The fundamental abnormality in thalassemia is impaired production of either the alpha or beta hemoglobin chain. Thalassemia is a difficult subject to explain, since the condition is not a single disorder, but a group of defects with similar clinical effects. More confusion comes from the fact that the clinical descriptions of thalassemia were in use before the molecular basis of the thalassemias were uncovered. A review of thalassemia is best approached by examining it from a genetic basis and from it’s clinical expression.

The thalassemias are a diverse group of genetic blood diseases characterized by absent or decreased production of normal hemoglobin, resulting in a microcytic anemia of varying degree. The thalassemias have a distribution concomitant with areas where P. falciparum malaria is common. The alpha thalassemias are concentrated in Southeast Asia, Malaysia, and southern China. The beta thalassemias are seen primarily in the areas surrounding Mediterranean Sea, Africa and Southeast Asia. Due to global migration patterns, there has been an increase in the incidence of thalassemia in North America in the last ten years, primarily due to immigration from Southeast Asia.

Genetic Classification of the Thalassemias

Alpha Thalassemia

Alpha thalassemia occurs when one or more of the four alpha chain genes fails to function. Alpha chain protein production, for practical purposes, is evenly divided among the four genes. With alpha thalassemia, the failed genes are almost invariably lost from the cell due to a genetic accident.

(a) The loss of one gene diminishes the production of the alpha protein only slightly. This condition is so close to normal that it can be detected only by specialized laboratory techniques that, until recently, were confined to research laboratories. A person with this condition is called a “silent carrier” because of the difficulty in detection.

(b) The loss of two genes (two-gene deletion alpha thalassemia) produces a condition with small red blood cells, and at most a mild anemia. People who have this condition look and feel normal, butt the condition can be detected by routine blood testing.

(c) The loss of three alpha genes produces a serious hematological problem (three-gene deletion alpha thalassemia). Patients with this condition have a severe anemia, and often require blood transfusions to survive. The severe imbalance between the alpha chain production (now powered by one gene, instead of four) and beta chain production (which is normal) causes an accumulation of beta chains inside the red blood cells. Normally, beta chains pair only with alpha chains. With three-gene deletion alpha thalassemia, however, beta chains begin to associate in groups of four, producing an abnormal hemoglobin, called “hemoglobin H”. The condition is called “hemoglobin H disease”. Hemoglobin H has two problems. First it does not carry oxygen properly, making it functionally useless to the cell. Second, hemoglobin H protein damages the membrane that surrounds the red cell, accelerating cell destruction. The combination of the very low production of alpha chains and destruction of red cells in hemoglobin H disease produces a severe, life-threatening anemia. Untreated, most patients die in childhood or early adolescence.

(d) The loss of all four alpha genes produces a condition that is incompatible with life. The gamma chains produced during fetal life associate in groups of four to form an abnormal hemoglobin called “hemoglobin Barts”. Most people with four-gene deletion alpha thalassemia die in utero or shortly after birth. Rarely, four-gene deletion alpha thalassemia has been detected in utero, usually in a family where the disorder occurred in an earlier child. In utero blood transfusions have saved some of these children. These patients require life-long transfusions and other medical support.

Beta Thalassemia

The fact that there are only two genes for the beta chain of hemoglobin makes beta thalassemia a bit simpler to understand than alpha thalassemia. Unlike alpha thalassemia, beta thalassemia rarely arises from the complete loss of a beta globin gene. The beta globin gene is present, but produces little beta globin protein. The degree of suppression varies. Many causes of suppressed beta globin gene expression have been found. In some cases, the affected gene makes essentially no beta globin protein (beta-(zero)-thalassemia). In other cases, the production of beta chain protein is lower than normal, but not zero (beta-(plus)-thalassemia). The severity of beta thalassemia depends in part on the type of beta thalassemic genes that a person has inherited.

(a) One-gene beta thalassemia has one beta globin gene that is normal, and a second, affected gene with a variably reduced production of beta globin. The degree of imbalance with the alpha globin depends on the residual production capacity of the defective beta globin gene. Even when the affected gene produces no beta chain, the condition is mild since one beta gene functions normally. The red cells are small and a mild anemia may exist. People with the condition generally have no symptoms. The condition can be detected by a routine laboratory blood evaluation. (Note that in many ways, the one-gene beta thalassemia and the two-gene alpha thalassemia are very similar, from a clinical point of view. Each results in small red cells and a mild anemia).

(b) Two-gene beta thalassemia produces a severe anemia and a potentially life-threatening condition. The severity of the disorder depends in part on the combination of genes that have been inherited: beta-zero-thal/ beta-zero-thal; beta-zero-thal/ beta-plus-thal; beta-plus-thal/ beta-plus-thal. The beta-plus-thalassemia genes vary greatly in their ability to produce normal hemoglobin. Consequently, the clinical picture is more complex than might otherwise be the case for three genetic possibilities outlined.

Clinical Classification of the Thalassemias

Alpha thalassemia

Alpha thalassemia has four manifestations, that correlate with the number of defective genes. Since the gene defect is almost invariably a loss of the gene, there are no “shades of function” to obscure the matter as occurs in beta thalassemia.

(a) Silent carrier state. This is the one-gene deletion alpha thalassemia condition. People with this condition are hematologically normal. They are detected only by sophisticated laboratory methods.

(b) Mild alpha-thalassemia. These patients have lost two alpha globin genes. They have small red cells and a mild anemia. These people are usually asymptomatic. Often, physicians mistakenly diagnose people with mild alpha-thalassemia as having iron deficiency anemia. Iron therapy, of course, does not correct the anemia.

(c) Hemoglobin H disease. These patients have lost three alpha globin genes. The result is a severe anemia, with small, misshapen red cells and red cell fragments. These patients typically have enlarged spleens. Bony abnormalities particularly involving the cheeks and forehead are often striking. The bone marrow works at an extraordinary pace in an attempt to compensate for the anemia. As a result, the marrow cavity within the bones is stuffed with red cell precursors. These cells gradually cause the bone to “mold” and flair out. Patients with hemoglobin H disease also develop large spleens. The spleen has blood forming cells, the same as the bone marrow. These cells become hyperactive and over expand, just as those of the bone marrow. The result is a spleen that is often ten-times larger than normal. Patients with hemoglobin H disease often are small and appear malnourished, despite good food intake. This feature results from the tremendous amount of energy that goes into the production of new red cells at an extremely accelerated pace. The constant burning of energy by these patients mimics intense aerobic exercise; exercise that goes on for every minute of every day.

(d) Hydrops fetalis. This condition results from the loss of all four alpha globin genes. The affected individual usually succumbs to the severe anemia and complications before birth.

Beta thalassemia

(a) Thalassemia minor, or thalassemia trait. These terms are used interchangeably for people who have small red cells and mild (or no) anemia due to thalassemia. These patients are clinically well, and are usually only detected through routine blood testing. Physicians often mistakenly diagnose iron deficiency in people with thalassemia trait. Iron replacement does not correct the condition. The primary caution for people with beta-thalassemia trait involves the possible problems that their children could inherit if their partner also has beta-thalassemia trait. These more severe forms of beta-thalassemia trait are outlined below.

(b) Thalassemia intermedia. Thalassemia intermedia is a confusing concept. The most important fact to remember is that thalassemia intermedia is a description, and not a pathological or genetic diagnosis. Patients with thalassemia intermedia have significant anemia, but are able to survive without blood transfusions. The factors that go into the diagnosis are the degree to which the patient tolerates the anemia and the threshold of the physician to transfuse patients with thalassemia.

With regard to the tolerance of the anemia, most patients with thalassemia have substantial symptoms with a Hemoglobin of much below 7 or 8gm/dl. With hemoglobins of this level, excess energy consumption due to the profound hemolysis can produce small stature, poor weight gain, poor energy levels, and susceptibility to infection. Further, the extreme activity of the bone marrow produces bone deformities of the face and other areas, along with enlargement of the spleen. The long bones of the arms and legs are weak and fracture easily. Patients with this clinical condition usually do better with regular transfusions. The need for regular transfusions would then place them under the heading of thalassemia major (see below). On the other hand, some patients with marked thalassemia can maintain a hemoglobin of about 9-10gm/dl. The exercise tolerance of these patients is significantly better.

The question then becomes whether the accelerated bone marrow activity needed to maintain this level of hemoglobin causes unacceptable side-effects such as bone abnormalities or an enlarged spleen. This is a judgment decision. A given patient at the critical borderline would be transfused by some physicians to prevent these problems, even if they are slight. The patient then would be clinically classified as having thalassemia major. Another physician might choose to avoid the complications of chronic transfusion. The same patient then would be clinically classified as thalassemia intermedia. The patient has thalassemia that is more severe than thalassemia trait, but not so severe as to require chronic transfusion as do the patients with thalassemia major.

A patient can change status, and the spleen is enlarged in these patients. The spleen plays a role in clearing damaged red cells from the blood stream. Since all of the red cells in patients with severe thalassemia have some degree of damage, clearance by the spleen accelerates the rate of cell loss. Therefore the bone marrow has to work harder to replace these cells. In some patients, removal of the spleen slows the rate of red cell destruction just enough, that they can manage without transfusion, and still not have the unacceptable side-effects. In this case, the patient converts clinically from thalassemia major to thalassemia intermedia.

(c) Thalassemia major. This is the condition of severe thalassemia in which chronic blood transfusions are needed. In some patients the anemia is so severe, that death occurs without transfusions. Other patients could survive without transfusions, for a while, but would have terrible deformities. While transfusions are life-saving in patients with thalassemia major, transfusions ultimately produce iron overload. Chelation therapy, usually with the iron-binding agent, desferrioxamine (Desferal), is needed to prevent death from iron-mediated organ injury.


Signs, symptoms & indicators of Thalassemia

Lab Values - Cells  

Microcytic red cells


Normal/high red blood cell count

Conditions that suggest Thalassemia

Organ Health  

Enlarged Spleen

The spleen is an organ that helps your body fight infection and remove unwanted material. When a person has a thalassemia, the spleen has to work very hard. As a result, the spleen becomes larger than normal. This makes anemia worse. If the spleen becomes too large, it must be removed.

Symptoms - Cardiovascular  

Absence of thalassemia

Risk factors for Thalassemia

Lab Values - Chemistries  

Normal/elevated ferritin levels

Recommendations for Thalassemia



People who have thalassemia should not take iron containing medications unless it has been established that an iron deficiency is present.



In Thalassemia major, treatment may include: frequent (every 3-4 weeks) transfusion; when iron build up occurs, Desferal treatment is added. This treatment is one that is used for patients who have simultaneous anemia and iron loading conditions. Desferal is administered subcutaneously (under the skin) from a small battery operated pump about the size of a portable cassette tape player.

Bone marrow transplantation may be considered but it is expensive and a suitable donor must be identified. Cord blood transplant is presently being done experimentally in China.

In Thalassemia Minor and Thalassemia Intermedia there is no treatment when asymptomatic. If the spleen is inflamed, splenectomy may be required.


Weak or unproven link
Strong or generally accepted link
Very strongly or absolutely counter-indicative
May do some good
May have adverse consequences



The thalassemias are a diverse group of genetic blood diseases characterized by absent or decreased production of normal hemoglobin, resulting in a microcytic anemia of varying degree. The thalassemias have a distribution concomitant with areas where P. falciparum malaria is common.


The oxygen-carrying protein of the blood found in red blood cells.


A condition resulting from an unusually low number of red blood cells or too little hemoglobin in the red blood cells. The most common type is iron-deficiency anemia in which the red blood cells are reduced in size and number, and hemoglobin levels are low. Clinical symptoms include shortness of breath, lethargy and heart palpitations.


Compounds composed of hydrogen, oxygen, and nitrogen present in the body and in foods that form complex combinations of amino acids. Protein is essential for life and is used for growth and repair. Foods that supply the body with protein include animal products, grains, legumes, and vegetables. Proteins from animal sources contain the essential amino acids. Proteins are changed to amino acids in the body.

Red Blood Cell

Any of the hemoglobin-containing cells that carry oxygen to the tissues and are responsible for the red color of blood.


Not showing symptoms.


An essential mineral. Prevents anemia: as a constituent of hemoglobin, transports oxygen throughout the body. Virtually all of the oxygen used by cells in the life process are brought to the cells by the hemoglobin of red blood cells. Iron is a small but most vital, component of the hemoglobin in 20,000 billion red blood cells, of which 115 million are formed every minute. Heme iron (from meat) is absorbed 10 times more readily than the ferrous or ferric form.


Using oxygen. For example, aerobic exercises such as running, swimming, bicycling or playing tennis use up lots of oxygen and burn up lots of calories and fat.


(Dropsy) An excessive accumulation of clear, watery fluid in any of the tissues or cavities of the body; edema, ascites, anasarca.


(gm): A metric unit of weight, there being approximately 28 grams in one ounce.


Breaking down of red blood cells.


Usually Chronic illness: Illness extending over a long period of time.


Chelation therapy uses EDTA or other supplements that carry heavy metals such as lead, cadmium and arsenic, as well as other foreign substances, from the body. In the process of chelation, a larger protein molecule surrounds or encloses a mineral atom. The purpose of chelation is to increase the flow of blood to the vital organs and tissues of the body by reducing calcium deposits in the arteries and blood vessels.

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