Sickle Cell Anemia 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 …