Aplastic anemia

Definition

Sickle cell anemia is an inherited blood disorder that arises from a single amino acid substitution in one of the component proteins of hemoglobin. The component protein, or globin, that contains the substitution is defective. Hemoglobin molecules constructed with such proteins have a tendency to stick to one another, forming strands of hemoglobin within the red blood cells. The cells that contain these strands become stiff and elongated--that is, sickle shaped.

Description

Sickle-shaped cells--also called sickle cells--die much more rapidly than normal red blood cells, and the body cannot create replacements fast enough. Anemia develops due to the chronic shortage of red blood cells. Further complications arise because sickle cells do not fit well through small blood vessels, and can become trapped. The trapped sickle cells form blockages that prevent oxygenated blood from reaching associated tissues and organs. Considerable pain results in addition to damage to the tissues and organs. This damage can lead to serious complications, including stroke and an impaired immune system. Sickle cell anemia primarily affects people with African, Mediterranean, Middle Eastern, and Indian ancestry. In the United States, African Americans are particularly affected.

Hemoglobin structure

Normal hemoglobin is composed of a heme molecule and two pairs of proteins called globins. Humans have the genes to create six different types of globins--alpha, beta, gamma, delta, epsilon, and zeta--but do not use all of them at once. Which genes are expressed depends on the stage of development: embryonic, fetal, or adult. Virtually all of the hemoglobin produced in humans from ages 2-3 months onward contains a pair of alpha-globin and beta-globin molecules.

Sickle cell hemoglobin

A change, or mutation, in a gene can alter the formation or function of its product. In the case of sickle cell hemoglobin, the gene that carries the blueprint for beta-globin has a minute alteration that makes it different from the normal gene. This mutation affects a single nucleic acid along the entire DNA strand that makes up the beta-globin gene. (Nucleic acids are the chemicals that make up deoxyribonucleic acid, known more familiarly as DNA.) Specifically, the nucleic acid, adenine, is replaced by a different nucleic acid called thymine.

Because of this seemingly slight mutation, called a point mutation, the finished beta-globin molecule has an amino acid substitution: valine occupies the spot normally taken by glutamic acid. (Amino acids are the building blocks of all proteins.) This substitution creates a beta-globin molecule--and eventually a hemoglobin molecule--that does not function normally.

Normal hemoglobin, referred to as hemoglobin A, transports oxygen from the lungs to tissues throughout the body. In the smallest blood vessels, the hemoglobin exchanges the oxygen for carbon dioxide, which it carries back to the lungs for removal from the body. The defective hemoglobin, designated hemoglobin S, can also transport oxygen. However, once the oxygen is released, hemoglobin S molecules have an abnormal tendency to clump together. Aggregated hemoglobin molecules form strands within red blood cells, which then lose their usual shape and flexibility.

The rate at which hemoglobin S aggregation and cell sickling occur depends on many factors, such as the blood flow rate and the concentration of hemoglobin in the blood cells. If the blood flows at a normal rate, hemoglobin S is reoxygenated in the lungs before it has a chance to aggregate. The concentration of hemoglobin within red blood cells is influenced by an individual's hydration level--that is the amount water contained in the cells. If a person becomes dehydrated, hemoglobin becomes more concentrated in the red blood cells. In this situation, hemoglobin S has a greater tendency to clump together and induce sickle cell formation.

Sickle cell anemia

Genes are inherited in pairs, one copy from each parent. Therefore, each person has two copies of the gene that makes beta-globin. As long as a person inherits one normal beta-globin gene, the body can produce sufficient quantities of normal beta-globin. A person who inherits a copy each of the normal and abnormal beta-globin genes is referred to as a carrier of the sickle cell trait. Generally, carriers do not have symptoms, but their red blood cells contain some hemoglobin S.

A child who inherits the sickle cell trait from both parents--a 25% possibility if both parents are carriers--will develop sickle cell anemia. Sickle cell anemia is characterized by the formation of stiff and elongated red blood cells, called sickle cells. These cells have a decreased life span in comparison to normal red blood cells. Normal red blood cells survive for approximately 120 days in the bloodstream; sickle cells last only 10-12 days. As a result, the bloodstream is chronically short of red blood cells and the affected individual develops anemia.

The sickle cells can create other complications. Due to their shape, they do not fit well through small blood vessels. As an aggravating factor, the outside surfaces of sickle cells may have altered chemical properties that increase the cell's "stickiness." These sticky sickle cells are more likely to adhere to the inside surfaces of small blood vessels, as well as to other blood cells. As a result of the sickle cells' shape and stickiness, blockages occasionally form in small blood vessels. Such blockages prevent oxygenated blood from reaching areas where it is needed, causing extreme pain, as well as organ and tissue damage.

However, the severity of the symptoms cannot be predicted based solely on the genetic inheritance. Some individuals with sickle cell anemia develop health- or life-threatening problems in infancy, but others may have only mild symptoms throughout their lives. For example, genetic factors, such as the continued production of fetal hemoglobin after birth, can modify the course of the disease. Fetal hemoglobin contains gamma-globin in place of beta-globin; if enough of it is produced, the potential interactions between hemoglobin S molecules are reduced.

Affected populations

Worldwide, millions of people carry the sickle cell trait. Individuals whose ancestors lived in sub-Saharan Africa, the Middle East, India, or the Mediterranean region are the most likely to have the trait. The areas of the world associated with the sickle cell trait are also strongly affected by malaria, a disease caused by blood-borne parasites transmitted through mosquito bites. According to a widely accepted theory, the genetic mutation associated with the sickle cell trait occurred thousands of years ago. Coincidentally, this mutation increased the likelihood that carriers would survive malaria outbreaks. Survivors then passed the mutation on to their offspring, and the trait became established throughout areas where malaria was common.

Although modern medicine offers drug therapies for malaria, the sickle cell trait endures. Approximately 2 million Americans are carriers of the sickle cell trait. Individuals who have African ancestry are particularly affected; one in 12 African Americans are carriers. An additional 72,000 Americans have sickle cell anemia, meaning they have inherited the trait from both parents. Among African Americans, approximately one in every 500 babies is diagnosed with sickle cell anemia. Hispanic Americans are also heavily affected; sickle cell anemia occurs in one of every 1,000-1,400 births. Worldwide, it has been estimated that 250,000 children are born each year with sickle cell anemia.

Causes & symptoms

Sickle cell anemia results from an inheritance of the sickle cell trait--that is, a defective beta-globin gene--from each parent. Due to this inheritance, hemoglobin S is produced. This hemoglobin has a tendency to aggregate and form strands, thereby deforming the red blood cells in which it is contained. The deformed, short-lived red blood cells cause effects throughout the body.

Symptoms typically appear during the first year or two of life, if the diagnosis has not been made at or before birth. However, some individuals do not develop symptoms until adulthood and may not be aware that they have the genetic inheritance for sickle cell anemia.

Anemia

Sickle cells have a high turnover rate, and there is a deficit of red blood cells in the bloodstream. Common symptoms of anemia include fatigue, paleness, and a shortness of breath. A particularly severe form of anemia--aplastic anemia--occurs following infection with parvovirus. Parvovirus causes extensive destruction of the bone marrow, bringing production of new red blood cells to a halt. Bone marrow production resumes after 7-10 days; however, given the short lives of sickle cells, even a brief shut-down in red blood cell production can cause a precipitous decline in hemoglobin concentrations. This is called "aplastic crisis."

Painful crises

Painful crises, also known as vaso-occlusive crises, are a primary symptom of sickle cell anemia in children and adults. The pain may be caused by small blood vessel blockages that prevent oxygen from reaching tissues. An alternate explanation, particularly with regard to bone pain, is that blood is shunted away from the bone marrow but through some other mechanism than blockage by sickle cells.

These crises are unpredictable, and can affect any area of the body, although the chest, abdomen, and bones are frequently affected sites. There is some evidence that cold temperatures or infection can trigger a painful crisis, but most crises occur for unknown reasons. The frequency and duration of the pain can vary tremendously. Crises may be separated by more than a year or possibly only by weeks, and they can last from hours to weeks.

The hand-foot syndrome is a particular type of painful crisis, and is often the first sign of sickle cell anemia in an infant. Common symptoms include pain and swelling in the hands and feet, possibly accompanied by a fever. Hand-foot syndrome typically occurs only during the first four years of life, with the greatest incidence at one year.

Enlarged spleen and infections

Sickle cells can impede blood flow through the spleen and cause organ damage. In infants and young children, the spleen is usually enlarged. After repeated incidence of blood vessel blockage, the spleen usually atrophies by late childhood. Damage to the spleen can have a negative impact on the immune system, leaving individuals with sickle cell anemia more vulnerable to infections. Infants and young children are particularly prone to life-threatening infections.

Anemia can also impair the immune system, because stem cells--the precursors of all blood cells--are earmarked for red blood cell production rather than white blood cell production. White blood cells form the cornerstone of the immune system within the bloodstream.

Delayed growth

The energy demands of the bone marrow for red blood cell production compete with the demands of a growing body. Children with sickle cell anemia have delayed growth and reach puberty at a later age than normal. By early adulthood, they catch up on growth and attain normal height; however, weight typically remains below average.

Stroke

Blockage of blood vessels in the brain can have particularly harsh consequences and can be fatal. When areas of the brain are deprived of oxygen, control of the associated functions may be lost. Sometimes this loss is permanent. Common stroke symptoms include weakness or numbness that affects one side of the body, sudden loss of vision, confusion, loss of speech or the ability to understand spoken words, and dizziness. Children between the ages of 1-15 are at the highest risk of suffering a stroke. Approximately two-thirds of the children who have a stroke will have at least one more.

Acute chest syndrome

Acute chest syndrome can occur at any age, and is caused by sickle cells blocking the small blood vessels of the lungs. This blockage is complicated by accompanying problems such as infection and pooling of blood in the lungs. Affected persons experience fever, cough, chest pain, and shortness of breath. Recurrent attacks can lead to permanent lung damage.

Other problems

Males with sickle cell anemia may experience a condition called priapism. (Priapism is characterized by a persistent and painful erection of the penis.) Due to blood vessel blockage by sickle cells, blood is trapped in the tissue of the penis. Damage to this tissue can result in permanent impotence in adults.

Both genders may experience kidney damage. The environment in the kidney is particularly conducive for sickle cell formation; even otherwise asymptomatic carriers may experience some level of kidney damage. Kidney damage is indicated by blood in the urine, incontinence, and enlarged kidneys.

Jaundice and an enlarged liver are also commonly associated with sickle cell anemia. Jaundice, indicated by a yellow tone in the skin and eyes, may occur if bilirubin levels increase. Bilirubin is the final product of hemoglobin degradation, and is typically removed from the bloodstream by the liver. Bilirubin levels often increase with high levels of red blood cell destruction, but jaundice can also be a sign of a poorly functioning liver.

Some individuals with sickle cell anemia may experience vision problems. The blood vessels that feed into the retina--the tissue at the back of the eyeball--may be blocked by sickle cells. New blood vessel can form around the blockages, but these vessels are typically weak or otherwise defective. Bleeding, scarring, and retinal detachment may eventually lead to blindness.

Diagnosis

Sickle cell anemia is suspected based on an individual's ethnic or racial background, and on the symptoms of anemia. A blood count reveals the anemia, and a sickle cell test reveals the presence of the sickle cell trait.

The sickle cell test involves mixing equal amounts of blood and a two percent solution of sodium bisulfite. Under these circumstances, hemoglobin exists in its deoxygenated state. If hemoglobin S is present, the red blood cells are transformed into the characteristic sickle shape. This transformation is observed with a microscope, and quantified by expressing the number of sickle cells per 1,000 cells as a percentage. The sickle cell test confirms that an individual has the sickle cell trait, but it does not provide a definitive diagnosis for sickle cell anemia.

To confirm a diagnosis of the sickle cell trait or sickle cell anemia, another laboratory test called gel electrophoresis is performed. This test uses an electric field applied across a slab of gel-like material to separate protein molecules based on their size, shape, or electrical charge. Although hemoglobin S (sickle) and hemoglobin A (normal) differ by only one amino acid, they can be clearly separated using gel electrophoresis. If both types of hemoglobin are identified, the individual is a carrier of the sickle cell trait; if only hemoglobin S is present, the person most likely has sickle cell anemia.

The gel electrophoresis test is also used as a screening method for identifying the sickle cell trait in newborns. More than 40 states screen newborns in order to identify carriers and individuals who have inherited the trait from both parents.

Treatment

Early identification of sickle cell anemia can prevent many problems. The highest death rates occur during the first year of life due to infection, aplastic anemia, and acute chest syndrome. If anticipated, steps can be taken to avert these crises. With regard to long-term treatment, prevention of complications remains a main goal. Sickle cell anemia cannot be cured--other than through a risky bone marrow transplant--but treatments are available for symptoms.

Pain management

Pain is one of the primary symptoms of sickle cell anemia, and controlling it is an important concern. The methods necessary for pain control are based on individual factors. Some people can gain adequate pain control through over-the-counter oral painkillers (analgesics), local application of heat, and rest. Others need stronger methods, which can include administration of narcotics.

Blood transfusions

Blood transfusions are usually not given on a regular basis but are used to treat painful crises, severe anemia, and other emergencies. In some cases, such as treating spleen enlargement or preventing stroke from recurring, blood transfusions are given as a preventative measure. Regular blood transfusions have the potential to decrease formation of hemoglobin S, and reduce associated symptoms. However, regular blood transfusions introduce a set of complications, primarily iron loading, risk of infection, and sensitization to proteins in the transfused blood.

Drugs

Infants are typically started on a course of penicillin that extends from infancy to age six. This treatment is meant to ward off potentially fatal infections. Infections at any age are treated aggressively with antibiotics. Vaccines for common infections, such as pneumococcal pneumonia, are administered when possible.

Emphasis is being placed on developing drugs that treat sickle cell anemia directly. The most promising of these drugs in the late 1990s is hydroxyurea, a drug that was originally designed for anticancer treatment. Hydroxyurea has been shown to reduce the frequency of painful crises and acute chest syndrome in adults, and to lessen the need for blood transfusions. Hydroxyurea seems to work by inducing a higher production of fetal hemoglobin. The major side effects of the drug include decreased production of platelets, red blood cells, and certain white blood cells. The effects of long-term hydroxyurea treatment are unknown.

Bone marrow transplantation

Bone marrow transplantation has been shown to cure sickle cell anemia in severely affected children. Indications for a bone marrow transplant are stroke, recurrent acute chest syndrome, and chronic unrelieved pain. Bone marrow transplants tend to be the most successful in children; adults have a higher rate of transplant rejection and other complications.

The procedure requires a healthy donor whose marrow proteins match those of the recipient. Typically, siblings have the greatest likelihood of having matched marrow. Given this restriction, fewer than 20% of sickle cell anemia individuals may be candidates. The percentage is reduced when factors such as general health and acceptable risk are considered. The procedure is risky for the recipient. There is approximately a 10% fatality rate associated with bone marrow transplants done for sickle cell anemia treatment. Survivors face potential long-term complications, such as chronic graft versus host disease (an immune-mediated attack by the donor marrow against the recipient's tissues), infertility, and development of some forms of cancer.

Alternative treatment

In general, treatment of sickle cell anemia relies on conventional medicine. However, alternative therapies may be useful in pain control. Relaxation, application of local warmth, and adequate hydration may supplement the conventional therapy. Further, maintaining good health through adequate nutrition, avoiding stresses and infection, and getting proper rest help prevent some complications.

Prognosis

Several factors aside from genetic inheritance determine the prognosis for affected individuals. Therefore, predicting the course of the disorder based solely on genes is not possible. In general, given proper medical care, individuals with sickle cell anemia are in fairly good health most of the time. The life expectancy for these individuals has increased over the last 30 years, and many survive well into their 40s or beyond. In the United States, the average life expectancy for men with sickle cell anemia is 42 years; for women, it is 48 years.

Prevention

The sickle cell trait is a genetically linked, inherited condition. Inheritance cannot be prevented, but it may be predicted. Screening is recommended for individuals in high-risk populations; in the United States, African Americans and Hispanic Americans have the highest risk of being carriers.

Screening at birth offers the opportunity for early intervention; more than 40 states include sickle cell screening as part of the usual battery of blood tests done for newborns. Pregnant women and couples planning to have children may also wish to be screened to determine their carrier status. Carriers have a 50% chance of passing the trait to their offspring. Children born to two carriers have a 25% chance of inheriting the trait from both parents and having sickle cell anemia. Carriers may consider genetic counseling to assess any risks to their offspring. The sickle cell trait can also be identified through prenatal testing; specifically through use of amniotic fluid testing or chorionic villus sampling.

Key Terms

Amino acid

A type of molecule used as a building block for protein construction.

Anemia

A condition in which the level of hemoglobin falls below normal values due to a shortage of mature red blood cells. Common symptoms include pallor, fatigue, and shortness of breath.

Bilirubin

A yellow pigment that is the end result of hemoglobin degradation. Bilirubin is cleared from the blood by action of liver enzymes and excreted from the body.

Bone marrow

A spongy tissue located in the hollow centers of certain bones, such as the skull and hip bones. Bone marrow is the site of blood cell generation.

Bone marrow transplantation

A medical procedure in which normal bone marrow is transferred from a healthy donor to an ailing recipient. An illness that prevents production of normal blood cells--such as sickle cell anemia--may be treated with a bone marrow transplant.

Gel electrophoresis

A laboratory test that separates molecules based on their size, shape, or electrical charge.

Globin

One of the component protein molecules found in hemoglobin. Normal adult hemoglobin has a pair each of alpha-globin and beta-globin molecules.

Heme

The iron-containing molecule in hemoglobin that serves as the site for oxygen binding.

Hemoglobin

The red pigment found within red blood cells that enables them to transport oxygen throughout the body. Hemoglobin is a large molecule composed of five component molecules: a heme molecule and two pairs of globin molecules.

Hemoglobin A

Normal adult hemoglobin which contains a heme molecule, two alpha-globin molecules, and two beta-globin molecules.

Hemoglobin S

Hemoglobin that is produced in association with the sickle cell trait; the beta-globin molecules of hemoglobin S are defective.

Hydroxyurea

A drug that has been shown to induce production of fetal hemoglobin. Fetal hemoglobin has a pair of gamma-globin molecules in place of the typical beta-globins of adult hemoglobin. Higher-than-normal levels of fetal hemoglobin can prevent sickling from occurring.

Iron loading

A side effect of frequent transfusions in which the body accumulates abnormally high levels of iron. Iron deposits can form in organs, particularly the heart, and cause life-threatening damage.

Jaundice

A condition characterized by higher-than-normal levels of bilirubin in the bloodstream and an accompanying yellowing of the skin and eyes.

Mutation

A change in a gene's DNA. Whether a mutation is harmful is determined by the effect on the product for which the gene codes.

Nucleic acid

A type of chemical that is used as a component for building DNA. The nucleic acids found in DNA are adenine, thymine, guanine, and cytosine.

Red blood cell

Hemoglobin-containing blood cells that transport oxygen from the lungs to tissues. In the tissues, the red blood cells exchange their oxygen for carbon dioxide, which is brought back to the lungs to be exhaled.

Screening

Process through which carriers of a trait may be identified within a population.

Sickle cell

A red blood cell that has assumed a elongated shape due to the presence of hemoglobin S.

Sickle cell test

A blood test that identifies and quantifies sickle cells in the bloodstream.

Further Reading

For Your Information

Books

• Beutler, Ernest. "The Sickle Cell Diseases and Related Disorders." In Williams Hematology, edited by Ernest Beutler, et al. 5th ed. New York: McGraw-Hill, 1995.
• Bloom, Miriam. Understanding Sickle Cell Disease. Jackson, MS: University Press of Mississippi, 1995.
• Embury, Stephen H., et al., eds. Sickle Cell Disease: Basic Principles and Clinical Practice. New York: Raven Press, 1994.

  Periodicals

• Davies, Sally C. "Management of Patients with Sickle Cell Disease." British Medical Journal 315 (September 13, 1997): 656.
• Reed, W., and E.P. Vichinsky. "New Considerations in the Treatment of Sickle Cell Disease." Annual Review of Medicine 49 (1998): 461.
• Serjeant, Graham R. "Sickle-Cell Disease." The Lancet 350 (September 6, 1997): 725.

  Organizations

• Sickle Cell Disease Association of America. 200 Corporate Point, Suite 495, Culver City, CA 90230-7633. (310) 216-6363. (800) 421-8453. http://sicklecelldisease.org/.
• Sickle Cell Disease Program, Division of Blood Diseases and Resources. National Heart, Lung, and Blood Institute. II Rockledge Centre, 6701 Rockledge Dr. MSC 7950, Bethesda, MD 20892-7950. (301) 435-0055.

Gale Encyclopedia of Medicine. Gale Research, 1999.