As a result, affected hemoglobin molecules have a tendency to stick to one another, forming abnormal strands of hemoglobin within the red blood cells. The cells that contain these strands become stiff and elongated—sickle-shaped.
Because sickle cell anemia is characterized by the rapid loss of red blood cells as they enter the circulation, it is classified as a hemolytic anemia, “hemolytic” referring to the destruction of the cell membrane of red blood cells, resulting in the release of hemoglobin.
Description
Sickle-shaped 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.
The damaged tissues and organs cause considerable pain and 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, 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.
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.
The type of genes expressed depends upon the stage of development: embryonic, fetal, or adult. Virtually all of the hemoglobin produced in humans from ages 2-3 months and 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 tiny 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 [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 a single amino acid substitution: valine occupies the spot normally taken by glutamic acid. (Amino acids are the building blocks of all proteins.) This substitution is incorporated into the beta-globin molecule—and eventually returning in 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 occurs 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 of 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 of each of the normal and abnormal betaglobin 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. 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.
The severity of the symptoms cannot be predicted based solely on the person’s 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 betaglobin; 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.
Causes and symptoms
Symptoms typically appear during the first year or two of life. 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 an ongoing deficit of red blood cells in the bloodstream. Common symptoms of anemia include fatigue, paleness, and shortness of breath.
A particularly severe form of anemia—aplastic anemia—occurs following infection with parvovirus. Though temporary, parvovirus infection 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, but given the short lives of sickle cells, even a brief shutdown in red blood cell production can cause a major decline in hemoglobin concentrations. This event is called “aplastic crisis.”
Painful crises
Painful crises, also known as vasoocclusive 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 mechanism other 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, but their 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 and 15 have a 30% risk of suffering a stroke.
Approximately two-thirds of the children who have a stroke will have at least one more; those who survive typically suffer severe learning disabilities. As of 2003, researchers are investigating various techniques for helping children with memory loss related to strokes caused by sickle cell disease.
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, 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 of the kidney is particularly conducive to 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 vessels 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 presence of anemia, and a sickle cell test reveals the presence of the sickle cell trait.
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
In general, treatment of sickle cell anemia relies on conventional medicine. However, alternative therapies may be useful in pain control.
Massage
The daily pain caused by sickle cell disease has been shown to be managed by massage. A pilot study whose results were published in 1999 indicated that those who received massage reported less perception of pain than those who were part of a relaxation control group during the research. Massage is recommended as a complementary treatment in the management of the chronic disease.
Pain diaries
A 2001 study revealed that diaries kept by children and adolescents could help the patients and their families better manage sickle cell pain from home. If children (who are old enough to read and write) can record pain episodes, they have better recall and provide improved documentation for physicians and parents so they can relate pain episodes to possible causes.
Acupuncture
Acupuncture may relieve some of the pain caused by sickle cell disease. For longer-lasting results, acupuncturists indicate that the treatment works with the body’s subtle energies by manipulating the “chi” to remove blockages and allow the body to heal itself.
Acupuncture uses extremely thin needles that are inserted into various areas of the body, with placement depending on the patient’s condition. Each treatment usually takes 20-45 minutes.
Diet
While the pain of sickle cell disease ranges from acute to chronic, simple alterations to the diet are one way to help those who endure the illness. Foods like horseradish, cassava, yams, corn, bamboo shoots, sweet potatoes, and lima beans contain cyanogenic glucosides, or natural plant compounds that are recommended additions to the diet.
These natural plant compounds interact with bacteria in the large intestine and aid the body in producing a type of hemoglobin that can effectively carry oxygen through blood cells—possibly leading to less pain.
Allopathic 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.
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; however, a nine-year follow-up study of 299 adults with frequent painful crises reported in 2003 that taking hydroxyurea was associated with a 40% reduction in mortality.
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.
Gene research
Replacing the gene that produces the defective hemoglobin in sickle cell disease patients with one that makes normal hemoglobin may be a possible treatment due to recent research. According to a 1998 report in Science,researchers studied the blood cells from people who carry the sickle cell gene. By using an enzyme called a ribosome, the study was able to alter sickle cells into normal cells.
The ribosome cut out the mutated instructions in the cells’ genetic pattern and replaced them with the correct instructions. Researchers hope that this gene therapy will allow the cells to make normal hemoglobin— leading to the ultimate treatment for those with sickle cell disease.
In late 2001 genetic scientists reported that they had designed a gene that might lead to a future treatment of sickle cell anemia. Although the gene had not tested in humans, early results showed that the injected gene protected cells from sickling.
As of 2003, experiments in gene therapy for sickle cell disease have been carried out in mice, using lentiviral vectors to transfer the corrective gene into the mouse’s stem cells. This technique, however, has not yet been attempted in human subjects as of late 2003.
Expected results
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, persons with sickle cell anemia are in fairly good health most of the time.
The life expectancy for these individuals has steadily increased over the last 30 years, and many are now surviving past the age of 50. In the United States, the average life expectancy for men with sickle cell anemia is 42 years; for women, it is 48 years.
The most common causes of death are infections, lung disease, the blocking of a blood vessel supplying a vital organ, and kidney failure. Pregnant women with sickle cell disease are particularly vulnerable to infection, most often pneumonia or urinary tract infections.
Prevention
The sickle cell trait is a genetically linked, inherited condition. Inheritance cannot be prevented but 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.
By maintaining a good diet, staying well hydrated with plenty of fluids, exercising regularly, and getting enough sleep those with sickle cell disease may help their bodies remain strong and ward off fatigue and dehydration.
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