sickle cell Disease

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Chapter 3
Sickle Cell Disease (SCD)
Ahmed K. Mansour, Sohier Yahia, Rasha El-Ashry, Angi Alwakeel,
Ahmad Darwish and Khalil Alrjjal
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/61162
Abstract
Sickle cell anemia (SCA) is a disease that is caused by the formation of an abnormal
hemoglobin type, which can bind with other abnormal hemoglobin molecules within
the red blood cells (RBCs) to cause rigid distortion of the cell. This distortion prevents
the cell from passing through small blood vessels; leading to occlusion of vascular
beds, followed by tissue ischemia and infarction. Infarction is frequent all over the
body in patients with SCA, leading to the acute pain crisis. Over time, such insults re‐
sult in medullary bone infarcts and epiphyseal osteonecrosis. In the brain, cognitive
impairment and functional neurologic deficits may occur due to white matter and
gray matter infarcts. Infarction may also affect the lungs increasing susceptibility to
pneumonia. The liver, spleen, and kidney may show infarction as well. Sequestration
crisis is an unusual life-threatening complication of SCA, in which a significant
amount of blood is sequestered in an organ (usually the spleen), leading to collapse.
Lastly, since the RBCs are abnormal, they are destroyed, resulting in a hemolytic ane‐
mia. However, the ischemic complications in patients with SCA disease far exceed the
anemia in clinical significance.
Keywords: Sickle, update, hydroxyuria
1. Introduction
1.1. Hemoglobinopathies
Hemoglobin is needed for transfer of oxygen to different body organs. The shape of the red
blood cell can be affected by the type of the hemoglobin. Hemoglobinopathies are hemoglobin
abnormalities that influence its formation. The severity of these disorders varies widely and
can lead to death. Hemolytic anemia is a common presentation for hemoglobinopathies. Sickle
cell anemia is one of these hemoglobinopathies.
© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
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1.2. Definition of sickle cell anemia
Sickle cell anemia is an inherited disease characterized by the presence of an abnormal
hemoglobin called hemoglobin S (HbS). During deoxygenation, the red blood cell (RBC) shape
changes from the biconcave shape to the sickle shape due to the abnormal hemoglobin. The
shape of the RBC changes back to the biconcave shape after reoxygenation. However, the
frequent sickling and unsickling leads to hemolysis and anemia. [1]
1.3. Inheritance of hemoglobinopathies
There are three types of normal hemoglobin: hemoglobin A (HbA), hemoglobin F (HbF), and
hemoglobin A2 (HbA2). Each hemoglobin molecule contains four polypeptide chains that differ
from one type to another. Hemoglobin A contains 2 alpha globin chains and two beta globin
chains and comprises 95–97% of the normal hemoglobin. Hemoglobin A2 contains 2 alpha
globin chains and two gamma globin chains and comprises 2.5–3.5% of the normal hemoglo‐
bin. Hemoglobin F contains 2 alpha globin chains and two delta globin chains and comprises
<1% of the normal hemoglobin. The gene coding for the α globin chain is sited on chromosome
16, however, the non-α globin gene cluster is located on chromosome 11. [2,3]
There is a transversion mutation at the sixth codon of the β globin gene from A to T which
produces HbS, with a substitution at the 6th amino acid position in the β globin polypeptide
chain to be valine instead of glutamic acid. Patients with sickle cell anemia (homozygous to HbS
gene) have HbS instead of HbA associated with formation of HbF and HbA2. Some patients
with sickle cell disease (double heterozygous) have got HbS together with other types of
abnormal hemoglobin or even they are sickle-thalassemia. However, thalassemias on their own
occur more frequently giving rise to homozygous disease conditions.[4]Abnormal hemoglo‐
bin is responsible for hemolysis and vaso-occlusion that can lead to tissue infarction. [5,6]
1.4. Pattern of inheritance of hemoglobinopathies
Hemoglobin abnormalities and the thalassemias are inherited as autosomal recessive (AR)
disorders, where carrier parents transmit the disease to their offspring. If both parents are
heterozygotes for HbS, there is a 25 per cent chance of having a homozygous HbSS (Sickle cell
anemia, SCA) child. A double heterozygote state occurs when one parent is a heterozygote for
HbS and the other is heterozygote for one of the abnormal HbS or thalassemias. Heterozygotes
are asymptomatic carriers (traits), while the SCD is presented in the homozygotes and the
double heterozygotes for two abnormal hemoglobin genes or HbS and the thalassemias.[6]
1.5. Pathophysiology of sickle cell anemia
Sickle cell anemia is a single gene disorder which is produced by a point mutation in the beta
globin gene which is found on chromosome 11. This leads to replacement of glutamic acid (a
hydrophilic amino acid) in the sixth position with valine (a hydrophobic amino acid). [7]
Hemoglobin S is formed from the association of two α-globin subunits with two mutant β-
globin subunits. On exposure to hypoxic conditions, the absence of a polar amino acid at
position six of the β-globin chain encourages the non-covalent polymerization (aggregation)
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of hemoglobin, which changes the shape and elasticity of RBCs.In low oxygen media, the cells
attain an abnormal shape which is not elastic. When normal oxygen tension is regained, the
cells fail to return to their normal shape. Therefore, these distorted RBCs cannot pass through
narrow capillaries, leading to occlusion of blood vessels. Vaso-occlusion results in hand-foot
syndrome in children. Furthermore, infections, stroke, and acute chest pain are some of the
major complications. Most of these complications start in early life, but become clearer with
advancing age. Infections, dehydration, cold weather, and stress are considered as precipitat‐
ing factors for these complications. Treatments of SCD are mostly directed toward prevention
of or decreasing sickling and thus reducing the incidence of vascular occlusion. [5-10]
The abnormal shape of the RBCs leads to their destruction by hemolysis. A compensatory bone
marrow hyperplasia is not able to match the rate of RBC destruction.[8] Sickle cells only survive
10–20 days in comparison to normal RBCs which typically live 90–120 days.[9]
2. Epidemiology of sickle cell gene
Sickle cell anemia is most common among people from Africa, India, the Caribbean, the Middle
East, and the Mediterranean. In the Middle East, the first report of HbS and thalassemias came
from Egypt. [11,12] The presence of HbS in Eastern Saudi Arabia was reported by Lehmann.
[13] Many studies on hemoglobinopathies have been documented from most countries of the
Middle East. Table (1) presents a brief history for identification of abnormal hemoglobins in
the Middle East. HbS is the major variant identified in all areas. [14]
Discovery country Year
First case of SCD in Egypt 1951
HbS in Middle East 1959
HbO-Arab in Egyptian family 1960
HbS in Saudi Arabia 1963
HbS and HbO-Arab in Sudan 1966
HbC in Egyptians 1967
Mild SCD in Saudi Arabia 1969
SCD in Kuwait 1969
HbH disease in Kuwait 1969
HbS in Egyptian western desert 1974
HbC in Libya 1975
HbS in Abu Dhabi 1980
HbC in Saudi Arabia 1979
HbE and HbD in Abu Dhabi 1979
HbO-Arab in Saudi Arabia 1980
HbS. α- and β-thal in several regions of Saudi Arabia 1967–1982
Table 1. Hemoglobinopathies in the Middle East Arab countries
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3. Clinical manifestations of sickle cell anemia
Sickle cell anemia presents with severe hemolytic anemia interrupted by crises. Symptoms of
anemia in SCD are often mild in relation to the severity of the anemia because HbS gives up
oxygen (O2) to tissues relatively easily compared with HbA, its O2 dissociation curve is shifted
to the right (see Figure 1). [15]
Figure 1. The hemoglobin oxygen dissociation curve. 2,3-DPG, 2,3-diphosphoglycerate.
The clinical presentation of SCD is variable, with some patients having a normal life; however,
some patients show increased morbidity and mortality due to severe thrombotic, aplastic, and
sequestration crises. [15]
3.1. Vaso-occlusive crises
The vaso-occlusive crises are the commonest. Their etiology is usually attributed to low oxygen
tension as in high altitude, water loss, and infection. Vaso-occlusion leads to severe pain
especially in bones (hips, shoulders, and vertebrae) (Figures 2–4). [15] Infarcts of the small
bones lead to painful dactylitis (hand-foot syndrome). It is usually the first presentation of the
disease and may lead to digits of varying lengths (Figure 4). [15] Soft tissues affected include
the lungs and the spleen. The most serious vaso-occlusive crisis is of the brain (a stroke occurs
in 7% of all patients) or spinal cord.
Transcranial Doppler ultrasonography detects abnormal blood flow indicative of arterial
stenosis. This can predict the occurrence of strokes in children.[15]
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Figure 2. Radiograph of the pelvis of a young man of West Indian origin, which shows avascular necrosis with flatten‐
ing of the femoral heads, more marked on the right hip, coarsening of the bone architecture, and cystic areas in the
right femoral neck caused by previous infarcts.
Figure 3. Sickle cell anemia. Coronal hip MRI image revealing established osteonecrosis of femoral heads bilaterally
(yellow arrow) with crescentric sclerotic margin (blue dot) as a consequence of sickle cell disease (Courtesy of Dr A.
Malhotra).
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8
Figure3:Sicklecellanemia.CoronalhipMRIimagerevealingestablishedosteonecrosisoffemoralheads
bilaterally(yellowarrow)withcrescentricscleroticmargin(bluedot)asaconsequenceofsicklecelldisease
(CourtesyofDrA.Malhotra).
Figure4:Sicklecellanemia:(a)painfulswollenfingers(dactylitis)inachild;and(b)thehandofan18‐year‐old
Nigerianboywiththe'hand‐foot'syndrome.Thereismarkedshorteningoftherightmiddlefingerbecause
ofdactylitisinchildhoodaffectingthegrowthoftheepiphysis..
Figure 4. Sickle cell anemia: (a) painful swollen fingers (dactylitis) in a child; and (b) the hand of an 18-year-old Niger‐
ian boy with the ' hand - foot ' syndrome. There is marked shortening of the right middle finger because of dactylitis in
childhood affecting the growth of the epiphysis..
3.2. Sequestration crises
These crises are caused by pooling of blood, with severe exacerbation of anemia. The acute
sickle chest syndrome is the most common cause of death after puberty. The patients present
with dyspnea, arterial hypoxia, chest pain, and lung infiltrates on chest X-ray. Treatment
includes analgesics, oxygen, exchange transfusion, and ventilator support if needed. Hepatic
and splenic sequestration may lead to severe disease necessitating exchange transfusion. The
splenic sequestration is characteristically found in infants and clinically presents with an
enlarging spleen, decreased hemoglobin, and abdominal pain. The patients are treated mainly
with blood transfusion, and they must be monitored frequently as rapid progression may
occur. The crises are usually recurrent and the patient is usually in need of splenectomy. [15]
3.2.1. Aplastic crises
Aplastic crises are due to parvovirus infection and are characterized by a sudden fall in
hemoglobin, usually requiring transfusion. The patient shows anemia together with reticulo‐
cytopenia. [15]
3.2.2. Hemolytic crises
In these crises, the patients show a higher rate of hemolysis with a decline in hemoglobin level
associated with reticulocytosis. Hemolytic crises usually accompany vaso-occlusive crises.
3.2.3. Other clinical features
Chronic hemolytic anemia is the main clinical presentation of SCD with recurrent attacks of
acute painful vaso-occlusive crises. SCD is also associated with multi-organ acute and chronic
complications. The clinical features of SCD are summarized in Table (2). The size of the spleen
is increased during infancy and early childhood but later is usually decreased due to infarction
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(autosplenectomy). Pulmonary hypertension and tricuspid regurgitation may occur and
increases the risk of mortality. Retinopathy and priapism may also complicate the course of
patients with SCD. Chronic liver damage may occur due to microinfarction associated with
gall bladder stones. Renal medullary infarction with papillary necrosis may be present in the
course of sickle cell anemia. The ability of the kidney to concentrate urine may be lost leading
to dehydration and vaso- occlusive crises, and nocturnal enuresis is common. [15]
Although the genetic aberration in SCD is precisely well understood, there is a clear variability
in the clinical severity of the disease among patients. Some patients lead a normal life, free of
problems; others may show severe crises or have fatal complications. The life expectancy of
patients with SCD is decreased but is increasing due to the improvement in supportive
therapies, especially prophylactic antibiotics, stroke screening in early childhood, increased
administration of hydroxycarbamide or transfusion, and improved care. Intensive care is
needed for patients complicated by acute chest syndrome (ACS), acute stroke, or acute renal
injury.[16]
Complication Clinical presentation
Painful crisis These crises occur in most of patients with SCD; they are variable in frequency and
severity
May lead to a chronic pain syndrome
Neurological Microvascular occlusion may be seen on MRI. May lead to cognitive disability.
Stroke affects 10% of children; it is a leading cause of morbidity and mortality. Can
be prevented by regular blood transfusion
Pulmonary Acute chest syndrome
Asthma, fibrotic lung disease
The main cause of death in adults, high risk of acute respiratory failure There is an
increased association with airway hyperactivity.
Gastrointestinal
Cholelithiasis Hepatopathy
Most patients have gall bladder stones due to hemolysis
Decompensated liver disease may be present in some patients
Renal, Urological Chronic renal failure occurs in 20% of patients
Priapism may be present leading to sexual dysfunction
Ophthalmology Proliferative retinopathy is common in patients with HbSC disease
Orthopedic
Avascular necrosis
Osteomyelitis
Common complication of hip and shoulders, requiring replacement
Salmonella is the most common organism
Hematological
Hemolytic anemia
Aplastic crisis
Splenic sequestration
Chronic hemolysis, usual Hb 6–9 g/dL, higher in HbSC
Parvovirus B19 infection may trigger red cell aplasia.
The combination of red cell aplasia and hemolysis can be fatal
Typically seen in infants with a rapidly enlarging spleen
Table 2. Clinical presentation of sickle cell disease (SCD)
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3.3. Diagnosis
In HbSS, the complete blood count shows hemoglobin levels in the range of 6-8 g/dL with
reticulocytosis (due to compensatory bone marrow hyperplasia). In other forms of sickle-cell
disease, Hb levels tend to be higher. A blood film may reveal sickle shaped cells and features
of hyposplenism (target cells and Howell-Jolly bodies) (Figure 5). [15]
Figure 5. Sickle cell anemia: peripheral blood films showing deeply staining sickle cells, target cells and polychroma‐
sia.
Hemoglobin electrophoresis is used to diagnose the presence of abnormal hemoglobin types.
Hemoglobin S and hemoglobin SC are the two most common forms detected in sickle cell-
diseased patients. High-performance liquid chromatography (HPLC) is used to confirm the
diagnosis. Genetic study is not frequently done as electrophoresis and HPLC are accurate in
detecting HbS and HbC.[17]
Infection may precipitate the acute sickle-cell crisis. Therefore, a urinalysis to detect an occult
urinary tract infection, and chest X-ray to look for occult pneumonia should be performed.[18]
Genetic counseling is usually needed for carriers of SCD before they have a child. Fetal blood
sampling or amniocentesis can be done to see if the fetus has the disease. Miscarriage is more
common with fetal blood sampling than with amniocentesis.
4. General principles of management of SCD
Crises management is usually supportive unless blood transfusion is indicated. The aim of
treatment is to prevent the sickling of RBCs, dehydration, hypoxia, and acidosis that can induce
sickling. Painful attack is the main presentation. Subcutaneous morphine or another strong
opiate is frequently required for management of severe attacks of pain. Pethidine can precip‐
itate Grand mal seizures; therefore, it is preferable to be avoided. Satisfactory fluid intake is
mandatory.
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4.1. Folic acid and penicillin
Children born with sickle-cell disease will take folic acid (1 mg dose) daily for life. In addition,
Patients from birth to five years of age have to take penicillin daily due to susceptibility to
pneumococcal infection.
4.2. Acute chest syndrome
Acute chest syndrome is an acute illness with fever and/or respiratory symptoms associated
with a new lung infiltrate. It is the main cause of mortality in adults with SCD and the most
common cause of intensive care unit admission. The patient who needs mechanical ventilation
is reported to have a mortality rate of 5%.[16] Symptoms include cough, wheeze, dyspnea, and
chest pain, which may be pleuritic or affect the ribs and sternum. The acute chest syndrome is
unique to SCD and is associated with a more severe course and worse outcome than pneu‐
monia.
Blood transfusion is used to treat patients with acute chest syndrome and will improve the
oxygenation. Blood transfusion is useful in less severe cases with a low Hb (<7 g/dL); however,
exchange transfusion is needed in severe cases, in patients with high Hb levels, or those with
severe hypoxia. The target is a final Hb level of 9–10 g/dL. Severe hypoxia, dyspnea and
respiratory acidosis are indications for initiating advanced respiratory support.[19]
4.3. Stroke
Patients with SCD are commonly associated with ischemic and hemorrhagic strokes, with a
prevalence rate of more than 5%. Incidence of stroke is greatly reduced after the introduction
of transcranial Doppler screening and primary stroke prevention with transfusion. A stroke
may be precipitated by dehydration or a coincident illness.
Early imaging is essential to confirm the diagnosis and exclude hemorrhage. MRI is the
imaging of choice with high sensitivity and specificity. If the MRI confirms a stroke, immediate
exchange transfusion should be done to achieve an HbS less than 30%. Ischemic stroke
prevention can be done by long-term exchange transfusion, however the efficacy of anti-
platelet therapy in primary or secondary stroke prevention in SCD is not proved.[20]
4.4. Sepsis
Patients with sickle cell anemia have functional hyposplenism. This makes them more
susceptible to infection by capsulated organisms. Sepsis caused by gram-negative organisms
is common together with osteomyelitis. Children with sickle cell anemia have to be vaccinated
against pneumococcal, meningococcal, and Hemophilus influenza infection. Oral penicillin
could be given on daily basis after the time of diagnosis to guard against pneumococcal
infection. [21]
4.5. Other complications of SCD
Patients with SCD have low renal concentrating ability and are therefore susceptible to
dehydration. Over time, the patients may show proteinuria and chronic renal impairment as
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a result of glomerular damage. This leaves patients liable to acute kidney injury during a crisis.
Chronic lung disease is common and manifests as either a restrictive lung defect or an
overnight hypoxia and sleep apnea. Pulmonary hypertension is more common in SCD and
can lead to marked hypoxia.[16]
4.5.1. Admission to critical care unit
Patients with sickle cell anemia may need admission to the intensive care unit either due to
liver cell failure, sepsis, or multi-organ damage. This acute deterioration may necessitate
urgent blood transfusion aiming for an Hb of 9–10 g/dL and HbS% of less than 30%. This will
improve tissue oxygenation and perfusion, whatever the underlying etiology.[22]
4.5.2. Transfusion in SCD patients
Regular blood transfusion is needed to prevent brain strokes. Special situations such as
circulatory disturbances, sequestration crises and priapism may need blood transfusion to
optimize oxygen transport. [23]
Partial exchange transfusion is usually preferred to simple transfusion if routine or multiple
transfusions are necessary. It decreases the iron overload and prevents increased blood
viscosity.
5. Health maintenance
There are some lines of treatment that decreases the morbidity and mortality in children with
sickle cell anemia, including:
1. Vaccination against capsulated organisms (e.g. Hib, Pneumococci, and meningococci).
2. Hydroxyurea and folic acid supplementation.
3. Oral penicillin prophylaxis in children less than 6 years.
4. Early detection and management of severe bacterial infections.
Hydroxyurea, by increasing HbF and thereby reducing sickling, decreases painful crises (by
50%) and decreases acute chest syndrome and transfusion requirements. The dose of hydrox‐
yurea is variable and is adjusted to increase HbF.
Hydroxyurea is more effective in some patients if given with erythropoietin (40,000-60,000
units/week). However, hydroxyurea can cause neutropenia and thrombocytopenia. Hydrox‐
yurea is also a teratogen and should not be given to females in the child-bearing period.
The screening for stroke in children with SCD is recommended to be done from age 2 to 16
years using transcranial Doppler flow studies. Risky children can get benefit from prophylac‐
tic, chronic partial exchange transfusions keeping HbS at < 30% of total Hb.
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Erythropoietin use in patients with anemia not related to chemotherapy is associated with high
incidence of venous thromboembolism and cardiopulmonary complications (as myocardial
infarction); it is not useful in patients with sickle cell disease except possibly if given in
combination with hydroxyurea.[23]
6. Novel medications
6.1.1. Omega-3 fatty acids
Omega-3 fatty acids are significantly reduced in SCD patients. In a single-center study
conducted in Sudan, there was a randomized, placebo-controlled, double-blind design for
studying the effect of omega-3 treatment on sickle cell anemia patients. One hundred and forty
patients were monitored for 1 year, and it was found that omega-3 treatment leads to a decline
in occlusive crises and blood transfusion. Treatment with omega-3 was well tolerated by the
patients and needs further study. [24]
6.1. Prasugrel
It is a new thienopyridine P2Y12 ADP receptor antagonist, which inhibits ADP-mediated
platelet activation and aggregation. Phase 2 randomized, double-blind, placebo controlled
studies to examine safety were completed in adults. There were no hemorrhagic events
requiring medical intervention in either study arm. Mean pain rates (percentage of days with
pain) and intensity in the prasugrel arm were decreased compared with placebo. But, these
results were not statistically significant. It was well tolerated and a phase 3 trial in children is
registered. [25]
7. Prognosis
The life span of homozygous patients with SCD has gradually increased to > 50 years. Common
causes of death are acute chest syndrome, recurrent infections, pulmonary embolism, infarc‐
tion of a vital organ, and renal failure. [23]
8. Summary
Sickle cell disease is an inherited hemoglobinopathy affecting mainly the black races and
leading to chronic hemolysis. The abnormal HbS found in homozygous patients changes the
shape of RBCs to become sickle-shaped. These cells can occlude small blood vessels leading
to ischemia and pain. The patients may be complicated by acute chest syndrome, sepsis,
sequestration, and aplastic crises. Sickle cell disease is characterized by anemia and can be
diagnosed by Hb electrophoresis. Blood transfusion may be needed for these patients.
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Occlusive crises are treated mainly by pain killers. Hydroxyurea may decrease the frequency
of these crises. Early management of bacterial infections and vaccination against capsulated
organisms can prevent sepsis.
Author details
Ahmed K. Mansour*, Sohier Yahia, Rasha El-Ashry, Angi Alwakeel, Ahmad Darwish and
Khalil Alrjjal
*Address all correspondence to: ak_mans@yahoo.com
Pediatric Hematology /Oncology Unit, Mansoura University Children`s Hospital, Mansoura
University, Mansoura, Egypt
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