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Sickle cell disease

Description

An in-depth report on the causes, diagnosis, and treatment of sickle cell disease.

Alternative Names

Sickle cell anemia

Introduction

Hemoglobin is a complex molecule and the most important component of red blood cells. Sickle cell disease occurs from genetic abnormalities in hemoglobin. Three forms of hemoglobin are important in this disorder:

• Hemoglobin A (HbA) . HbA is the hemoglobin molecule found in normal red blood cells during childhood and adulthood .
• Hemoglobin S (HbS) . HbS (S is for sickle) is the abnormal variant of hemoglobin A, which occurs in sickle-red blood cells and is the primary characteristic of the disease. The difference between hemoglobin A (HbA) and hemoglobin S (HbS) lies in only one protein out of about 300 that are common to both. This protein lies along an amino-acid chain called beta-globin, where even a tiny abnormality has disastrous results.
• Hemoglobin F (HbF) . HbF (F is for fetal) is a form of hemoglobin that is produced during fetal development in the womb and for a short time after birth. Normally, most HbF is later replaced by hemoglobin A, although some HbF may persist throughout life. Importantly, HbF is able to block the sickling action of red blood cells. Infants who have inherited sickle cell disease do not develop symptoms of the illness while they still have HbF. People with the sickle cell gene who continue to carry some fetal hemoglobin are better protected, therefore, from severe forms of the disease. It is being used as the basis for therapies used in treating sickle cell disease.

Changes that Lead to Sickle Cell Disease

Sickle cell disease is a result of changes in hemoglobin S:

• The destructive nature of the sickle hemoglobin develops when it loses oxygen.
• The deoxygenated molecules form rigid rods called polymers that distort the red blood cells into a sickle or crescent shape. This process is called polymerization and is the primary change leading to disease and destruction.
• These abnormally sickle-shaped cells are both rigid and sticky. They stick to the walls and cannot squeeze through the capillaries. Blood flow becomes obstructed, depriving tissues and organs of oxygen. In the immediate setting, oxygen deprivation (hypoxia) can cause severe pain (the sickle cell crisis). Over time, it leads to chronic and progressive destruction in organs and tissues throughout the body.

• In a vicious cycle, oxygen deprivation in cells leads to more polymerization and increased production of sickle cells. The higher the concentration of sickle hemoglobin and the more acidic the environment, the faster the sickle cell process. (Fortunately, in most cases the majority of blood cells have traveled out of the capillaries before they have time to be affected, and only about 20% of all red blood cells polymerize and become sickle-shaped.)
• Excessive acidity and the abnormal shape of the sickle cell also cause water and potassium loss from the cell, resulting in dehydration. Cell dehydration is another major destructive factor in the sickling process of red blood cells. To maintain the proper inflow and outflow of water, a cell uses a pump controlled by calcium and potassium. Potassium can be lost and calcium increased through a number of mechanisms. These minerals have electric charges that open and close a channel known as the Gardos channel in the cell membrane. If there is too little potassium and too much calcium in the bloodstream, the channel doesn't close and water flows out. The resulting dehydration increases the density of hemoglobin S within the cell, thereby speeding up the sickling process.
• High levels of hemoglobin S are released from red blood cells into the bloodstream. Importantly, hemoglobin eliminates nitric oxide, a soluble gas that prevents blood clotting and keeps the blood vessels flexible. Deficiencies in nitric oxide, which can result in severe narrowing of blood, are an important cause of the intense pain in sickle cells disease. In adults, men may be more susceptible to this effect than women.
• Sickle cells also have a shorter life span (10 - 20 days) than that of normal red blood cells (90 - 120 days). Every day the body produces new red blood cells to replace old ones, but sickle cells become destroyed so fast that the body cannot keep up. The red blood cell count drops, which results in anemia. This gives sickle cell disease its more common name, sickle cell anemia .
• The sickle cell disease process is triggered when red blood cells become deprived of oxygen. When they are re-exposed to oxygen, the polymerized hemoglobin molecules fall apart into harmless forms.

The severity of sickle cell disease generally depends on a number of factors:

• The extent of oxygen loss. Prolonged oxygen deprivation contributes to the severe pain experienced as a sickle cell crisis. It also produces both short- and long-term organ damage. The lungs are specifically critical targets of the disease process. Because they supply oxygen, they can restore the sickle molecules to a normal form. Unfortunately, once the process occurs, the lungs become major sites for sickle cell damage, particularly for dangerous acute episodes of chest pain.
• The acidity of the environment. The lower the better. The organs most seriously affected are those with an acidic environment (such as the spleen and bone marrow).
• The concentration of hemoglobin S within the cell. The lower the better.
• The amount of a protective hemoglobin F (for fetal). The more the better.

Blood Blood has two major components: Plasma is a clear yellow liquid that contains proteins, nutrients, hormones, electrolytes, and other substances. It constitutes about 55% of blood. White and red blood cells and platelets make up the balance of blood. The white cells are the infection fighters for the body, and platelets are necessary for blood clotting. The important factors in anemia, however, are red blood cells. Red blood cells (RBCs), also known as erythrocytes , carry oxygen throughout the body to nourish tissues and sustain life. Red blood cells are the most abundant cells in our bodies. Men have about 5.2 million red blood cels per cubic millimeter of blood, and women have about 4.7 million red blood cells per cubic millimeter of blood. To understand red blood cells and their role in anemia, it is useful to know certain facts about them. Hemoglobin and Iron Each red blood cell contains 200 - 300 hemoglobin molecules. Hemoglobin is a complex molecule and the most important component of red blood cells. It is composed of protein ( globulin ) and a molecule ( heme ), which binds to iron. In the lungs, the heme component binds to oxygen in exchange for carbon dioxide. The oxygenated red blood cells are then transported to the body's tissues, where the hemoglobin releases the oxygen in exchange for carbon dioxide, and the cycle repeats. The oxygen is used in the mitochondria , the power source within all cells. Red blood cells typically circulate for about 120 days before they are broken down in the spleen. Most of the iron present in hemoglobin can be recycled and reused. Structure and Shape Red blood cells are extremely small and look something like tiny, flexible inner tubes. This unique shape offers many advantages: It provides a large surface area to absorb oxygen and carbon dioxide. Its flexibility allows it to squeeze through capillaries, the tiny blood vessels that join the arteries and veins. Abnormally shaped or sized erythrocytes are typically destroyed and eliminated. Blood Cell Production (Erythropoiesis) The actual process of making red blood cells is called erythropoiesis. (In Greek, erythro means "red" and poiesis means "the making of things.") The process of manufacturing, recycling, and regulating the number of red blood cells is complex and involves many parts of the body: The body carefully regulates its production of red blood cells so that enough are manufactured to carry oxygen but not so many that the blood becomes thick or sticky ( viscous ). Most of the work of erythropoiesis occurs in the bone marrow. In children younger than 5 years old, the marrow in all the bones of the body is enlisted for producing red blood cells. As a person ages, red blood cells are eventually produced only in the marrow of the spine, ribs, and pelvis. If the body requires an increase in oxygen (at high altitudes, for instance), the kidney triggers the release of erythropoietin (EPO), a hormone that acts in the bone marrow to increase the production of red blood cells. The life span of a red blood cell is 90 - 120 days. Old red blood cells are removed from the blood by the liver and spleen. There they are broken down and iron is returned to the bone marrow to make new cells. Oxygen Loss in Red Blood Cells with Normal Hemoglobin In everyone, hemoglobin loses its oxygen normally in a number of ways: To sustain life, oxygen regularly passes from red blood cells to the tissues where it is needed to perform vital functions. Hemoglobin loses oxygen if blood cells become too acidic, for example, after strenuous exercise. Going to high altitudes or any stressful activity or situation that increases the body's demand for oxygen depletes its supply in red blood cells. Such situations do not affect normal red blood cells that contain hemoglobin A.

• Review Date: 1/17/2007
• Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

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