Sickle Cell Disease - Introduction

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 three hundred 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 in everyone 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, then, 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 sickle cell.

Hemoglobin is the most important component of red blood cells. It is composed of a protein called heme, which binds oxygen. In the lungs, oxygen is exchanged for carbon dioxide. Abnormalities of an individual's hemoglobin value can indicate defects in red blood cell balance. Both low and high values can indicate disease states.

Changes that Lead to Sickle Cell Disease

Sickle cells 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.

Click the icon to see an image of sickle cells.

• 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 arereleased 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 to 20 days) than that of normal red blood cells (90 to 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.