21]
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.[22] Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases.[23]
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 tends to decline in the affected population by natural selection, and now artificially through prenatal genetic screening. However, the African American community descends from a significant admixture of 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 that limits 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.[24]
 
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.[25] Healthy red blood cells typically function for 90–120 days, but sickled cells only last 10–20 days.[26]

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.[27]
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.[28]
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.[29]

Management[edit]

Folic acid and penicillin[edit]

Children born with sickle-cell disease undergo close observation by the pediatrician and require management by a haematologist to assure they remain healthy. These patients take a 1 mg dose of folic acid daily for life. From birth to five years of age, they 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.[30]

Vaso-occlusive crisis[edit]

Most people with sickle-cell disease have intensely painful episodes called vaso-occlusive crises. However, the frequency, severity, and duration of these crises vary tremendously. Painful crises are treated symptomatically with pain medications; 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 doctors frequently prescribe to help control 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),[31] 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 patient with suspected acute chest syndrome should be admitted to the hospital with worsening A-a gradient an indication for ICU admission [11]

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.)[32] and shown to possibly increase survival time in a study in 2003 (Steinberg et al.).[33] 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.[2][34]

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.[35] 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.[36][37]

Bone marrow transplants[edit]

Bone marrow transplants have proven effective in children. Bone marrow transplants are the only known cure for SCD.[38] 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.[39] 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.[40]

Complications[edit]