Sickle Cell Anemia Essay Research Paper We

Sickle Cell Anemia Essay, Research Paper We feel that this report looks a lot better single-spaced. A Brief History of Sickle Cell Disease Sickle Cell Disease in African Tradition Sickle cell disease

Sickle Cell Anemia Essay, Research Paper

We feel that this report looks a lot better single-spaced. A Brief History of

Sickle Cell Disease Sickle Cell Disease in African Tradition Sickle cell disease

has been known to the peoples of Africa for hundreds, and perhaps thousands, of

years. In West Africa various ethnic groups gave the condition different names:

Ga tribe: Chwechweechwe Faute tribe: Nwiiwii Ewe tribe: Nuidudui Twi tribe:

Ahotutuo Sickle Cell Disease in the Western Literature Description of Sickle

Cell Disease In the western literature, the first description of sickle cell

disease was by a Chicago physician, James B. Herrick, who noted in 1910 that a

patient of his from the West Indies had an anemia characterized by unusual red

cells that were "sickle shaped". Relationship of Red Cell Sickling to

Oxygen In 1927, Hahn and Gillespie showed that sickling of the red cells was

related to low oxygen. Deoxygenation and Hemoglobin In 1940, Sherman (a medical

student at Johns Hopkins) noted a birefringence of deoxygenated red cells,

suggesting that low oxygen altered the structure of the hemoglobin in the

molecule. Protective Role of Fetal Hemoglobin in Sickle Cell Disease Janet

Watson, a pediatric hematolist in New York, suggested in 1948 that the paucity

of sickle cells in the peripheral blood of newborns was due to the presence of

fetal hemoglobin in the red cells, which consequently did not have the abnormal

sickle hemoglobin seen in adults. Abnormal Hemoglobin in Sickle Cell Disease

Using the new technique of protein electrophoresis, Linus Pauling and colleagues

showed in 1949 that the hemoglobin from patients with sickle cell disease is

different than that of normals. This made sickle cell disease the first disorder

in which an abnormality in a protein was known to be at fault. Amino Acid

Substitution in Sickle Hemoglobin In 1956, Vernon Ingram, then at the MRC in

England, and J.A. Hunt sequenced sickle hemoglobin and showed that a glutamic

acid at position 6 was replaced by a valine in sickle cell disease. Using the

known information about amino acids and the codons that coded for them, he was

able to predict the mutation in sickle cell disease. This made sickle cell

disease the first known genetic disorder. Preventive Treatment for Sickle Cell

Disease Hydroxyurea became the first (and only) drug proven to prevent

complications of sickle cell disease in the Multicenter Study of Hydroxyurea in

Sickle Cell Anemia, which was completed in 1995. How Does Sickle Cell Cause

Disease? The Mutation in Hemoglobin Sickle cell disease is a blood condition

primarily affecting people of African ancestry. The disorder is caused by a

single change in the amino acid building blocks of the oxygen-transport protein,

hemoglobin. This protein, which is the component that makes red cells

"red", has two subunits. The alpha subunit is normal in people with

sickle cell disease. The ?-subunit has the amino acid valine at position 6

instead of the glutamic acid that is there normally. 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 ?-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. 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 ?-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 infrequently. Therefore, the inheritance of sickle

cell disease depends totally on the genes of the parents. If only one of the ?-globin

genes is the "sickle" gene and the other is normal, the person is a

carrier. The condition is called sickle cell trait. With a few rare exceptions,

people with sickle cell trait are completely normal. If both ?-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. The hemoglobin molecule (made of alpha and ?-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. 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 polymers distort the cell and cause it to bend out of shape. 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

"Ping-Pong" alteration in the state of the molecules damages the

hemoglobin and ultimately the red cell itself. 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 a braid. These bundles

self-associate into even larger structures that stretch and distort the cell. An

analogy would be a water ballon that formed ice sickles that extended and

stretched the ballon. The stretching of the rubber of the ballon is similar to

what happens to the membrane of the red cell. Despite their imposing appearance,

the forces that hold these sickle hemoglobin polymers together are very weak.

The abnormal valine amino acid at position 6 in the ?-globin chain interacts

weakly with the ? 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. On the other hand, 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 hemoglobin S molecules. All

people have fetal hemoglobin in their circulation before birth. Fetal hemoglobin

protects the unborn 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

patients. The Sickle Red Cell The schematic diagram 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 move through

the microcirculation (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 microcirculation, 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. The damage to red cell membranes plays an important role in the

development of complications in 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 oxygen radicals. These

molecules damage both the lipid and protein components of the red cell membrane.

As a consequence, the membranes become stiff. Also, the damaged proteins tend to

clump together to form abnormal clusters in the red cell membrane. Antibodies

develop to these protein clusters, leading to even more red cell destruction (hemolysis).

Red cell destruction or hemolysis causes the anemia in sickle cell disease. 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 expanded in-patients with sickle cell disease relative to nomal

in response to demands for higher 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 ?-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. How Do

People Get Sickle Cell Disease? Sickle cell disease is an inherited condition.

The genes received from one’s parents before birth determine whether a person

will have sickle cell disease. Sickle cell disease cannot be caught or passed on

to another person. The severity of sickle cell disease varies tremendously. Some

people with sickle cell disease lead lives that are nearly normal. Others are

less fortunate, and can suffer from a variety of complications. How Are Genes

Inherited? At the time of conception, a person receives one set of genes from

the mother (egg) and a corresponding set of genes from the father (sperm). The

combined effects of many genes determine some traits (hair color and height, for

instance). One gene pair determines other characteristics. Sickle cell disease

is a condition that is determined by a single pair of genes (one from each

parent). Inheritance of Sickle Cell Disease The genes are those which control

the production of a protein in red cells called hemoglobin. Hemoglobin binds

oxygen in the lungs and delivers it to the peripheral tissues, such as the

liver. Most people have two normal genes for hemoglobin. Some people carry one

normal gene and one gene for sickle hemoglobin. This is called "sickle cell

trait". These people are normal in almost all respects. Problems from the

single sickle cell gene develop only under very unusual conditions. People who

inherit two genes for sickle hemoglobin (one from each parent) have sickle cell

disease. With a few exceptions, a child can inherit sickle cell disease only if

both parents have one gene for sickle cell hemoglobin. The most common situation

in which this occurs is when each parent has one sickle cell gene. In other

words, each parent has sickle cell trait. Figure 1 shows the possible

combination of genes that can occur for parents each of whom has sickle cell

trait. Figure 1. (ABOVE) Inheritance of sickle genes from parents with sickle

cell trait. As shown in the graphic, the couple has one chance in four that the

child will be normal, one chance in four that the child will have sickle cell

disease, and one chance in two that the child will have sickle cell trait. A

one-in-four chance exists that a child will inherit two normal genes from the

parents. A one-in-four chance also exists that a child will inherit two sickle

cell genes, and have sickle cell disease. A one-in-two chance exists that the

child will inherit a normal gene from one parent and a sickle gene from the

other. This would produce sickle trait. These probabilities exist for each child

independently of what happened with prior children the couple may have had. In

other words, each new child has a one-in-four chance of having sickle cell

disease. A couple with sickle cell trait can have eight children, none of whom

have two sickle genes. Another couple with sickle trait can have two children

each with sickle cell disease. The inheritance of sickle cell genes is purely a

matter of chance and cannot be altered. Do Factors Other Than Genes Influence

Sickle Cell Disease? Sickle cell disease is quite variable in itself. Other

blood conditions can influence sickle cell disease, however. One of the most

important is thalassemia. One form of thalassemia, called ?-thalassemia,

reduces the production of normal hemoglobin. A person with one normal hemoglobin

gene and one thalassemia gene has thalassemia trait (also called thalassemia

minor). Parents who have sickle cell trait and thalassemia trait have one chance

in four of having a child with one gene for sickle cell disease and one gene for

?-thalassemia (Figure 2). This condition is sickle ?-thalassemia. The severity

varies. Some patients with sickle ?-thalassemia have a condition as severe as

sickle cell disease itself. People of Mediterranean origin who have a sickle

condition most often have sickle ?-thalassemia. Figure 2. (BELOW ON LAST PAGE)

Inheritance of hemoglobin genes from parents with sickle cell trait and

thalassemia trait. As illustrated, the couple has one chance in four that the

child will have the genes both for sickle hemoglobin and for thalassemia. The

child would have sickle ?-thalassemia. The severity of this condition is quite

variable. The nature of the thalassemia gene (?o or ?+) greatly influences the

clinical course of the disorder. Another disorder that interacts with sickle

cell disease is "hemoglobin SC disease". The abnormal hemoglobin C

gene is relatively harmless. Even people with two hemoglobin C genes have a

relatively mild clinical condition. When hemoglobin C combines with hemoglobin

S, the result is "hemoglobin SC disease". On average, hemoglobin SC

disease is milder than sickle cell disease. However, some patients with

hemoglobin SC disease have a clinical condition as severe as any with sickle

cell disease. The reason for the marked variability in the clinical course of

hemoglobin SC disease is unknown. We do know that the tendency of hemoglobin C

to produce red cell dehydration is a major reason that the combination of

hemoglobins S and C is so problematic. Figure 3. (ABOVE) Inheritance of

hemoglobin genes from parents with sickle cell trait and hemoglobin C trait. As

illustrated, the couple has one chance in four that the child will have the

genes both for sickle hemoglobin and for hemoglobin C. The child would have

hemoglobin SC disease. Most patients with hemoglobin SC disease have a milder

condition than occurs with sickle cell disease (two sickle genes).

Unfortunately, some patients run a clinical course that is undistinguishable

from sickle cell disease. Are There Tests That Can Tell Me Whether I Have Sickle

Cell Trait? The answer is yes. Routine "blood counts" commonly

performed in doctors’ offices do not give hints about the presence of sickle

cell trait. The blood counts of most people with sickle cell trait are normal.

Only a special test, called a "hemoglobin electrophoresis" indicates

reliably whether a person has sickle trait. In addition, the hemoglobin

electrophoresis will detect hemoglobin C and ?-thalassemia. How Can I Be Tested

for Sickle Cell Trait? Most large hospitals and clinics can perform routine

hemoglobin electrophoresis. Smaller laboratories send the test to commercial

firms for testing. If you are concerned about the possibility of having sickle

cell trait, you should speak with your doctor. Overview Everyone with sickle

cell disease shares the same gene mutation. A thymine replaces an adenine in the

DNA encoding the ?-globin gene. Consequently, the amino acid valine replaces

glutamic acid at the sixth position in the ?-globin protein product. The change

produces a phenotypically recessive characteristic. Most commonly sickle cell

disease reflects the inheritance of two mutant alleles, one from each parent.

The final product of this mutation, hemoglobin S is a protein whose quaternary

structure is a tetramer made up of two normal alpha-polypeptide chains and two

aberrant ?s-polypeptide chains. The primary pathological process leading

ultimately to sickle shaped red blood cells involves this molecule. After

deoxygenation of hemoglobin S molecules, long helical polymers of HbS form

through hydrophobic interactions between the ?s-6 valine of one tetramer and

the ?-85 phenylalanine and ?-88 leucine of an adjacent tetramer. Deformed,

sickled red cells can occlude the microvascular circulation, producing vascular

damage, organ infarcts, painful crises and other such symptoms associated with

sickle cell disease. Although everyone with sickle cell disease shares a

specific, invariant genotypic mutation, the clinical variability in the pattern

and severity of disease manifestations is astounding. In other genetic disorders

such as cystic fibrosis, phenotypic variability between patients can be traced

genotypic variability. Such is not the case, however, with sickle cell disease.

Physicians and researchers have sought explanations of the variability

associated with the clinical expression of this disease. The most likely causes

of this inconstancy are disease-modifying factors. I have reviewed the role of

some of these factors, and tried to ascertain the clinical importance of each.

Fetal Hemoglobin Augmented post-natal expression of fetal hemoglobin is perhaps

the most widely recognized modulator of sickle cell disease severity. Fetal

hemoglobin, as its name implies is the primary hemoglobin present in the fetus

from mid to late gestation. The protein is composed of two alpha-subunits and

two gamma-subunits. The gamma-subunit is a protein product of the ?-gene

cluster. Duplicate genes duplicate upstream of the ?-globin gene encodes fetal

globin. Fetal hemoglobin binds oxygen more tightly than does adult hemoglobin A.

The characteristic allows the developing fetus to extract oxygen from the

mother’s blood supply. After birth, this trait is no longer necessary and the

production of the gamma-subunit decreases as the production of the ?-globin

subunit increases. The ?-globin subunit replaces the gamma-globin subunit in

the hemoglobin tetramer so that eventually adult hemoglobin replaces fetal

hemoglobin as the primary component red cells. HbF levels stabilize during the

first year of life, at less than 1% of the total hemoglobin. In cases of

hereditary persistence of fetal hemoglobin, that percentage is much higher. This

persistence substantially ameliorates sickle cell disease severity. Mechanism of

Protection Two properties of fetal hemoglobin help moderate the severity of

sickle cell disease. First, HbF molecules do not participate in the

polymerization that occurs between molecules of deoxyHbS. The gamma-chain lacks

the valine at the sixth residue to interact hydrophobically with HbS molecules.

HbF has other sequence differences from HbS that impede polymerization of

deoxyHbS. Second, higher concentrations of HbF in a cell infer lower

concentrations of HbS. Polymer formation depends exponentially on the

concentration of deoxyHbS. Each of these effects reduces the number of

irreversibly sickle cells (ISC). Hemoglobin F Levels and Amelioration of Sickle

Cell Disease The level of HbF needed to benefit people with sickle cell disease

is a key question to which different studies supply varying answers. Bailey

examined the correlation between early manifestation of sickle cell disease and

fetal hemoglobin level in Jamaicans. They concluded that moderate to high levels

of fetal hemoglobin (5.4-9.7% to 39.8%) reduced the risk for early onset of

dactylics, painful crises, acute chest syndrome, and acute splenic

sequestration. Platt examined predictive factors for life expectancy and risk

factors for early death (among Black Americans). In their study, a high level of

fetal hemoglobin (*8.6%) augured improved survival. Koshy et al. reported that

fetal hemoglobin levels above 10% were associated with fewer chronic leg ulcers

in American children with sickle cell disease. Other studies, however, suggest

that protection from the ravages of sickle cell disease occur only with higher

levels of HbF. In a comparison of data from Saudi Arabs and information from

Jamaicans and Black Americans, Perrine et al. found that serious complications

occurred only 6% to 25% as frequently in Saudi Arabs as North American Blacks.

In addition mortality under the age of 15 was 10% as great among Saudi Arabs.

Further, these patients experienced no leg ulcers, reticulocyte counts were

lower and hemoglobin levels were higher on average. The average a fetal

hemoglobin level in the Saudi patients ranged between 22-26.8%. This is more

than twice that reported in studies mentioned above. Kar et al. compared

patients from Orissa State, India to Jamaican patients with sickle cell. These

patients also had a more benign course when compared with Jamaican patients. The

reported protective level of fetal hemoglobin in this study was on average

16.64%, with a range of 4.6% to 31.5%. Interestingly, ?-globin locus haplotype

analysis shows that the Saudi HbS gene and that in India have a common origin

(see below). These studies suggest that the level of fetal hemoglobin that

protects against the complications of sickle cell disease depend strongly on the

population group in question. Among North American blacks, fetal hemoglobin

levels in the 10% range ameliorate disease severity. The higher average level of

fetal hemoglobin could contribute to the generally less severe disease in

Indians and Arabs. Another study that suggests only a small role at best for

fetal hemoglobin as a modifier of sickle cell disease severity was reported by

El-Hazmi. The subjects were Saudi Arabs in whom a variety of symptoms associated

with sickle cell disease were assessed to form a "severity" index. The

author concluded that among his patients, no correlation existed between HbF and

the severity index. However, his analysis has a fundamental flaw. El-Hazmi

failed to examine the effect of HbF on each of these symptoms individually.

Their important information and an association between fetal hemoglobin levels

specific disease manifestations could be concealed in his data. However, the

study reinforces the conclusion that fetal hemoglobin levels most likely work in

conjunction with other moderating factors to determine clinical severity

in-patients with sickle cell disease. Alpha-Thalassemia Concurrent alpha-thalassemia

has also been examined as a modifier of sickle cell disease severity. Alpha-thalassemia,

like sickle cell disease, is a genetically inherited condition. The loss of one

or more of the four genes encoding the alpha globin chain (two each on

chromosome 16) produces alpha-thalassemia. A gene deletion most commonly is at

fault. The deletion results from unequal crossover between adjacent alpha-globin

genes during the prophase I of meiosis I. Such a crossover leaves one gamete

with one alpha-gene and the other gamete with three alpha genes. Upon

fertilization the zygote can have 2, 3, 4, or 5 alpha genes depending on the

make up of the other parental gamete. In people of African descent, the most

common haploid gamete of this type is alpha-thal-2 in which there is one

deletion on each of the number 16 chromosomes in the patient. Heterozygotes for

this allele, therefore, have three alpha genes (one alpha gene on one of the

number 16 chromosomes, two alpha genes on the other). Embury et al. (1984)

examined the effect of concurrent alpha-thalassemia and sickle cell disease.

Based on prior studies, they proposed that alpha-thalassemia reduces

intraerythrocyte HbS concentration, with a consequent reduction in

polymerization of deoxyHbS and hemolysis. They investigated the effect of alpha

gene number on properties of sickle erythrocytes important to the hemolytic and

rheological consequences of sickle cell disease. Specifically they looked for

correlations between the alpha gene number and irreversibly sickled cells, the

fraction of red cells with a high hemoglobin concentration (dense cells), and

red cells with reduced deformabilty. The investigators found a direct

correlation between the number of alpha-globin genes and each of these indices.

A primary effect of alpha-thalassemia was reduction in the fraction of red blood

cells that attained a high hemoglobin concentration. These dense cells result

from potassium loss due to acquired membrane leaks. The overall deformability of

dense RBCs is substantially lower than normal. This property of alpha-thalassemia

was confirmed by comparison of red cells in people with or without 2-gene

deletion alpha-thalassemia (and no sickle cell genes). The cells in the

nonthalassemic individuals were denser than those from people with 2-gene

deletion alpha-thalassemia. The difference in median red cell density produced

by alpha-thalassemia was much greater in-patients sickle cell disease. Reduction

in overall hemoglobin concentration due to absent alpha genes is not the only

mechanism by which alpha-thalassemia reduces the formation of dense and

irreversibly sickled cells. In reviewing the available literature, Embry and

Steinburg suggested that alpha-thalassemia moderate’s red cell damage by

increasing cell membrane redundancy. This protects against sickling-induced

stretching of the cell membrane. Potassium leakage and cell dehydration would be

minimized. These two papers by Embury et al. give some insight into the

moderation of sickle cell disease severity by alpha thalassemia. Some

deficiencies exist, nonetheless. The first paper makes no mention of the patient

pool. Unspecified are the number of patients used, their ethnicity, or their

state of health when blood samples were taken. This information would help

establish the statistical reliability of the data, and its applicability across

patient groups. Despite these limitation, the work provides important insight

into the mechanisms by which alpha-thalassemia ameliorates sickle cell disease

severity. Ballas et al reached different conclusions regarding alpha thalassemia

and sickle cell disease than did Embury et al . They reported that decreased red

blood cell deformability was associated with reduced clinical severity of sickle

cell disease. Patients with more highly deformabile red cells had more frequent

crises. They also found that fewer dense cells and irreversible sickle cells

correlated inversely with the severity of painful crises. Like Embury et al.,

Ballas and colleagues found alpha thalassemia was associated with fewer dense

red cells. In addition, Ballas’ group found that alpha thalassemia was

associated with less severe hemolysis. However they reached no clear conclusion

concerning alpha gene number and deformability of RBC except to note that the

alpha thalassemia was associated with less red cell dehydration. The two studies

are not completely at odds. Both state that concurrent alpha-thalassemia reduces

hemolytic anemia. They agree that this occurs through reduction in the number of

dense cells, a number directly related to the fraction of irreversibly sickled

cells. Embury et al. concludes that through this mechanism red blood cell

deformability is increased. The investigators diverge, however, on the

relationship to clinical severity of dense cells and rigid cells. Ballas et al.

asserts that both the reduction of dense cells and rigid cells contribute to

disease severity.