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Sickle-cell disease

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 circum-
stances. Sickle-cell disease is associated with a number
of acute and chronic health problems, such as severe in-
fections, 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 ab-
normal 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 sin-
gle abnormal copy does not experience symptoms and is Sickle-cells in human blood: both normal red blood cells and
sickle-shaped cells are present.
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, pre-
ventive antibiotics, blood transfusion, and the drug
hydroxyurea/hydroxycarbamide. A small proportion of
patients require 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 contri-
butions by Nobel prize-winner Linus Pauling made it the
first disease where the exact genetic and molecular defect
was elucidated.

1 Signs and symptoms


Sickle-cell disease may lead to various acute and chronic
complications, several of which have a high mortality Normal blood cells next to a sickle-blood cell, colored scanning
rate.[2] electron microscope image

1.1 Sickle-cell crisis


The terms “sickle-cell crisis” or “sickling crisis” may be haemolytic crisis, and others. Most episodes of sickle-
used to describe several independent acute conditions cell crises last between five and seven days.[3] “Although
occurring in patients with SCD. SCD results in anemia infection, dehydration, and acidosis (all of which favor
and crises that could be of many types including the sickling) can act as triggers, in most instances, no predis-
vaso-occlusive crisis, aplastic crisis, sequestration crisis, posing cause is identified.”[4]

1
2 2 GENETICS

1.2 Vaso-occlusive crisis 1.4 Aplastic crisis

The vaso-occlusive crisis is caused by sickle-shaped red Aplastic crises are acute worsenings of the patient’s
blood cells that obstruct capillaries and restrict blood flow baseline anaemia, producing pale appearance, fast heart
to an organ resulting in ischaemia, pain, necrosis, and rate, and fatigue. This crisis is normally triggered by
often organ damage. The frequency, severity, and du- parvovirus B19, which directly affects production of red
ration of these crises vary considerably. Painful crises blood cells by invading the red cell precursors and mul-
are treated with hydration, analgesics, and blood transfu- tiplying in and destroying them.[14] Parvovirus infection
sion; pain management requires opioid administration at almost completely prevents red blood cell production for
regular intervals until the crisis has settled. For milder two to three days. In normal individuals, this is of lit-
crises, a subgroup of patients manage on NSAIDs (such tle consequence, but the shortened red cell life of SCD
as diclofenac or naproxen). For more severe crises, patients results in an abrupt, life-threatening situation.
most patients require inpatient management for intra- Reticulocyte counts drop dramatically during the disease
venous opioids; patient-controlled analgesia devices are (causing reticulocytopenia), and the rapid turnover of red
commonly used in this setting. Vaso-occlusive crisis cells leads to the drop in haemoglobin. This crisis takes
involving organs such as the penis[5] or lungs are con- 4 days to one week to disappear. Most patients can be
sidered an emergency and treated with red-blood cell managed supportively; some need blood transfusion.[15]
transfusions. Incentive spirometry, a technique to en-
courage deep breathing to minimise the development of
1.5 Haemolytic crisis
atelectasis, is recommended.[6]
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
1.2.1 Splenic sequestration crisis with coexistent G6PD deficiency.[16] Management is
supportive, sometimes with blood transfusions.[6]
Because of its narrow vessels and function in clearing de-
fective red blood cells, the spleen is frequently affected.[7]
1.6 Other
It is usually infarcted before the end of childhood in in-
dividuals suffering from sickle-cell anemia. This spleen
One of the earliest clinical manifestations is dactylitis,
damage increases the risk of infection from encapsulated
presenting as early as six months of age, and may occur in
organisms;[8][9] preventive antibiotics and vaccinations
children with sickle-cell trait.[17] The crisis can last up to a
are recommended for those lacking proper spleen func-
month.[18] Another recognised type of sickle crisis, acute
tion.
chest syndrome, is characterised by fever, chest pain, dif-
Splenic sequestration crises are acute, painful enlarge- ficulty breathing, and pulmonary infiltrate on a chest X-
ments of the spleen, caused by intrasplenic trapping of ray. Given that pneumonia and sickling in the lung can
red cells and resulting in a precipitous fall in hemoglobin both produce these symptoms, the patient is treated for
levels with the potential for hypovolemic shock. Seques- both conditions.[19] It can be triggered by painful crisis,
tration crises are considered an emergency. If not treated, respiratory infection, bone-marrow embolisation, or pos-
patients may die within 1–2 hours due to circulatory fail- sibly by atelectasis, opiate administration, or surgery.
ure. Management is supportive, sometimes with blood
transfusion. These crises are transient, they continue for
3–4 hours and may last for one day.[10] 2 Genetics
Normally, humans have haemoglobin A, which consists
of two alpha and two beta chains, haemoglobin A2,
1.3 Acute chest syndrome which consists of two alpha and two delta chains, and
haemoglobin F, consisting of two alpha and two gamma
Acute chest syndrome (ACS) is defined by at least two of chains in their bodies. Of these, haemoglobin F dom-
the following signs or symptoms: chest pain, fever, pul- inates until about 6 weeks of age then A dominates
monary infiltrate or focal abnormality, respiratory symp- throughout life.
toms, or hypoxemia.[11] It is the second-most common Sickle-cell conditions have an autosomal recessive pat-
complication and it accounts for about 25% of deaths in tern of inheritance from parents. The types of
patients with SCD, majority of cases present with vaso- haemoglobin a person makes in the red blood cells de-
occlusive crises then they develop ACS.[12][13] Neverthe- pend on what haemoglobin genes are inherited from her
less, about 80% of patients have vaso-occlusive crises or his parents. If one parent has sickle-cell anaemia and
during ACS. the other has sickle-cell trait, then the child has a 50%
3

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 suscep-
tible to breaking within capillaries. Carriers have symp-
toms 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
Distribution of the sickle-cell trait shown in pink and purple 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, his-
toric 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 nor-
mal adult HbA. The genetic disorder is due to the muta-
tion of a single nucleotide, from a GAG to GTG codon
Historical distribution of malaria (no longer endemic in Europe)
shown in green
on the coding strand, which is transcribed from the tem-
plate 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 con-
ditions of normal oxygen concentration. What it does al-
low 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 pro-
tein 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
Modern distribution of malaria
form fibrous precipitates.
The allele responsible for sickle-cell anaemia can be
chance of having sickle-cell disease and a 50% chance of found on the short arm of chromosome 11, more specif-
having sickle-cell trait. When both parents have sickle- ically 11p15. A person who receives the defective gene
cell trait, a child has a 25% chance of sickle-cell disease,
from both father and mother develops the disease; a per-
25% do not carry any sickle-cell alleles, and 50% have son who receives one defective and one healthy allele re-
the heterozygous condition. mains healthy, but can pass on the disease and is known
Sickle-cell gene mutation probably arose spontaneously as a carrier or heterozygote. Heterozygotes are still able
in different geographic areas, as suggested by restric- to contract
[21]
malaria, but their symptoms are generally less
tion endonuclease analysis. These variants are known severe.
as Cameroon, Senegal, Benin, Bantu, and Saudi-Asian. Due to the adaptive advantage of the heterozygote,
Their clinical importance is because some are associated the disease is still prevalent, especially among people
with higher HbF levels, e.g., Senegal and Saudi-Asian with recent ancestry in malaria-stricken areas, such as
variants, and tend to have milder disease.[20] Africa, the Mediterranean, India, and the Middle East.[22]
In people heterozygous for HgbS (carriers of sickling Malaria was historically endemic to southern Europe, but
haemoglobin), the polymerisation problems are minor, it was declared eradicated in the mid-20th [23]
century, with
because the normal allele is able to produce over 50% the exception of rare sporadic cases.
4 4 DIAGNOSIS

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 de-
fective 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 actu-
ally 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 dis-
advantageous, and tends to decline in the affected pop-
ulation by natural selection, and now artificially through
prenatal genetic screening. However, the African Amer-
ican 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 pres- Scanning electron micrograph showing a mixture of red blood
sure through slavery may be the most plausible explana- cells, some with round normal morphology, some with mild sick-
tions for the lower prevalence of sickle-cell anaemia (and, ling showing elongation and bending
possibly, other genetic diseases) among African Ameri-
cans compared to sub-Saharan Africans. Another factor
that limits the spread of sickle-cell genes in North Amer-
3 Pathophysiology
ica is the absence of cultural proclivities to polygamy,
which allows affected males to continue to seek unaf- The loss of red blood cell elasticity is central to the patho-
fected children with multiple partners.[24] physiology 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 de-
crease the cell’s elasticity. These cells fail to return to nor-
mal shape when normal oxygen tension is restored. As a
Unaffected Unaffected consequence, these rigid blood cells are unable to deform
"Carrier" "Carrier"
Father Mother as they pass through narrow capillaries, leading to vessel
occlusion and ischaemia.
The actual anaemia of the illness is caused by haemolysis,
R r R r 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
R R R r R r r r destruction.[25] Healthy red blood cells typically function
for 90–120 days, but sickled cells only last 10–20 days.[26]

4 Diagnosis
In HbSS, the complete blood count reveals haemoglobin
levels in the range of 6–8 g/dl with a high reticulocyte
Unaffected Unaffected "Carrier" Affected
1 in 4 chance 2 in 4 chance 1 in 4 chance count (as the bone marrow compensates for the destruc-
tion of sickled cells by producing more red blood cells).
In other forms of sickle-cell disease, Hb levels tend to be
Sickle-cell disease is inherited in the autosomal recessive pattern. 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 in-
5.3 Vaso-occlusive crisis 5

duced by the addition of sodium metabisulfite. The pres- 5.3 Vaso-occlusive crisis
ence of sickle haemoglobin can also be demonstrated with
the “sickle solubility test”. A mixture of haemoglobin S Most people with sickle-cell disease have intensely
(Hb S) in a reducing solution (such as sodium dithion- painful episodes called vaso-occlusive crises. However,
ite) gives a turbid appearance, whereas normal Hb gives the frequency, severity, and duration of these crises vary
a clear solution. tremendously. Painful crises are treated symptomatically
with pain medications; pain management requires opioid
Abnormal haemoglobin forms can be detected on
administration at regular intervals until the crisis has set-
haemoglobin electrophoresis, a form of gel electrophore-
tled. For milder crises, a subgroup of patients man-
sis on which the various types of haemoglobin move
age on NSAIDs (such as diclofenac or naproxen). For
at varying speeds. Sickle-cell haemoglobin (HgbS) and
more severe crises, most patients require inpatient man-
haemoglobin C with sickling (HgbSC)—the two most
agement for intravenous opioids; patient-controlled anal-
common forms—can be identified from there. The di-
gesia (PCA) devices are commonly used in this setting.
agnosis can be confirmed with high-performance liquid
Diphenhydramine is also an effective agent that doctors
chromatography. Genetic testing is rarely performed,
frequently prescribe to help control itching associated
as other investigations are highly specific for HbS and
with the use of opioids.
HbC.[27]
An acute sickle-cell crisis is often precipitated by infec-
tion. Therefore, a urinalysis to detect an occult urinary 5.4 Acute chest crisis
tract infection, and chest X-ray to look for occult pneu-
monia, should be routinely performed.[28] Management is similar to vaso-occlusive crisis, with the
People who are known carriers of the disease often un- addition of antibiotics (usually a quinolone or macrolide,
dergo genetic counseling before they have a child. A test since cell wall-deficient ["atypical"] [31]
bacteria are thought
to see if an unborn child has the disease takes either a to contribute to the syndrome), oxygen supplementa-
blood sample from the fetus or a sample of amniotic fluid. tion for hypoxia, and close observation. Should the pul-
Since taking a blood sample from a fetus has greater risks, monary infiltrate worsen or the oxygen requirements in-
the latter test is usually used. Neonatal screening provides crease, simple blood transfusion or exchange transfusion
not only a method of early detection for individuals with is indicated. The latter involves the exchange of a sig-
sickle-cell disease, but also allows for identification of the nificant portion of the patients red cell mass for normal
groups of people that carry the sickle cell trait.[29] 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]

5 Management
5.5 Hydroxyurea
5.1 Folic acid and penicillin
The first approved drug for the causative treatment of
Children born with sickle-cell disease undergo close ob- sickle-cell anaemia, hydroxyurea, was shown to decrease
servation by the pediatrician and require management by the number and severity of attacks in a study in 1995
a haematologist to assure they remain healthy. These pa- (Charache et al.)[32] and shown to possibly increase sur-
tients take a 1 mg dose of folic acid daily for life. From vival time in a study in 2003 (Steinberg et al.).[33] This is
birth to five years of age, they also have to take penicillin achieved, in part, by reactivating fetal haemoglobin pro-
daily due to the immature immune system that makes duction in place of the haemoglobin S that causes sickle-
them more prone to early childhood illnesses. 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 ben-
efits outweigh the risks.[2][34]
5.2 Malaria chemoprophylaxis

The protective effect of sickle-cell trait does not ap- 5.6 Transfusion therapy
ply to people with sickle cell disease; in fact, they are
more vulnerable to malaria, since the most common cause Blood transfusions are often used in the management of
of painful crises in malarial countries is infection with sickle-cell disease in acute cases and to prevent complica-
malaria. It has therefore been recommended that people tions by decreasing the number of red blood cells (RBC)
with sickle-cell disease living in malarial countries should that can sickle by adding normal red blood cells.[35]
receive anti-malarial chemoprophylaxis for life.[30] In children prophylactic chronic red blood cell (RBC)
6 6 PROGNOSIS

transfusion therapy has been shown to be efficacious to a • Cholelithiasis (gallstones) and cholecystitis may re-
certain extent in reducing the risk of first stroke or silent sult from excessive bilirubin production and precip-
stroke when transcranial Doppler (TCD) ultrasonography itation due to prolonged haemolysis.
shows abnormal increased cerebral blood flow velocities.
In those who have sustained a prior stroke event it also • Avascular necrosis (aseptic bone necrosis) of the
reduces the risk of recurrent stroke and additional silent hip and other major joints may occur as a result of
strokes.[36][37] ischaemia.[44]

• Decreased immune reactions due to hyposplenism


5.7 Bone marrow transplants (malfunctioning of the spleen)[45]

Bone marrow transplants have proven effective in chil- • Priapism and infarction of the penis[46]
dren. Bone marrow transplants are the only known cure
for SCD.[38] However, bone marrow transplants are diffi- • Osteomyelitis (bacterial bone infection), the
cult to obtain because of the specific HLA typing neces- most common cause of osteomyelitis in SCD
sary. Ideally, a twin family member (syngeneic) or close is Salmonella (especially the atypical serotypes
relative (allogeneic) would donate the bone marrow nec- Salmonella typhimurium, Salmonella enteritidis,
essary for transplantation. Salmonella choleraesuis and Salmonella paraty-
phi B), followed by Staphylococcus aureus and
Gram-negative enteric bacilli perhaps because
intravascular sickling of the bowel leads to patchy
6 Prognosis ischaemic infarction.[47]

About 90% of patients survive to age 20, and close to 50% • Opioid tolerance can occur as a normal, physiologic
survive beyond the fifth decade.[39] In 2001, according response to the therapeutic use of opiates. Addic-
to one study performed in Jamaica, the estimated mean tion to opiates occurs no more commonly among in-
survival for sickle-cell patients was 53 years old for men dividuals with sickle-cell disease than among other
and 58 years old for women with homozygous SCD.[40] individuals treated with opiates for other reasons.

• Acute papillary necrosis in the kidneys


6.1 Complications
• Leg ulcers[48]
Sickle-cell anaemia can lead to various complications, in-
• In eyes, background retinopathy, proliferative
cluding:
retinopathy, vitreous haemorrhages, and retinal de-
tachments can result in blindness.[49] Regular annual
• Increased risk of severe bacterial infections due eye checks are recommended.
to loss of functioning spleen tissue (and compa-
rable to the risk of infections after having the • During pregnancy, intrauterine growth retardation,
spleen removed surgically). These infections are spontaneous abortion, and pre-eclampsia
typically caused by encapsulated organisms such
as Streptococcus pneumoniae and Haemophilus in- • Chronic pain: Even in the absence of acute vaso-
fluenzae. Daily penicillin prophylaxis is the most occlusive pain, many patients have unreported
commonly used treatment during childhood, with chronic pain.[50]
some haematologists continuing treatment indefi-
nitely. Patients benefit today from routine vaccina- • Pulmonary hypertension (increased pressure on the
tion for S. pneumoniae.[41] pulmonary artery) can lead to strain on the right ven-
tricle and a risk of heart failure; typical symptoms
• Stroke, which can result from a progressive narrow- are shortness of breath, decreased exercise toler-
ing of blood vessels, prevents oxygen from reaching ance, and episodes of syncope. 21% of children and
the brain. Cerebral infarction occurs in children and 30% of adults have evidence of pulmonary hyper-
cerebral haemorrhage in adults. tension when tested; this is associated with reduced
walking distance and increased mortality.[51]
• Silent stroke causes no immediate symptoms, but is
associated with damage to the brain. Silent stroke • Chronic kidney failure due to sickle-cell nephropa-
is probably five times as common as symptomatic thy manifests itself with hypertension, protein loss in
stroke. About 10–15% of children with SCD suf- the urine, loss of red blood cells in urine and wors-
fer strokes, with silent strokes predominating in the ened anaemia. If it progresses to end-stage renal
younger patients.[42][43] failure, it carries a poor prognosis.[52]
7.3 France 7

7 Epidemiology 7.3 France

The highest frequency of sickle cell disease is found in As a result of population growth in African-Caribbean
tropical regions, particularly sub-Saharan Africa, tribal regions of overseas France and immigration from North
regions of India and the Middle-East.[53] Migration of and sub-Saharan Africa to mainland France, sickle-cell
substantial populations from these high prevalence areas disease has become a major health problem in France.[65]
to low prevalence countries in Europe has dramatically SCD has become the most common genetic disease in the
increased in recent decades and in some European coun- country, with an overall birth prevalence of 1/2,415 in
tries sickle-cell disease has now overtaken more familiar mainland France, ahead of phenylketonuria (1/10,862),
genetic conditions such as haemophilia and cystic fibro- congenital hypothyroidism (1/3,132), congenital adrenal
sis.[54] In 2013 it resulted in 176,000 deaths due to SCD hyperplasia (1/19,008) and cystic fibrosis (1/5,014) for
up from 113,000 deaths in 1990.[1] the same reference period. In 2010, 31.5% of all new-
borns in mainland France (253,466 out of 805,958) were
Sickle-cell disease occurs more commonly among peo- screened for SCD (this percentage was 19% in 2000).
ple whose ancestors lived in tropical and sub-tropical sub- 341 newborns with SCD and 8,744 heterozygous car-
Saharan regions where malaria is or was common. Where riers were found representing 1.1% of all newborns in
malaria is common, carrying a single sickle-cell allele mainland France. The Paris metropolitan district (Île-de-
(trait) confers a selective advantage—in other words, be- France) is the region that accounts for the largest num-
ing a heterozygote is advantageous. Specifically, humans ber of newborns screened for SCD (60% in 2010). The
with one of the two alleles of sickle-cell disease show less second largest number of at-risk is in Provence-Alpes-
severe symptoms when infected with malaria.[55] Côte d'Azur at nearly 43.2% and the lowest number is in
Brittany at 5.5%.[66][67]

7.1 Africa

Three quarters of sickle-cell cases occur in Africa. A 7.4 United Kingdom


recent WHO report estimated that around 2% of new-
borns in Nigeria were affected by sickle cell anaemia, In the United Kingdom (UK) it is thought that between
giving a total of 150,000 affected children born every 12,000 to 15,000 people have sickle cell disease [68] with
year in Nigeria alone. The carrier frequency ranges be- an estimate of 250,000 carriers of the condition in Eng-
tween 10% and 40% across equatorial Africa, decreasing land alone. As the number of carriers is only estimated,
to 1–2% on the north African coast and <1% in South all newborn babies in the UK receive a routine blood test
Africa.[56] There have been studies in Africa that show to screen for the condition.[69] Due to many adults in high
a significant decrease in infant mortality rate, ages 2–16 risk groups not knowing if they are carriers, pregnant
months, because of the sickle-cell trait. This happened in women and both partners in a couple are offered screen-
predominant areas of malarial cases.[57] ing so they can get counselling if they have the sickle
cell trait.[70] In addition blood donors from those in high
risk groups are also screened to confirm whether they
are carriers and whether their blood filters properly.[71]
7.2 United States Donors who are found to be carriers are then informed
and their blood, while often used for those of the same
The prevalence of the disease in the United States is ap- ethnic group, is not used for those with sickle cell disease
proximately 1 in 5,000, mostly affecting Americans of who require a blood transfusion.[72]
Sub-Saharan African descent, according to the National
Institutes of Health.[58] In the United States, about one
out of 500 African-American children and one in ev-
ery 36,000 Hispanic-American children have sickle-
cell anaemia.[59] It is estimated that sickle-cell disease 7.5 Middle East
affects 90,000 Americans.[60] Most infants with SCD
born in the United States are now identified by rou- In Saudi Arabia about 4.2% of the population carry the
tine neonatal screening. Forty-four states along with the sickle-cell trait and 0.26% have sickle-cell disease. The
District of Columbia, Puerto Rico and the Virgin Is- highest prevalence is in the Eastern province where ap-
lands currently provide universal neonatal screening for proximately 17% of the population carry the gene and
SCD.[61][62] Sickle cell trait occurs among about 1:12 1.2% have sickle-cell disease.[73] In 2005 in Saudi Arabia
African-Americans and 1:100 Hispanic-Americans.[63] It a mandatory pre-marital test including HB electrophore-
is estimated that 2.5 million Americans are heterozygous sis was launched and aimed to decrease the incidence of
carriers for the sickle-cell trait.[64] SCD and thalassemia.[74]
8 9 RESEARCH

7.6 India and Nepal were elucidated by James V. Neel and E.A. Beet.[82] 1949
was the year when Linus Pauling described the unusual
Sickle-cell disease is common in the tribal people of cen- chemical behaviour of haemoglobin S, and attributed this
tral India who share a genetic linkage with the African to an abnormality in the molecule itself.[82][86] The ac-
race, where the prevalence has ranged from 9.4 to 22.2% tual molecular change in HbS was described in the late
in endemic areas of Madhya Pradesh, Rajasthan and 1950s BY Vernon Ingram.[82] The late 1940s and early
Chhattisgarh.[75] It is also endemic among Tharu people 1950s saw further understanding in the link between
of Nepal and India, however, they have a sevenfold lower malaria and sickle cell disease. In 1954, the introduction
incidence of malaria despite living in a malaria infested of haemoglobin electrophoresis allowed the discovery of
zone.[76] particular subtypes, such as HbSC disease.[82]
Large scale natural history studies and further interven-
7.7 Caribbean Islands tion studies were introduced in the 1970s and 1980s, lead-
ing to the more widespread use of prophylaxis against
In Jamaica, 10% of the population carries the sickle-cell pneumococcal infections amongst other interventions. In
gene, making it the most prevalent genetic disorder in the 1972, Bill Cosby's Emmy-winning TV movie, To All My
country.[77] Friends on Shore, depicted the story of the parents of
a child suffering from sickle-cell disease.[87] The 1990s
saw the development of hydroxycarbamide, and reports
of cure through bone marrow transplantation appeared in
8 History 2007.[82]

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 9 Research
of the spleen.[78][79] There were also reports amongst
African slaves in the United States exhibiting resistance See also: List of sickle-cell disease researchers
to malaria but being prone to leg ulcers.[79] The abnor-
mal 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 9.1 Umbilical cord blood transplant
cardiologist and professor of medicine James B. Her-
rick (1861–1954), in 1910. Irons saw “peculiar elon- In December 1998, researchers from Emory University
gated and sickle-shaped” cells in the blood of a man conducted an experimental bone marrow transplant pro-
named Walter Clement Noel, a 20-year-old first-year cedure on a group of 22 children under 16 years old.[88]
dental student from Grenada. Noel had been admit- One of those patients, 12-year-old Keone Penn, was ap-
ted to the Chicago Presbyterian Hospital in December parently the first person to be cured of sickle-cell dis-
1904 suffering from anaemia.[80][81] Noel was readmit- ease through this method.[89] The stem cells were sourced
ted several times over the next three years for “mus- from a donor unrelated to Penn. A 2007 Georgia Sen-
cular rheumatism” and “bilious attacks” but completed ate bill proposing the collection and donation of stem
his studies and returned to the capital of Grenada (St. cell material, the “Saving the Cure Act”, was nicknamed
George’s) to practice dentistry. He died of pneumonia in “Keone’s Law” in his honor. [90]
1916 and is buried in the Catholic cemetery at Sauteurs
By mid-2007 a similar set of clinical trials in Baltimore
in the north of Grenada.[81][82] Shortly after the report
had also cured several adults.[91]
by Herrick, another case appeared in the Virginia Med-
ical Semi-Monthly with the same title, “Peculiar Elon-
gated and Sickle-Shaped Red Blood Corpuscles in a Case 9.2 Gene therapy
of Severe Anemia.”[83] This article is based on a pa-
tient admitted to the University of Virginia Hospital on In 2001 it was reported that sickle-cell disease had been
November 15, 1910.[84] In the later description by Verne successfully treated in mice using gene therapy.[92][93]
Mason in 1922, the name “sickle cell anemia” is first The researchers used a viral vector to make the mice—
used.[82][85] Childhood problems related to sickle cells which have essentially the same defect that causes hu-
disease were not reported until the 1930s, despite the man sickle cell disease—express production of fetal
fact that this cannot have been uncommon in African- hemoglobin (HbF), which an individual normally ceases
American populations.[79] to produce shortly after birth. In humans, using hydrox-
The Memphis physician Lemuel Diggs, a prolific re- yurea to stimulate production of HbF has been known to
searcher into sickle cell disease, first introduced the dis- temporarily alleviate sickle cell disease symptoms. The
tinction between sickle cell disease and trait in 1933, al- researchers demonstrated that this gene therapy method
though it took until 1949 until the genetic characteristics is a more permanent way to increase therapeutic HbF
9

production.[94] [9] Wong WY, Powars DR, Chan L, Hiti A, Johnson C, Over-
turf G (Mar 1992). “Polysaccharide encapsulated bac-
A 1 clinical trials of gene therapy for sickle cell disease in terial infection in sickle cell anaemia: a thirty year epi-
humans were started in 2014.[95][96] As of 2014 however demiologic experience”. Am J Hematol 39 (3): 176–82.
no randomized controlled trials have been reported.[97] doi:10.1002/ajh.2830390305. PMID 1546714.
[10] Khatib R, Rabah R, Sarnaik SA (January 2009). “The
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PMID 19002450.
• Haematopoietic ulcer [11] Glassberg, J (August 2011). “Evidence-based manage-
ment of sickle cell disease in the emergency department.”.
Emergency medicine practice 13 (8): 1–20; quiz 20. PMID
22164362.
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12 Further reading
[83] Washburn, R.E. (1911). “Peculiar elongated and sickle-
shaped red blood corpuscles in a case of severe anemia”. • Brown, Robert T., ed. (2006). Comprehensive
The Virginia Medical Semi-Monthly 15 (21): 490–493. handbook of childhood cancer and sickle cell dis-
[84] “UVa Hospital Celebrating 100 Years”. University of Vir- ease: a biopsychosocial approach. Oxford Univer-
ginia. Retrieved 28 January 2015. sity Press. ISBN 978-0-19-516985-0.

[85] Mason VR (1922). “Sickle cell anemia”. JAMA 79 (14): • Hill, Shirley A. (2003). Managing Sickle Cell Dis-
1318–1320. doi:10.1001/jama.254.14.1955. PMID ease in Low-Income Families. Temple University
3900438. Press. ISBN 978-1-59213-195-2.
13

• Serjeant, Graham R. & Beryl E. (2001). Sickle Cell


Disease. Oxford University Press. ISBN 978-0-19-
263036-0.

• Tapper, Melbourne (1999). In the blood: sickle cell


anemia and the politics of race. University of Penn-
sylvania Press. ISBN 978-0-8122-3471-8.

13 External links
• Sickle cell at DMOZ
• Sickle Cell Anaemia OER Project
14 14 TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

14 Text and image sources, contributors, and licenses


14.1 Text
• Sickle-cell disease Source: https://en.wikipedia.org/wiki/Sickle-cell_disease?oldid=679998755 Contributors: AxelBoldt, Magnus
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14.2 Images 15

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14.2 Images
• File:1911_Sickle_Cells.jpg Source: https://upload.wikimedia.org/wikipedia/commons/4/4b/1911_Sickle_Cells.jpg License: CC BY 3.0
Contributors: Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013. Original artist: OpenStax
College
• File:Autorecessive.svg Source: https://upload.wikimedia.org/wikipedia/commons/3/3e/Autorecessive.svg License: CC-BY-SA-3.0 Con-
tributors: Own work in Inkscape Original artist: en:User:Cburnett
• File:Commons-logo.svg Source: https://upload.wikimedia.org/wikipedia/en/4/4a/Commons-logo.svg License: ? Contributors: ? Original
artist: ?
• File:Malaria_distribution.jpg Source: https://upload.wikimedia.org/wikipedia/commons/6/65/Malaria_distribution.jpg License: CC-
BY-SA-3.0 Contributors: Transferred from en.wikipedia to Commons. Original artist: Muntuwandi at English Wikipedia
• File:Paludisme_-_Frequence_statistique.png Source: https://upload.wikimedia.org/wikipedia/commons/0/08/Paludisme_-_
Frequence_statistique.png License: CC-BY-SA-3.0 Contributors: CHU de Rouen - Frequence du paludisme Original artist: Percherie
• File:Sickle_cell_distribution.jpg Source: https://upload.wikimedia.org/wikipedia/commons/2/24/Sickle_cell_distribution.jpg License:
CC-BY-SA-3.0 Contributors: Transferred from en.wikipedia to Commons. Original artist: Muntuwandi at English Wikipedia
• File:Sickle_cells.jpg Source: https://upload.wikimedia.org/wikipedia/commons/a/a1/Sickle_cells.jpg License: CC BY-SA 3.0 Contribu-
tors: Own work Original artist: Dr Graham Beards
• File:Sicklecells.jpg Source: https://upload.wikimedia.org/wikipedia/commons/9/92/Sicklecells.jpg License: Public domain Contributors:
(US government agency) site at http://www.cc.nih.gov/ccc/ccnews/nov99/ . The photo is attributed to Drs. Noguchi, Rodgers, and
Schechter of NIDDK. Original artist: NIDDK

14.3 Content license


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