Hemoglobin is a protein that is carried by red cells. It picks up oxygen in the lungs and delivers it to the peripheral tissues to maintain the viability of cells. Hemoglobin is made from two similar proteins that "stick together". Both proteins must be present for the hemoglobin to pick up and release oxygen normally. One of the component proteins is called alpha, the other is beta. Before birth, the beta protein is not expressed. A hemoglobin protein found only during fetal development, called gamma, substitutes up until birth. Like all proteins, the "blueprint" for hemoglobin exists in DNA (the material that makes up genes). Normally, an individual has four genes that code for the alpha protein, or alpha chain. Two other genes code for the beta chain. (Two additional genes code for the gamma chain in the fetus). The alpha chain and the beta chain are made in precisely equal amounts, despite the differing number of genes. The protein chains join in developing red blood cells, and remain together for the life of the red cell.

Hemoglobin performs thre functions, each of which is vital to life.

Sickle cell anemia is caused by an abnormal type of hemoglobin(oxygen carrying molecule) called hemoglobin S. It is inherited as an autosomal recessive trait -- that is, it occurs in someone who has inherited hemoglobin S from both parents.Someone who inherits hemoglobin S from one parent and normal hemoglobin (A) from the other parent will have sickle cell trait.Approximately 8% of African Americans have sickle cell trait. Someone who inherits hemoglobin S from one parent and another type of abnormal hemoglobin from the other parent will have another form of sickle cell disease, such as sickle cell-b ⁰ thalassemia, hemoglobin SC disease, or sickle cell-b ⁺ thalassemia. Someone with sickle cell trait or these forms of sickle cell disease will usually have no symptoms or only mild ones. However, some of these conditions can cause symptoms similar to sickle cell anemia. Although sickle cell disease is inherited and present at birth, symptoms usually don't occur until after 4 months of age. Sickle cell anemia may become life-threatening when damaged red blood cells break down (hemolytic crisis), when the spleen enlarges and traps the blood cells (splenic sequestration crisis), or when a certain type of infection causes the bone marrow to stop producing red blood cells (aplastic crisis). Repeated crises can cause damage to the kidneys, lungs, bones, eyes, and central nervous system. Blocked blood vessels and damaged organs can cause acute painful episodes. These painful crises, which occur in almost all patients at some point in their lives, can last hours to days, affecting the bones of the back, the long bones, and the chest. Many manifestations of this disease are a result of the fragility and inflexibility of the sickle red blood cells. When patients experience dehydration, infection, and low oxygen supply, these fragile red blood cells assume a crescent shape, causing red blood cell destruction and poor flow of these blood cells through blood vessels, resulting in a lack of oxygen to the body's tissues.

Symptoms

attacks of abdominal pain

Patients with sickle cell disease need certain treatment and follow-up even when not having a painful crisis. Supplementation with folic acid an essential element in producing cells, is required because of the rapid red blood cell turnover. Bacterial infections in children are common and antibiotics and vaccines are given to prevent this complication. Eye examinations by an ophthalmologist are important because of the risk of damage to the retina. Treatment for sickle cell disease usually focuses on symptoms. While bone marrow transplant can be curative, this therapy is indicated in only a minority of patients, predominantly because of the high risk of the procedure and difficulty in finding suitable donors. Therefore, the purpose of therapy is to manage and control symptoms resulting from crises and to try to limit the frequency of crises. During a sickle crisis, certain therapies may be necessary. Acute painful episodes are treated with analgesics and adequate liquid intake. Treatment of pain with adequate analgesics is critical. Additional treatments include: antibiotics for infection; partial exchange transfusion for acute chest syndrome; potentially partial exchange transfusions or surgery for neurological events, such as strokes, dialysis, or kidney transplant for kidney disease, irrigation or surgery for priapism, surgery for eye problems; hip replacement for avascular necrosis of the hip (death of the joint); gallbladder removal (if there is significant gallstone disease); wound care, zinc oxide, or surgery for leg ulcers; drug rehabilitation and counseling for the psychosocial complications. Hydroxyurea (Hydrea) was found to help some patients by reducing the frequency of painful crises and episodes of acute chest syndrome and decreasing the need for blood transfusions. There has been some concern about the possibility of this drug causing leukemia, but as yet there are no definitive data that Hydrea causes leukemia in sickle cell patients. Newer drugs are being developed to manage sickle cell anemia. Some of these agents work by trying to induce the body to produce more fetal hemoglobin (therefore decreasing the amount of sickling) or by increasing the binding of oxygen to sickle cells. But as yet, there are no other widely used drugs that are available for treatment. Bone marrow transplants are currently the only potential cure for sickle cell anemia. In this treatment the patient's bone marrow (which makes the sickled red blood cells) is replaced with bone marrow from another individual without sickle cell disease. However, it is difficult to find the right bone marrow donor, and the drugs needed to make the transplant possible are highly toxic. Also, bone marrow transplants are much more expensive than other treatments. Gene therapy (replacing the Hemoglobin S with a normal Hemoglobin A) may be the ideal treatment, but it has proven to be very difficult in humans.

Thalassemia is an inherited condition. The genes received from one's parents before birth determine whether a person will have thalassemia. Thalassemia cannot be caught or passed on to another person. The clinical severity of thalassemia varies tremendously depending on the exact nature of the genes that a person inherits. 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). Traits determined by a combination of genes often have gradations in magnitude (the difference between Michael Keaton and Kareem Abdul-Jabbar, for instance). Other characteristics are determined by a single gene pair (a person's sex, for instance). A person is either a biological male or female. The inheritance pattern is complicated in patients with thalassemia because two sets of genes on different chromosomes cooperate to produce hemoglobin. A defect anywhere in this complex can produce thalassemia. The expression of thalassemia, therefore, more closely resembles that of height, with gradations in effect. The genes involved in thalassemia control the production of a protein in red cells called hemoglobin. Hemoglobin binds oxygen in the lungs and releases it when the red cells reach peripheral tissues, such as the liver. The binding and release of oxygen by hemoglobin is essential for survival. Thalassemia occurs when one or more of the genes fails to produce protein, leading to a shortage of one of the subunits. If one of the beta globin genes fails, the condition is called beta thalassemia. Beta thalassemia, therefore, is due to a shortage of beta subunits. If an alpha globin gene fails, the condition is called alpha thalassemia. In this case, a shortage of alpha subunits occurs.

1. Beta Thalassemia

A defect in the production of beta globin protein from the beta genes is the most common cause of beta thalassemia. Both globin genes are present in the cell, but fail to produce hemoglobin adequately. If one of the beta globin genes fails, the amount of beta globin in the cell is reduced by half. This situation is called thalassemia trait or thalassemia minor. If both genes fail, no beta globin protein is produced. This is called thalassemia major. The beta globin genes exist in the cell, but fail to operate normally in beta thalassemia. In some cases, the gene failure is not total. The gene produces a small amount of normal beta protein. Sometimes, a person inherits two beta thalassemia genes in which the production of beta globin protein from each is reduced, but is not zero. The resulting clinical condition is more severe that thalassemia minor, where one gene fails but the other works normally. The condition is less severe than thalassemia major, where both beta globin genes fail completely. The clinical condition is termed, thalassemia intermedia. A variety of different beta thalassemia genes cause only a partial failure in beta globin protein production. In their partial functioning, some of these genes produce more beta globin protin than others. For this reason, the course of thalassemia intermedia varies greatly between patients. A person with two defective beta globin genes that nonetheless produce a reasonable amount of beta globin protein can have a clinical condition that is close to someone with thalassemia minor. In other instances, the two failing genes produce very little beta globin protein, and the person has a clinical condition similar to thalassemia major. Thalassemia intermedia is a clinical condition that varies and must be constantly evaluated by the hematologist. No two people with thalassemia intermedia are the same. 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 severe thalassemia. A couple in which each has thalassemia trait can have eight children, none of whom have two thalassemia genes. Another similar couple can have two children each with severe thalassemia. The inheritance of thalassemia genes is purely a matter of chance and cannot be altered. The clinical severity of the thalassemia in a person who inherits two thalassemia genes will depend on the amount of beta globin protein produced by the defective genes. Some thalassemia genes produce essentially no beta globin protein, and are called beta⁰ thalassemia genes. A person with two such genes has severe, transfusion-dependent thalassemia, called thalassemia major. Often, the thalassemia genes produce some beta globin protein, but the amount is reduced. These thalassemia genes are called beta⁺ thalassemia genes. A person who has one beta⁺ and one beta⁰ thalassemia gene will have thalassemia major. Usually, a person with two beta⁺ thalassemia genes also requires chronic transfusion therapy, and therefore also has thalassemia major. As noted, some beta⁺ thalassemia genes produce reduced, but reasonable amounts of beta globin protein. Two such genes can sometimes together produce enough beta globin protein so that the patient does not require chronic transfusions to live. This condition is thalassemia intermedia. Thalassemia intermedia is defined clinically by the transfusion requirement of the patient. Many considerations go into the decision to transfuse a patient chronically. Therefore, a person can change clinically from thalassemia intermedia to thalassemia major at some point during their life, while no chance occurs in their genetic makeup.

2. Alpha Thalassemia

Alpha thalassemia develops because one or more of the four alpha globin genes fail to produce alpha globin protein. The defect in alpha thalassemia almost always involves the loss of one or more of the alpha globin genes from chromosome #16. The inheritance of alpha thalassemia is complex because each parent potentially passes two of their four alpha globin genes to the offspring. One aspect of the inheritance that simplifies predictions is that alpha genes are on the the same chromsosome and are inherited as pairs. The key issue is whether two alpha genes on the same chromosome are deleted. If so, the offspring has the chance of having a very severe alpha thalassemia condition in which two alpha globin genes are missing on one chromosome #16, and one is missing on the other chromsome #16. In that instance, only the person has only one functional alpha globin gene. The result is a severe, transfusion-dependent anemia called Hemoglobin H Disease. If all four alpha globin genes are missing, the condition is incompatible life. Most fetuses die in utero with this condition (hydrops fetalis). Alpha thalassemia in which two genes are missing on the same chromosome occurs commonly in people of Asian ancestry. Alpha thalassemia also occurs in people of African ancestry. Here, the loss of two alpha globin genes on the same chromosome #16 is extremely rare.