SICKLE CELL DISEASE

The sickle cell diseases are a group of disorders that have in common the propensity of the red blood cells to become deformed when oxygen tension in the blood is lowered, causing anemia, occlusion of blood vessels by misshapen cells, and various associated clinical consequences, including death. In sickle cell disease, a mutation of the beta-globin gene results in the substitution of valine for glutamic acid in the sixth amino acid of the chain, producing a hemoglobin, designated hemoglobin S, that has less solubility than does normal hemoglobin A. Inheriting one gene for hemoglobin S, together with a normal gene, results in the formation of red cells that contain approximately 40 percent of the abnormal hemoglobin and 60 percent of the normal hemoglobin, an essentially harmless state that is designated as sickle cell trait. But if the gene inherited together with the sickle gene is not normal, then the sickle cell disease may develop. The most common hemoglobin that interacts with sickle hemoglobin is hemoglobin C, and the ß-thalassemia (beta-thalassemia) mutation also interacts with the sickle gene by restricting the formation of normal hemoglobin.

The sickle gene, and genes that interact with it, are common in a number of different populations, but the highest gene frequencies are observed in Africa. The gene is also found in southern Europe, the Middle East, and India. A single dose of the sickle gene provides protection against malaria. Since malaria was a major cause of death in Africa, persons who carried the sickle gene had a survival advantage over those who did not. Thus, the number of persons carrying this mutation has tended to increase generation after generation in areas where malaria was a major killer. Among African Americans, approximately 7.8 percent are carriers of the sickle mutation, that is, they have sickle cell trait; while 2.3 percent have hemoglobin C trait (one copy of the hemoglobin C gene); and0.8 percent have ß-thalassemia trait.

Although a single copy of the hemoglobin S gene is quite harmless, if a person inherits two copies of the hemoglobin S genes, he or she will have sickle cell disease. If one hemoglobin S gene and one hemoglobin C gene are inherited, the patient has hemoglobin S-C disease. Coinheritance of the beta-thalassemia and sickle hemoglobin result in sickle cell thalassemia. Patients with these three disorders have a similar clinical disease. Anemia occurs as a result of the rapid destruction of red blood cells. The red cells may have the shape of sickles, hence the term "sickle cell disease." However, the cells may assume may other forms. The misshapen red cells occlude blood vessels and cause pain and even tissue death.

In small children, one of the great problems incident to sickle cell disease is infections. If these are treated promptly, most children with sickle cell disease survive into adult life. One of the most characteristic manifestations of the disease in adults and older children is "pain crises." These occur at regular intervals, often at a time of stress, and may cause frequent hospitalizations and varying degrees of dependence upon pain-killing drugs. As patients with the sickle cell disease grow older they begin to suffer from the results of accumulated damage in small blood vessels all through the body. Dysfunction of the lungs, kidneys, and heart are common. Strokes may occur. Interruption of the blood supply to bones may result in areas of bone death, particularly in the hips.

Although sickle cell disease is a disorder that has been better understood and studied in more detail than most other disorders, treatment is still very unsatisfactory. Prenatal diagnosis can be carried out quite easily and very reliably, and parents are provided with the option of terminating the pregnancy. Antibiotics and immunization programs have drastically reduced the mortality rate among young children. Transfusion of red blood cells improves the flow properties of blood and may ameliorate the symptoms. Hydroxyurea has been administered to increase the amount of fetal hemoglobin, a hemoglobin that does not interact with sickle hemoglobin. This treatment has met with some success.

The disease is cured by bone marrow transplantation, a procedure with a relatively high risk, even in those patients in whom a match can be found. Ultimately the disease may be treated by putting a normal beta-globin gene into a stem cell of the patient, and then transplanting that patient with his or her own transduced cells, but there are many barriers to implementing such a strategy. Because stem cells do not divide often, they are relatively resistant to many gene-transfer methods. It is not enough to put a normal globin gene in the cell; the abnormal globin gene needs to be inactivated. There is also a tendency for normal human cells to shut off the function of foreign genes that are implanted in them. It is likely that these technical obstacles to gene therapy will be overcome eventually, and that the treatment of this group of diseases will give better results in the future.

Ernest Beutler

(see also: Genes; Genetic Disorders; Hemoglobin; Hemoglobinopathies; Malaria; Medical Genetics )

sickle cell disease or sickle cell anemia, inherited disorder of the blood in which the oxygen-carrying hemoglobin pigment in erythrocytes (red blood cells) is abnormal. This "hemoglobin-S" crystallizes in small capillaries, where the concentration of oxygen in the blood is low (but sufficient for normal hemoglobin), causing the red blood cells to assume distorted, sicklelike shapes. Linus Pauling discovered the chemical abnormality of the hemoglobin molecule that causes the erythrocyte sickling in 1949.

The sickled red blood cells tend to clog small blood vessels, depriving the tissues they serve of blood and oxygen. Painful "crises" result, with symptoms depending on the site affected (e.g., joint and abdominal pain or kidney damage). Strokes or seizures can occur if the brain is affected. Lung infections resulting from the patient's disinclination to take painful deep breaths are a frequent complication. In addition, the sickled erythrocytes are fragile and subject to rupture and destruction, leading to hemolytic anemia (reduction of oxygen-carrying hemoglobin caused by premature destruction of red blood cells) and such symptoms as fatigue, jaundice, and headaches.

Treatment

There is no cure for the disease, but advancements in treatment have improved median survival to 42 years for men and 48 years for women. Cerebral hemorrhage or shock is the usual cause of mortality in children. Recent studies have indicated that regular blood transfusions can prevent strokes in children. Anemia is treated with folic acid. Sickle cell crises may be treated with intravenous hydration, pain medication, antibiotics, oxygen, and transfusions. Hydroxyurea, formerly used as a cancer treatment, has been helpful to many adults with the disease, lessening the frequency and severity of crises. New drugs for reducing the severity of crises are being tested as well. One acts as a lubricant, allowing sickled cells to flow more easily through tiny vessels. The other helps to prevent tissue deprived of blood from dying during a crisis.

Incidence

The disease is confined mainly to blacks, especially those of W African descent, but it also occurs in persons of Mediterranean, Middle Eastern, and Indian origin. The mutation may at one time have had an advantageous effect; those afflicted with the abnormality have a higher survival rate in malaria-infested zones.

Under normal circumstances the disease occurs only in those patients who inherit the gene for the abnormal hemoglobin from both parents. This so-called homozygous form of the disease occurs in 1 in 400 African Americans. About 8% of African Americans have sickle cell trait; that is, they are heterozygotes, usually symptomless carriers who have inherited a normal hemoglobin gene from one parent and hemoglobin-S from the other. There are also intermediate forms of the disease that result when a gene for hemoglobin-S is inherited from one parent and a gene for any of several other abnormal kinds of hemoglobin is inherited from the other. Genetic screening is recommended for prospective parents at risk of passing on the disease. If both parents are carriers (i.e., have sickle cell trait), then each child has a one in four chance of having sickle cell disease.

Sickle Cell Anemia. A genetically transmitted blood disease most commonly found in persons of African‐American ancestry. In late‐twentieth‐century America an estimated 72,000 persons had sickle cell disease and approximately 8 percent of the African‐American population carried the sickle cell genetic trait.

In 1910 James B. Herrick published an article describing a twenty‐year‐old Grenadian dental student in Chicago with “sickle‐shaped and crescent‐shaped” red blood cells. This was the first fully documented description of sickle cell anemia (SCA). The condition, which had existed for centuries in Africa and the southern Mediterranean, had been transported by black slaves to North and South America. Sickle cell genes were thus present among blacks in early America, where white planters and physicians noted that blacks often appeared immune to malaria. Racial theories regarding medical differences between whites and blacks arose around such observations and became incorporated into the pro‐slavery arguments of antebellum America. (Today it is known that people carrying at least one sickle cell gene are resistant to the most virulent form of malarial parasite.)

Other case reports followed Herrick's, and by the mid‐ to late 1920s medical investigators were identifying SCA as a genetic disease usually seen in blacks. In 1933 L.W. Diggs of Memphis demonstrated the existence of both the asymptomatic sickle‐cell trait and the actual disease SCA. In 1949, when Linus Pauling revealed that SCA was caused by an alteration in the usual structure of the hemoglobin molecule, a new era in SCA research and molecular biology began.

Until the civil rights movement of the 1960s and 1970s, neither physicians nor community health leaders paid much attention to SCA, although SCA was occasionally used as a reason for segregating blood supplies or as a test for racial “whiteness.” Government funding for testing and research remained low. When public‐health officials attempted to institute genetic screening for sickle cell carriers, some African‐Americans suspected their motives.

By the end of the twentieth century, sickle cell anemia was the subject of extensive research. Treatment included pain control; regular blood transfusion; and, in rare instances, bone‐marrow transplant. To facilitate early identification and treatment, a number of states required sickle cell screening of all newborns. Through government pamphlets, the Internet, and other means, much information was available to persons with the disease or the genetic trait. The Georgia Comprehensive Sickle Cell Center at Grady Health Systems in Atlanta was a major research and information center.
See also Disease; Medicine: From the 1870s to 1945; Medicine: Since 1945; Public Health; Race, Concept of.

Bibliography

Todd L. Savitt , The Invisible Malady: Sickle Cell Anemia in America, 1910–1970, Journal of the National Medical Association 73 (1981), 739–746.
Keith Wailoo , Drawing Blood: Technology and Disease Identity in Twentieth‐Century America, 1997.

Todd L. Savitt

SICKLE CELL ANEMIA

DEFINITION

Sickle cell anemia is an inherited blood disorder in which the body produces c-shaped red blood cells. Because of their shape, these cells may stick to each other or to the sides of blood vessels, and cause serious health disorders.

DESCRIPTION

Blood is made up of many kinds of cells, including red blood cells (RBCs). An important function of RBCs is to carry oxygen from the lungs to cells throughout the body. Red blood cells contain a molecule known as hemoglobin (pronounced HEE-muh-GLOW-bihn) that collects oxygen from the lungs then releases it when the RBC reaches other cells in the body.

Normally, red blood cells have a plump doughnut shape. In some cases, however, a person's body makes red blood cells that are curved with sharp points at the end. They are called sickle cells because they look like a sickle (a long farm tool with a curved blade that is used to cut grain).

Hemoglobin Genes

Sickle cell anemia is caused by defective genes. Genes are chemical units found in all cells that tell cells what functions to perform. For example, RBCs contain genes that tell the cell how to make hemoglobin molecules.

When a gene becomes damaged, the message it carries to the cell is incorrect. A damaged gene for hemoglobin tells the cell to make the wrong kind of hemoglobin. This defective hemoglobin creates a sickle shaped RBC rather than the correct doughnut-shaped RBC.

Sickle Cell Anemia: Words to Know

Anemia:

A condition caused by a decrease in the number of red blood cells in the blood, characterized by fatigue, pale color of the skin, and shortness of breath.

Antibiotic:

A substance derived from bacteria or other organisms that fights the growth of other bacteria or organisms.

Bone marrow:

A spongy tissue in the center of bones where blood cells are produced.

Bone marrow transplantation:

A process by which marrow is removed from the bones of a healthy donor and transferred to the bones of a person's with some kind of blood disorder.

Gel electrophoresis:

A laboratory test that separates different types of molecules from each other.

Hemoglobin:

A molecule found in blood that gives blood its red color. Hemoglobin is responsible for transporting oxygen through the blood stream.

Hydroxyurea:

An experimental drug being tested for use with sickle cell anemia patients.

Red blood cell (RBC):

Blood cells that transport oxygen and carbon dioxide through the blood stream.

Sickle cell:

A red blood cell with an abnormal shape due to the presence of an abnormal form of hemoglobin.

Genes are passed from both parents to their children. A person who receives a damaged hemoglobin gene from just one parent will not get sickle cell anemia. People who have only one defective hemoglobin gene are called carriers. Being a carrier of this particular defective gene may actually increase a person's resistance to malaria (see malaria entry), a dangerous infectious disease. However, if a person receives a defective hemoglobin gene from both parents, he or she will develop sickle cell anemia.

Problems Associated with Sickle Cell Anemia

The presence of sickle cells in the blood can cause many health problems. For instance, sickle cells die more rapidly than normal cells. When this happens, the body often cannot produce new blood cells fast enough to replace the dying ones. Such a loss of RBCs can lead to anemia (pronounced uh-NEE-mee-uh; see anemia entry). Anemia is a disorder caused by an insufficient number of red blood cells.

Sickle cells can also cause health problems because of they tend to stick to each other and to the sides of blood vessels. As they clump or build up they can eventually block the flow of blood through a blood vessel. This blockage limits the flow of blood to cells, keeping them from getting the oxygen they need, and can eventually cause the cells to die.

Blockage can also lead to a stroke. If the clump of cells blocking a vessel breaks loose it may travel to the brain. If the clump blocks blood flow

to the brain it can cause damage to the brain known as a stroke (see stroke entry).

Sickle cell anemia occurs primarily among people with African, Mediterranean, Middle Eastern, and Indian ancestry. Worldwide, about 250,000 children are born each year with sickle cell anemia. About two million Americans are thought to have at least one damaged hemoglobin gene. Approximately 72,000 Americans have two damaged hemoglobin genes and therefore have sickle cell anemia.

In the United States, the condition is most common among African Americans. About 1 in 12 African Americans is a carrier for sickle cell anemia. Hispanic Americans are also heavily affected. About 1 in every 1,000 to 1,400 Hispanic American babies are born with sickle cell anemia.

CAUSES

Sickle cell anemia is caused when a person receives a defective hemoglobin gene from both parents, causing the body to make abnormal red blood cells, which may clump and tend not to live as long as normal red blood cells. A person with sickle cell anemia may become anemic or develop other health problems.

SYMPTOMS

The symptoms of sickle cell anemia usually appear during the first year or two of life. However, some individuals do not develop symptoms until they become adults, and may not be aware for many years that they have the disorder. Some typical symptoms of sickle cell anemia include:

• Anemia. Anemia is caused by an inadequate number of red blood cells. It can result in fatigue, paleness, shortness of breath, headache, mild fever, and general ill health.
• Painful crises. Pain can strike the patient in any part of the body without notice. These attacks can occur as rarely as once a year or as often as every few weeks. They can also last for a variable period of time, from a few hours to a few weeks. Pain in the hands and feet are sometimes the earliest symptoms of sickle cell anemia in a child.
• Enlarged spleen and infections. Sickle-cell blockages can affect any of the body's organs. The organs do not receive the oxygen they need to grow normally. The spleen is especially at risk and may become enlarged or it may die completely. This can weaken the immune system and increase the chance that a patient will develop infections.
• Delayed growth. Children with sickle cell anemia usually do not grow as fast as other children. They may also reach puberty (sexual maturity) at a later age.
• Stroke. Blockages of blood vessels in the brain are especially dangerous. The brain may not get the oxygen it needs to function normally. When blockages occur, a person may become numb on one side of the body, may lose vision or the ability to speak, and may experience dizziness. Children between the ages of one and fifteen are at the highest risk for having a stroke due to sickle cell anemia.
• Acute chest syndrome. Acute chest syndrome is caused by blockage of blood vessels in the lungs. Symptoms of the condition include fever, cough, chest pain, and shortness of breath. The condition can reoccur many times and may cause permanent lung damage.

Other problems caused by blood vessel blockage include kidney damage, enlarged liver, vision problems, and priapism (a condition in which a man experiences repeated and painful erections of the penis not related to sexual arousal; pronounced PREE-uh-piz-um).

DIAGNOSIS

Anemia is easily diagnosed from its symptoms. Once a patient is diagnosed with anemia, a doctor will then try to trace the cause of the disorder. If the person is of African American or other high-risk heritage, sickle cell anemia may be suspected. This diagnosis can be confirmed by at least two laboratory tests. In the first test, a sample of the patient's blood is examined under the microscope where the presence of sickle cells is easy to see.

A doctor can confirm that sickle cells are present with a second test, called gel electrophoresis (pronounced jel ih-LEK-tro-fuh-REE-siss). Gel electrophoresis is a method for distinguishing similar kinds of molecules from each other and will show whether abnormal forms of hemoglobin are present in the blood.

TREATMENT

Sickle cell anemia cannot be cured. However, many of its symptoms can be treated. Its most serious complications can also be prevented. The important factor is to diagnose the disorder as early as possible and begin treatment immediately. Methods used to treat symptoms include:

• Pain management. Pain is a common problem with sickle cell anemia. Some patients get the relief they need from over-the-counter medication, such as aspirin and acetaminophen. Others need stronger painkillers. Care givers should be careful giving aspirin to children as it has been linked with development of Reye's syndrome (see Reye's syndrome entry).
• Blood transfusions. Blood transfusions are generally used only in extreme situations, such as severe anemia or especially bad episodes of pain.

• Drugs. Infants are often treated with antibiotics to prevent infections. (Antibiotics are substances derived from bacteria or other organisms that fight the growth of other bacteria or organisms.) Such treatments may last to the age of six. Research is constantly being conducted to develop drugs for the cure of sickle cell anemia. One promising candidate is hydroxyurea, which seems to reduce pain and acute chest syndrome and can limit the need for blood transfusions in some cases.
• Bone marrow transplantation. Bone marrow transplantation is used in only the most severe cases of sickle cell anemia. It is based on the fact that new blood cells are made in the marrow of bones. The marrow is soft tissue found in the center of bones. In a bone marrow transplant, marrow is removed from the bones of a healthy donor. It is then injected into the bones of a person with sickle cell anemia. If the procedure is successful, the donor marrow begins making normal, rather than sickle cell, RBCs. Bone marrow transplantation is a very risky procedure with only limited chances of success.

Alternative Treatment

Sickle cell anemia is best treated by conventional medical techniques. However, alternative treatments may help ease some symptoms of the condition. Relaxation techniques, application of warm compresses, and adequate hydration may increase a patient's comfort. Good nutrition, the avoidance of stress, and proper rest may also help prevent some complications of the disorder.

PROGNOSIS

The average life expectancy for men with sickle cell anemia in the United States is forty-two years. For women, it is forty-eight years. The prognosis for any one individual depends on many factors but in general, patients receiving proper medical care may learn to lead relatively normal lives with the disorder.

PREVENTION

Sickle cell anemia is a genetic disorder. There is no prevention for the disease other than genetic screening. Adults can have tests to find out if they carry the gene for sickle cell anemia. If they find they are carriers they can decide whether or not they want to have children. If they decide to have children, there is a known risk that the children may develop sickle cell anemia.

FOR MORE INFORMATION

Books

Bloom, Miriam. Understanding Sickle Cell Disease. Jackson, MS: University Press of Mississippi, 1995.

Beshore, George W., ed. Sickle Cell Anemia. New York: Franklin Watts, Inc., 1994.

Silverstein, Alvin, Virginia Silverstein, and Laura Silverstein Nunn. Sickle Cell Anemia. Hillside, NJ: Enslow Publishers, Inc., 1997.

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. 11 Rockledge Centre, 6701 Rockledge Dr., MSC 7950, Bethesda, MD 20892–7950. (301) 435–0055.

sickle-cell disease (drepanocytosis) (sik-ŭl-sel) n. a hereditary blood disease that mainly affects people of African ancestry. It occurs when the sickle-cell gene has been inherited from both parents and is characterized by the production of an abnormal type of haemoglobin, which precipitates in the red blood cells when the blood is deprived of oxygen. The affected cells are distorted into the characteristic sickle shape and are rapidly removed from the circulation, leading to anaemia.

sick·le cell a·ne·mi·a / ˈsikəl sel əˈnēmēə/ (also sick·le cell dis·ease) • n. a severe hereditary form of anemia in which a mutated form of hemoglobin distorts the red blood cells into a crescent shape at low oxygen levels. It is commonest among those of African descent.

sickle-cell disease Inherited blood disorder featuring an abnormality of haemoglobin. The haemoglobin is sensitive to a deficiency of oxygen and it distorts erythrocytes, causing them to become rigid and sickle shaped. Sickle cells are rapidly lost from the circulation, giving rise to anaemia and jaundice.

sickle-cell disease See polymorphism.