Genetics, Different forms of SCD, Pathophysiology, and Treatment. This video is available for licensing on our website. Click HERE!
Sickle cell disease is a group of inherited blood disorders in which the body produces abnormally-shaped red blood cells that look like crescent moons or sickles. Sickle cells have a shorter-than-normal life span; their premature destruction results in shortage of red cells, known as anemia. Signs of anemia include shortness of breath, fatigue, and delayed growth in children. Unlike normal red cells which are pliant, sickle cells are rigid and also sticky. They may clump together and stick to the walls of blood vessels, causing obstruction in small vessels and subsequent reduced oxygen supply to various organs. This happens repeatedly and manifests as periodic episodes of pain, called crises, which can last hours to days, and may result in organ damage, especially in the eyes, lungs, kidneys, bones and brain. The spleen has to handle large numbers of dead red cells and becomes enlarged and fibrous, its immune function declines, making the body more vulnerable to infections. In an attempt to compensate for blood cell loss, the bone marrow tries to produce more cells and grows larger, causing bones to weaken. Other signs include jaundice, a result of rapid destruction of heme.
Hemoglobin is the major component of red blood cells and is responsible for oxygen transport. The adult hemoglobin, or hemoglobin A, is composed of 4 protein chains: 2 alpha and 2 beta. The beta subunit is encoded by the HBB gene. Several mutations in HBB gene are responsible for the disease. Each individual has two copies of HBB gene. The disease develops when both copies are mutated, producing no normal beta globin. The 2 copies may be mutated differently, producing two different forms of abnormal beta subunits in the same person. Various combinations of these mutations produce different forms of sickle cell disease, but the most common and also most severe, called sickle cell anemia, is caused by 2 copies of the same mutation producing the mutated hemoglobin S. Each copy comes from a parent. The 2 parents each carry one copy of the mutated gene, but they typically do not show any symptoms. This pattern of inheritance is called autosomal recessive.
Hemoglobin S has the tendency to form polymers under low oxygen conditions. This process is called sickling, or gelation, for the gel-like consistency of the resulting polymer. As the polymer filaments grow, they eventually involve the cell membrane and distort the cell into the characteristic crescent shape. Apart from oxygen tension, the presence of other hemoglobins also seems to affect the sickling process. Normal adult hemoglobin inhibits sickling and this explains why heterozygous parents, who produce both mutated hemoglobin S and normal hemoglobin A, do not usually develop the disease. Fetal hemoglobin F, which has 2 gamma chains in place of 2 beta chains, also suppresses sickling. Infants born with the condition seem to benefit from high levels of fetal hemoglobin in the first few months of life: they do not develop symptoms until the age of 6 months or so, when fetal hemoglobin levels drop.
Bone marrow transplantation is currently the only known cure for sickle cell disease. It involves replacing the diseased stem cells in the bone marrow with healthy cells from an eligible donor, usually a relative. The procedure however is complex and finding a suitable donor can be difficult. In most cases, treatments aim to avoid crises, relieve symptoms and prevent complications. These include:
– Prophylactic antibiotics, vaccinations to prevent infections,
– Pain medication to relieve pain,
– Drugs that promote formation of fetal hemoglobin, to suppress sickling,
– Periodic blood transfusions, to reduce anemia and prevent crises,
– and early detection and treatment for complications when these occur.
