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Its All about Sickle Cell Anemia
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SSICKLEICKLE C CELLELL A ANEMIANEMIA
Introduction:
Sickle-cell disease or sickle-cell anemia (or drepanocytosis) is a life-long blood disorder characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickle cell anemia is a serious disease in which the body makes sickle-shaped red blood cells. “Sickle-shaped” means that the red blood cells are shaped like a "C."
Normal red blood cells are disc-shaped and look like doughnuts without holes in the center. They move easily through blood vessels. Red blood cells contain the protein hemoglobin. This iron-rich protein gives blood its red color and carries oxygen from the lungs to the rest of the body.
Sickle cells contain abnormal hemoglobin that causes the cells to have a sickle shape. Sickle-shaped cells don’t move easily through blood vessels. They’re stiff and sticky and tend to form clumps and get stuck in the blood vessels. (Other cells also may play a role in this clumping process.)
The clumps of sickle cells block blood flow in the blood vessels that lead to the limbs and organs. Blocked blood vessels can cause pain, serious infections, and organ damage. Sickling decreases the cells' flexibility and results in a risk of various complications.
The sickling occurs because of a mutation in the hemoglobin gene. Life expectancy is shortened, with studies reporting an average life expectancy of 42 and 48 years for males and females, respectively.
Sickle-cell disease, usually presenting in childhood, occurs more commonly in people (or their descendants) from parts of tropical and sub-tropical regions where malaria is or was common. One-third of all aboriginal inhabitants of Sub-Saharan Africa carry the gene because in areas where malaria is common, there is a survival value in carrying only a single sickle-cell gene (sickle cell trait). Those with only one of the two alleles of the sickle-cell disease are more resistant to malaria, since the infestation of the malaria plasmodium is halted by the sickling of the cells which it infests.
The prevalence of the disease in the United States is approximately 1 in 5,000, mostly affecting African Americans according to National Institute of Health.
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9Figure 1 shows normal red blood cells flowing freely in a blood vessel. The inset image shows a cross-section of a normal red blood cell with normal hemoglobin. Figure B shows abnormal, sickled red blood cells clumping and blocking blood flow in a
blood
Overview of the Disease
Sickle cell anemia is one type of anemia. Anemia is a condition in which blood has a lower than normal number of red blood cells. This condition also can occur if red blood cells don’t have enough hemoglobin.
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Red blood cells are made in the spongy marrow inside the large bones of the body. Bone marrow is always making new red blood cells to replace old ones. Normal red blood cells last about 120 days in the bloodstream and then die. They carry oxygen and remove carbon dioxide (a waste product) from your body.
In sickle cell anemia, a lower-than-normal number of red blood cells occurs because sickle cells don’t last very long. Sickle cells usually die after only about 10 to 20 days. The bone marrow can’t make new red blood cells fast enough to replace the dying ones.
Distribution of “Sickle Cell Anemia” worldwide
Due to the adaptive advantage of the heterozygote, the disease is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such as Africa, the Mediterranean, India and the Middle East. Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid 20th century with the exception of rare sporadic cases.
In the USA, where there is no endemic malaria, the prevalence of sickle-cell anemia among blacks is lower (about 0.25%) than in West Africa (about 4.0%), and is falling. Without endemic malaria from Africa, the condition is purely disadvantageous, and will tend to be bred out of the affected population. Another factor limiting the spread of sickle-cell genes in North America is the absence of cultural proclivities to polygamy.
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Figure 2 Distribution of the sickle-cell trait shown in pink and purple
Genetic basis of “Sickle Cell Anemia”
Inheritance
Sickle-cell conditions are inherited from parents in much the same way as blood type, hair color and texture, eye color, and other physical traits.
The types of haemoglobin a person makes in the red blood cells depend upon what haemoglobin genes are inherited from his parents. 1. If one parent has sickle-cell anaemia (SS) and the other has sickle-cell trait (AS),
there is a 50% chance (or 1 out of 2) of a child's having sickle-cell disease (SS) and a 50% chance of a child's having sickle-cell trait (AS).
2. When both parents have sickle-cell trait (AS), they have a 25% chance (1 of 4) of a child's having sickle-cell disease (SS), as shown in the diagram.
Sickle-cell anemia appears to be caused by a recessive allele. Two carrier parents have a one in four chance of having a child with the disease. The child will be homozygous-recessive.
It has been argued that the allele, although appearing outwardly recessive, is in fact co-dominant, due to the resistance to a malaria that is obtained by those of the AS genotype. Since a separate phenotype from that of Normal (AA) has therefore been expressed, it is impossible to argue that the S allele is homozygous-recessive.
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Figure 3 Sickle-cell disease is inherited in the autosomal recessive pattern.
Molecular Phenomena occurring in “Sickle Cell Anemia”
Clinically significant sickle cell syndromes also occur in people of Mediterranean and Middle Eastern background. Here, the most common problem is a combination sickle cell and beta thalassemia genes. The sickle cell mutation reflects a single change in the amino acid building blocks of the oxygen-transport protein, hemoglobin. This protein, which is the component that gives red cells their color, has two subunits. The alpha subunit is normal in people with sickle cell disease. The beta subunit has the amino acid valine at position 6 instead of the glutamic acid that is normally present. The alteration is the basis of all the problems that occur in people with sickle cell disease. The schematic diagram shows the first eight of the 146 amino acids in the beta globin subunit of the hemoglobin molecule. The amino acids of the hemoglobin protein are represented as a series of linked, colored boxes. The lavender box represents the normal glutamic acid at position 6. The dark green box represents the valine in sickle cell hemoglobin. The other amino acids in sickle and normal hemoglobin are identical.
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Schematic Represntation of the Amino Acid Substitution in Sickle Cell Disease
Figure 4 The chain of colored boxes represent the first eight amino acids in the beta chain of hemoglobin. The sixth position in the normal beta chain has glutamic acid, while sickle beta chain has valine. This is the sole difference between the two.
.
The molecule, DNA (deoxyribonucleic acid), is the fundamental genetic material that determines the arrangement of the amino acid building blocks in all proteins. Segments of DNA that code for particular proteins are called genes. The gene that controls the production of the beta globin subunit of hemoglobin is located on one of the 46 human chromosomes (chromosome #11). People have twenty-two identical chromosome pairs (the twenty-third pair is the unlike X and Y chromosomes that determine a person's sex). One of each pair is inherited from the father, and one from the mother. Occasionally, a gene is altered in the exchange between parent and offspring. This event, called mutation, occurs extremely rarely. Therefore, the inheritance of sickle cell disease depends totally on the genes of the parents.
If only one of the beta globin genes is the "sickle" gene and the other is normal, the person is a carrier for sickle cell disease. The condition is called sickle cell trait. With a few rare exceptions, people with sickle cell trait are completely normal. If both beta globin genes code for the sickle protein, the person has sickle cell disease. Sickle cell disease is determined at conception, when a person acquires his/her genes from the parents. Sickle cell disease cannot be caught, acquired, or otherwise transmitted. Also, sickle cell trait does not develop into sickle cell disease. Sickle cell trait partially protects people from the deadly consequences of malaria. The
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frequency of the sickle cell gene reached high levels in Africa and India due to the protection against malaria that occurred for people with sickle cell trait
The hemoglobin molecule (made of alpha and beta globin subunits) picks up oxygen in the lungs and releases it when the red cells reach peripheral tissues, such as the muscles. Ordinarily, the hemoglobin molecules exist as single, isolated units in the red cell, whether they have oxygen bound or not. Normal red cells maintain a basic disc shape, whether they are transporting oxygen or not.
The picture is different with sickle hemoglobin (Figure 5). Sickle hemoglobin exists as isolated units in the red cells when they have oxygen bound. When sickle hemoglobin releases oxygen in the peripheral tissues, however, the molecules tend to stick together and form long chains or polymers. These rigid polymers distort the cell and cause it to bend out of shape. While most distorted cells are simply shaped irregularly, a few have a cresent-like appearence under the microscope. These cresent-like or "sickle shaped" red cells gave the disorder its name. When the red cells return to the lungs and pick up oxygen again, the hemoglobin molecules resume their solitary existence (the left of the diagram).
A single red cell may traverse the circulation four times in one minute. Sickle hemoglobin undergoes repeated episodes of polymerization and depolymerization. This cyclic alteration in the state of the molecules damages the hemoglobin and ultimately the red cell itself.
Oxygen and the Formation of Polymers of Sickle Hemoglobin
Figure 5 Normal hemglobin exists as solitary units whether oxygenated or deoxygenated (upper panel). In contrast, sickle hemoglobin molecules adhere when they are deoxygenated, forming sickle hemoglobin polymers (lower panel).
Polymerized sickle hemoglobin does not form single strands. Instead, the molecules group in long bundles of 14 strands each that twist in a regular fashion, much like braid (Figure 6). These bundles self-associate into even larger structures that stretch and distort the cell. An analogy will be an water balloon which was stretched and deformed by icicles. The stretching of the
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balloon's rubber is similar to what happens to the membrane of the red cell. Polymers tend to grow from a single start site (called a nucleation site) and often grow in multiple directions. Star-shaped clusters of hemoglobin S polmers develop commonly.
Schematic Representaion of Polymerized Sickle Hemoglobin
Figure 6 Polymers of deoxygenated sickle hemoglobin molecules. Each hemoglobin molecule is represented as a sphere. The spheres twist in an alpha helical bundle made of 14 sickle hemoglobin chains.
Despite their imposing appearance, the sickle hemoglobin polymers are held together by very weak forces. The abnormal valine amino acid at position 6 in the beta globin chain interacts weakly with the beta globin chain in an adjacent sickle hemoglobin molecule. The complex twisting, 14-strand structure of the bundles produces multiple interactions and cross-interactions between molecules. The weak nature of the interaction opens one strategy to treat sickle cell disease.
Some types of hemoglobin molecules, such as that found before birth (fetal hemoglobin), block the interactions between the deoxygenated hemoglobin S molecules. All people have fetal hemoglobin in their circulation before birth. Fetal hemoglobin protects the unborn child and newborns from the effects of sickle cell hemoglobin. Unfortunately, this hemoglobin disappears within the first year after birth. One approach to treating sickle cell disease is to rekindle production of fetal hemoglobin. The drug, hydroxyurea induces fetal hemoglobin production in some patients with sickle cell disease and improves the clinical condition of some people.
Pathophysiology of “Sickle Cell Anemia”
Figure 7 shows the changes that occur as sickle or normal red cells release oxygen in the microcirculation. The upper panel shows that normal red cells retain their biconcave shape and
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move through the smallest vessels (capillaries) without problem. In contrast, the hemoglobin polymerizes in sickle red cells when they release oxygen, as shown in the lower panel. The polymerization of hemoglobin deforms the red cells. The problem, however, is not simply one of abnormal shape. The membranes of the cells are rigid due in part to repeated episodes of hemoglobin polymerization/depolymerization as the cells pick up and release oxygen in the circulation. These rigid cells fail to move through the small blood vessels, blocking local blood flow to a microscopic region of tissue. Amplified many times, these episodes produce tissue hypoxia (low oxygen supply). The result is pain, and often damage to organs.
Capillary Flow of Normal and Sickle Red Cells
Figure 7 Normal red cells maintain their shape as they pass through the capillaries and release oxygen to the peripheral tissues (upper panel). Hemoglobin polymers form in the sickle rell cells with oxygen release, causing them to deform. The
deformed cells block the flow of cells and interrupt the delivery of Oxygen to the tissues (Lower Panel)
The damage to red cell membranes promotes many of the complications of sickle cell disease. Robert Hebbel at the University of Minnesota and colleagues were among the first workers to show that the heme component of hemoglobin tends to be released from the protein with repeated episodes of sickle hemoglobin polymerization. Some of this free heme lodges in the red cell membrane. The iron in the center of the heme molecule promotes formation of very dangerous compounds, called reactive oxygen species. These molecules damage both the lipid and protein components of the red cell membrane. Membrane stiffness is one of the consequences of this injury. Also, the damaged proteins tend to clump together to form
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abnormal clusters in the red cell membrane. Antibodies develop to these protein clusters, leading to even more red cell destruction (hemolysis).
The anemia in sickle cell disease is caused by red cell destruction, or hemolysis. The production of red cells by the bone marrow increases dramatically, but is unable to keep pace with the destruction. Red cell production increases by five to ten-fold in most patients with sickle cell disease. The average half-life of normal red cells is about 40 days. In patients with sickle cell disease, this value can fall to as low as four days. The volume of "active" bone marrow is much greater than normal in patients with sickle cell disease due to the demand for greater red cell production.
The degree of anemia varies widely between patients. In general, patients with sickle cell disease have hematocrits that are roughly half the normal value (e.g., about 25% compared to about 40-45% normally). Patients with hemoglobin SC disease (where one of the beta globin genes codes for hemoglobin S and the other for the variant, hemoglobin C) have higher hematocrits than do those with homozygous Hb SS disease. The hematocrits of patients with Hb SC disease run in low- to mid-thirties. The hematocrit is normal for people with sickle cell trait.
Prevention of “Sickle Cell Anemia”
If you carry the sickle cell trait, you may wish to see a genetic counselor before trying to conceive a child. A genetic counselor can help you understand your risk of having a child with sickle cell anemia. He or she can also explain possible treatments, preventive measures and reproductive options.
There is an in vitro fertilization procedure that improves the chances for parents who both carry the sickle cell gene to have a child with normal hemoglobin. This procedure is known as preimplantation genetic diagnosis. First, eggs are taken from the mother. Then, sperm is taken from the father. In a laboratory, the eggs are fertilized with the sperm. The fertilized eggs are then tested for the presence of the sickle cell gene. Fertilized eggs free of the sickle cell gene can be implanted into the mother for normal development. However, this procedure is expensive and not always successful.
Risk factors
The risk of inheriting sickle cell anemia comes down to genetics. For a baby to be born with sickle cell anemia, both parents must carry a sickle cell gene.
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The gene is particularly common among people with African, Spanish, Mediterranean, Middle Eastern and Indian ancestry. In the United States, it most commonly affects blacks and Hispanics.
Symptoms of the Disease
Anemia. Sickle cells are fragile. They break apart easily and die, leaving you chronically short on red blood cells. Red blood cells usually live for about 120 days before they die and need to be replaced. However, sickle cells die after only 10 to 20 days. The result is a chronic shortage of red blood cells, known as anemia. Without enough red blood cells in circulation, your body can't get the oxygen it needs to feel energized. That's why anemia causes fatigue.
Episodes of pain. Periodic episodes of pain, called crises, are a major symptom of sickle cell anemia. Pain develops when sickle-shaped red blood cells block blood flow through tiny blood vessels to your chest, abdomen and joints. Pain can also occur in your bones. The pain may vary in intensity and can last for a few hours to a few weeks. Some people experience only a few episodes of pain. Others experience a dozen or more crises a year. If a crisis is severe enough, you may need hospitalization so that pain medication can be injected into your veins (intravenously).
Hand-foot syndrome. Swollen hands and feet may be the first signs of sickle cell anemia in babies. The swelling is caused by sickle-shaped red blood cells blocking blood flow out of their hands and feet.
Jaundice. Jaundice is a yellowing of the skin and eyes that occurs because of liver damage or dysfunction. Occasionally, people who have sickle cell anemia have some degree of jaundice because the liver, which filters harmful substances from the blood, is overwhelmed by the rapid breakdown of red blood cells. In people with dark skin, jaundice is visible mostly as yellowing of the whites of the eyes.
Frequent infections. Sickle cells can damage your spleen, an organ that fights infection. This may make you more vulnerable to infections. Doctors commonly give infants and children with sickle cell anemia antibiotics to prevent potentially life-threatening infections, such as pneumonia.
Delayed growth. Red blood cells provide your body with the oxygen and nutrients you need for growth. A shortage of healthy red blood cells can slow growth in infants and children and delay puberty in teenagers.
Vision problems. Some people with sickle cell anemia experience vision problems. Tiny blood vessels that supply your eyes may become plugged with sickle cells. This can damage the retina — the portion of the eye that processes visual images.
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When to see a doctor?
Although sickle cell anemia is usually diagnosed in infancy, if you or your child develops any of the following problems, see your doctor right away or seek emergency medical care.
Any signs or symptoms of stroke. If you notice any one-sided paralysis or weakness in the face, arms or legs, confusion, trouble walking or talking, sudden vision problems or numbness or a headache call 911 or your local emergency number right away.
Swelling in the hands or feet. Abdominal swelling, especially if the area is tender to touch. Fever. People with sickle cell anemia have an increased risk of infection, and fever can
be the first sign of an illness. Pale skin or nail beds. Yellow tint to the skin or the whites of the eyes.
Tests and Diagnosis of the Disease
Clinical Diagnosis
The term sickle cell disease (SCD) encompasses a group of symptomatic disorders defined by the presence of hemoglobin S (Hb S).
Sickle cell anemia (Hb SS) accounts for 60-70% of sickle cell disease in the United States. The other forms of sickle cell disease result from co-inheritance of Hb S with other
abnormal globin beta chain variants, the most common forms being sickle-hemoglobin C disease (Hb SC) and two types of sickle β-thalassemia (Hb S -thalassemia and Hb S -thalassemia).
Other globin beta chain variants such as D-Punjab and O-Arab also result in sickle cell disease when co-inherited with Hb S.
Most individuals with sickle cell disease are healthy at birth and become symptomatic later in infancy or childhood after fetal hemoglobin (Hb F) levels decrease and hemoglobin S (Hb S) levels increase. The diagnosis of sickle cell disease is suspected in infants or young children with painful swelling of the hands and feet (dactylitis or "hand-foot syndrome"), pallor, jaundice, pneumococcal sepsis or meningitis, severe anemia with splenic enlargement, or acute chest syndrome.
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Testing
Hematologic Testing
Table given below summarizes the relative quantity of hemoglobins observed by six weeks of age and typical hematologic studies by two years of age for the four most common sickle cell diseases.
Table: Sickle Cell Disease: Diagnostic Test Results
The diagnosis of sickle cell disease is established by demonstrating the presence of significant quantities of Hb S (by high-performance liquid chromatography, isoelectric focusing, or less commonly, cellulose acetate or citrate agar electrophoresis) and the lack of a normal βglobin gene. A cbc and measure of iron status (e.g., zinc-protoporphrin) help distinguish between specific diagnostic entities.
High-performance liquid chromatography (HPLC)
o Readily separates proteins that cannot be resolved by other means o Allows for accurate quantification of normal and variant hemoglobins even at
low concentrations, enabling differentiation of Hb S -thalassemia from sickle cell trait (Hb AS) as well as identification of compound heterozygous disorders such as Hb S-HPFH (hereditary persistence of fetal hemoglobin) and Hb S -thalassemia
o Does not allow identification of Hb S- -thalassemia, which requires hemoglobin electrophoresis
Isoelectric focusing (IEF) o Capable of much higher resolution than hemoglobin electrophoresis.
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o Capillary isoelectric focusing technology allows for separation of very small samples, quantification, and automation of sampling.
Cellulose acetate and citrate agar electrophoresis o Useful for quick screening of a small number of samples o Sample bands are relatively wide and many abnormal hemoglobins overlap. o Quantitative densitometry of abnormal hemoglobins is inaccurate at low
concentrations (i.e., Hb A2, Hb F). o Is being supplanted by HPLC
Peripheral blood smear o Sickle cells, nucleated red blood cells, and target cells may be seen. Other
abnormal forms may be present depending on the specific genotype. o Presence of Howell-Jolly bodies indicates hyposplenism. o Neutrophil and platelet numbers are often increased.
Kleihauer-Betke test. This acid-elution test detects the presence of cells with a high fetal hemoglobin content and can be used to characterize co-existent HPFH with sickle cell disease.
The solubility test (i.e., sickledex, sickleprep, or sicklequick) utilizes the relative insolubility of deoxygenated Hb S in solutions of high molarity. Hemolysates containing Hb S precipitate in the test solution while those without Hb S remain in solution. The solubility test has no place in the diagnosis of sickle cell disease because (1) it does not differentiate sickle cell disease from sickle cell trait (Hb AS); (2) high levels of Hb F may cause false negative results in neonates with sickle cell disease; and (3) it may miss some clinically significant forms of sickle hemoglobinopathies (e.g., Hb S/C).
Newborn screening. Because of the high morbidity and mortality of sickle cell disease in undiagnosed toddlers, all 50 states, the District of Columbia, Puerto Rico, and the Virgin Islands currently provide universal newborn screening for sickle cell disease. The vast majority of new cases are diagnosed at birth.
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Note: New Hampshire has approved, but not yet implemented, newborn screening.
The majority of newborn screening programs perform isoelectric focusing of an elute of the dried blood spots obtained for screening [Kleman et al 1989, Steinberg 1991, Shafer et al 1996]. A few programs use HPLC or cellulose acetate electrophoresis as the initial screening method.
Hemoglobins identified by newborn screening are generally reported in order of quantity. For example, more fetal hemoglobin (Hb F) than adult hemoglobin (Hb A) is present at birth; thus, most infants show Hb FA on newborn screening.
Specimens with abnormal screening results are retested using a second, complementary electrophoretic technique, HPLC, immunologic tests, or DNA-based assay [Steinberg 1991].
Infants with hemoglobins that suggest sickle cell disease or other clinically significant hemoglobinopathies require confirmatory testing of a separate blood sample by six weeks of age.
Molecular Genetic Testing
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. The term sickle cell disease encompasses a group of symptomatic disorders associated with mutations in the HBB gene and defined by the presence of hemoglobin S (Hb S; E6V mutation).
Sickle cell anemia (also known as homozygous sickle cell disease and Hb SS) used to account for 60-70% of sickle cell disease in the United States; however, because of increasing numbers of births with mixed ethnic background, this number is falling.
Sickle cell disease may also result from co-inheritance of the E6V hemoglobin S mutation with an HBB mutation associated with another abnormal hemoglobin variants including:
Hemoglobin C (Hb C; E6K mutation): sickle-hemoglobin C disease (Hb SC) Beta-thalassemia mutations: S -thalassemia and S -thalassemia Hemoglobin D (D-Punjab; E121Q mutation)
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Hemoglobin O (O-Arab; E121K mutation)
Molecular genetic testing: Clinical uses
Confirmatory testing Carrier testing Prenatal diagnosis
Molecular genetic testing: Clinical methods
Targeted mutation analysis. Testing for the E6V mutation of HBB associated with hemoglobin S, the E6K mutation associated with hemoglobin C, the E121Q mutation associated with hemoglobin D, the E121K mutation associated with hemoglobin O-Arab, β-thalassemia mutations, and other mutations associated with other specific hemoglobin variants is available on a clinical basis. The Hb S mutation destroys the recognition sites for the restriction enzymes Mni I, Dde I, Mst II, and others, making it easily detectable by restriction fragment length polymorphism (RFLP) analysis. Increasingly, a variety of PCR-based techniques are being used to identify the Hb S mutation.
Sequence analysis. HBB sequence analysis may be used following targeted mutation analysis if it is uninformative or as the primary test to detect mutations associated with β-thalassemia hemoglobin variants.
Table given below summarizes molecular genetic testing for this disorder.
Table : Molecular Genetic Testing for Carrier Testing and Prenatal Diagnosis in Sickle Cell Disease
1. Targeted mutation analysis for additional HBB mutations is available on a clinical basis.
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2. As reported by laboratories in the GeneTests Laboratory Directory
Testing Strategy for a Proband
The multiple testing strategies possible vary depending on the specific diagnosis, proband's age, family history, and availability of parents for testing.
Newborns. When screening with IEF or HPLC detects a clinically significant hemoglobinopathy, the result should be confirmed within six weeks with either of these assays or DNA testing.
For compound heterozygotes (e.g., Hb SC, SD, or SO) a repeat test is adequate. Newborns with Hb F>Hb S could have homozygous sickle cell (Hb SS), S -thalassemia, or
S -thalassemia with a low level of Hb A. These hemoglobinopathies can be difficult to distinguish in the newborn period when 95% of hemoglobin is Hb F. Further testing for these infants, as well as newborns diagnosed with S -thalassemia can include molecular testing and/or hematologic testing of parents as described above.
Infants about one year of age. Regardless of the outcome of testing in the newborn period, additional testing that should be done at about one year of age (once Hb F levels have fallen) includes a cbc, reticulocyte count, some form of electrophoresis or HPLC, a measure of iron status, and inclusion body preparation. This helps assess co-existing alpha-thalassemia and increases detection of Sβ-thalassemia syndromes. This is important for genetic counseling and for providing insight into disease-specific outcomes.
Individuals over age one year. A one-time assessment with a cbc, reticulocyte count, some form of electrophoresis or HPLC, a measure of iron status, and inclusion body preparation are indicated.
Differential Diagnosis
Once the presence of Hb S has been confirmed, the differential diagnosis is between clinically significant, less significant, and carrier states.
Clinically significant
Homozygous S/S (i.e., Hb SS) Compound heterozygotes including:
o Hb SC, Hb SD, Hb SO-Arab o Hb S -thalassemia
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o Some forms of Hb S –thalassemia
Less clinically significant
o Some forms of Hb S -thalassemia o Hb SE
Treatment and drugs
Bone marrow transplant offers the only potential cure for sickle cell anemia. But, finding a donor is difficult and the procedure has serious risks associated with it, including death.
As a result, treatment for sickle cell anemia is usually aimed at avoiding crises, relieving symptoms and preventing complications. If you have sickle cell anemia, you'll need to make regular visits to your doctor to check your red blood cell count and monitor your health. Treatments may include medications to reduce pain and prevent complications, blood transfusions and supplemental oxygen, as well as bone marrow transplant.
Medications
Medications used to treat sickle cell anemia include:
Antibiotics. Children with sickle cell anemia usually begin taking the antibiotic penicillin when they're about 2 months of age and continue taking it until they're 5 years old. Doing so helps prevent infections, such as pneumonia, which can be life-threatening to an infant or child with sickle cell anemia. Antibiotics may also help adults with sickle cell anemia fight certain infections.
Pain-relieving medications. To relieve pain during a sickle crisis, your doctor may advise over-the-counter pain relievers and application of heat to the affected area. You may also need stronger prescription pain medication.
Hydroxyurea (Droxia, Hydrea). Hydroxyurea, the most prescribed therapy for sickle cell disease, may benefit individuals with SCD via several mechanisms:
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Induction of Hb F synthesis resulting in decreased sickling and improved red-cell survival
Lowering the white blood cell (WBC) count Metabolization into nitric oxide, a potent vasodilator
Individuals treated with hydroxyurea have significantly fewer acute painful episodes, fewer episodes of acute chest syndrome, decreased need for transfusion, and most importantly, improved survival [Steinberg et al 2003]. However, hydroxyurea does not appear to prevent the cerebrovascular complications of sickle cell disease.
Individuals treated with hydroxyurea must be monitored closely for significant myelosuppression.
Assessing stroke risk
Using a special ultrasound machine (transcranial), doctors can learn which children have a higher risk of stroke. This test can be used on children as young as 2, and those who are found to have a high risk of stroke are then treated with regular blood transfusions.
Blood transfusions
In a red blood cell transfusion, red blood cells are removed from a supply of donated blood. These donated cells are then given intravenously to a person with sickle cell anemia.
Blood transfusions increase the number of normal red blood cells in circulation, helping to relieve anemia. In children with sickle cell anemia at high risk of stroke, regular blood transfusions can decrease their risk of stroke.
Blood transfusions carry some risk. Blood contains iron. Regular blood transfusions cause an excess amount of iron to build up in your body. Because excess iron can damage your heart, liver and other organs, people who undergo regular transfusions must often receive treatment to reduce iron levels. Deferasirox (Exjade) is an oral medication that can reduce excess iron levels. It can be used in people older than 2.
Supplemental oxygen
Breathing supplemental oxygen through a breathing mask adds oxygen to your blood and helps you breathe easier. It may be helpful if you have acute chest syndrome or a sickle cell crisis.
Bone marrow transplant
This procedure replaces bone marrow affected by sickle cell anemia with healthy bone marrow from a donor who doesn't have the disease. It can be a cure, but the procedure is risky, and it's
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difficult to find suitable donors. Researchers are still studying bone marrow transplants for people with sickle cell anemia. Currently, the procedure is recommended only for people who have significant symptoms and problems from sickle cell anemia.
Bone marrow transplant requires a lengthy hospital stay. After the transplant, you'll need drugs to help prevent rejection of the donated marrow.
Treating complications
Doctors treat most complications of sickle cell anemia as they occur. Treatment may include antibiotics, vitamins, blood transfusions, pain-relieving medicines, other medications and possibly surgery, such as to correct vision problems or to remove a damaged spleen.
Experimental treatments
Scientists continue to gain new insights into the symptoms and causes of sickle cell anemia. Some possible new treatments being studied include:
Gene therapy. Gene therapy. The importance of a single nucleotide substitution in the pathogenesis of sickle cell disease makes the presence of the sickle cell allele an ideal candidate for gene therapy. Ideally gene therapy would lead to an increase in non-sickle beta-like chains, while lowering the number of sickle chains.
While many approaches could increase the synthesis of non-sickle chains (e.g., using transactivators to stimulate the minimally expressed delta gene or the fetal or embryonic genes), the primary focus has been to add a normal beta-like gene, potentially modified to have additional anti-sickling properties.
Other promising approaches are induction of embryonic alpha-like chains that, when forming tetramers with sickle chains, are less likely to polymerize, or addition of a vector to inhibit production of the sickle globin.
Combined approaches, simultaneously expressing a normal beta-chain while inhibiting sickling, have shown promise.
Successful expression of the human beta globin gene by retroviral vectors in a mouse model for sickle cell anemia has demonstrated the potential of these approaches. The
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efficiency of gene transfer is still a hurdle, but strategies for in vivo selection may be useful. The safety of these approaches in human subjects has recently been called into question by the development of leukemia in individuals participating in a clinical trial of gene therapy for X-linked severe combined immunodeficiency (XLSCID).
Stem cell transplantation. Stem cell transplantation from a normal donor or one with sickle cell trait can be curative in individuals with sickle cell disease, but the risks and morbidity associated with this procedure have limited its use to a select group of individuals with significant complications who have a matched sibling stem-cell donor [Walters et al 2000]. Among these individuals, more than 90% survive and approximately 85% survive free from sickle cell disease. New developments in stem cell transplantation such as non-myeloablative regimens, better immunosuppression, and alternative sources of stem cells are making stem cell transplantation an option for an increasing number of individuals with sickle cell disease.Because the criteria, risks, and benefits of transplantation are changing rapidly, it is important for families and providers to discuss the risks and benefits with a transplantation center.
Butyric acid. Normally used as a food additive, butyric acid may increase the amount of fetal hemoglobin in the blood.
Clotrimazole. This over-the-counter antifungal medication helps prevent a loss of water from red blood cells, which may reduce the number of sickle cells that form.
Nitric oxide. Sickle cell anemia causes low levels of nitric oxide, a gas that helps keep blood vessels open and reduces the stickiness of red blood cells. Treatment with nitric oxide may prevent sickle cells from clumping together.
Nicosan. This is an herbal treatment in early trials in the U.S. Nicosan has been used to prevent sickle crises in Nigeria.
Agents/Circumstances to Avoid
Education for individuals with SCD involves learning how to control one's environment to minimize the chance of exacerbations. Environmental controls include avoiding the following:
Dehydration Extremes of temperature (e.g., swimming in cold water can trigger a pain episode) Physical exhaustion Extremely high altitude without oxygen supplementation
Meperidine should be avoided as first-line therapy because of potential CNS toxicity.
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Lifestyle and home remedies
Taking steps to stay healthy is critical for anyone with sickle cell anemia. Eating well, getting adequate rest and protecting yourself from infections are good ways to maintain your health and prevent crises.
Infants and children with sickle cell disease need to receive regular childhood vaccinations. Children and adults with sickle cell anemia also should have a yearly flu shot and be immunized against pneumonia.
If a child has sickle cell anemia, follow these suggestions to help stay healthy:
Take folic acid supplements daily, and eat a balanced diet. Bone marrow needs folic acid and other vitamins to make new red blood cells.
Drink plenty of water. Staying hydrated helps keep your blood diluted, which reduces the chance that sickle cells will form.
Avoid temperature extremes. Exposure to extreme heat or cold can trigger the formation of sickle cells. .
Exercise regularly, but don't overdo it. Talk with your doctor about how much exercise is right for you.
Use over-the-counter medications with caution. Some medications, such as the decongestant pseudoephedrine, can constrict your blood vessels and make it harder for the sickle cells to move through freely.
Fly on airplanes with pressurized cabins. Unpressurized aircraft cabins may not provide enough oxygen. Low oxygen levels can trigger a sickle crisis. Additionally, be sure to drink extra water when traveling by air, as pressurized cabins can be dehydrating.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions.
Related Genetic Counseling Issues
It must be kept in mind that non-sickle beta globin disorders (e.g., beta-thalassemia) can interact with a sickle cell disease mutation to cause clinically significant disease. As a result,
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family members with no Hb S can still have a child with a significant sickle hemoglobinopathy. For example, if one parent has sickle cell trait and the other has beta-thalassemia trait, it would be correct to state that although one parent is not a sickle cell carrier, there is still a 25% chance that each pregnancy would have a significant hemoglobinopathy.
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
Early testing. Building community awareness of SCD in populations at high risk is an important component in facilitating early testing.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See DNA Banking for a list of laboratories offering this service.
Coping and support
If someone in family has sickle cell anemia, one may wants help with the stresses of this lifelong disease. Sickle cell centers and clinics can provide information and counseling. Ask a doctor or the staff at a sickle cell center if there are support groups for families in your area. Talking with others who are facing the same challenges you are can be helpful.
It's especially important to find ways to control — and cope with — pain. Different techniques work for different people, but it might be worth trying heating pads, hot baths, massages or physical therapy. Prayer, family and friends also can be sources of support.
If one have a child with sickle cell anemia, one should learn as much as you can about the disease and make sure your child gets the best health care possible. A child with sickle cell disease has special needs and requires regular medical care. Your doctor can explain how often to bring your child for medical care and what you can do if he or she becomes ill.
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Reference:
1. www.wikipedia.org/en/Sickle-cell disease.2. www.mayoclinic.com 3. www.teenshealth.com 4. Vernon M. Ingram, Sickle-Cell Anemia Hemoglobin: The Molecular Biology of the First
"Molecular Disease"—The Crucial Importance of Serendipity, Genetics, Vol. 167, May 2004, Page 1-7.
5. www.genereviews.com 6. www.nhlbi.com 7. www.scienceandtechnology.com
