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Thalassemia

Posted Jul 31 2009 11:55am

thalassemia

Next stop along our journey through the hereditary hemolytic anemias is a group of disorders called the thalassemias. Remember when we talked about sickle cell anemia? That disorder is part of a larger group of disorders called hemoglobinopathies, in which there is a qualitative abnormality in hemoglobin. Thalassemias are similar, in that they are caused by a genetic defect in one of the globin chains. However, instead of a qualitative abnormality, like you have in hemoglobinopathy, in thalassemia the abnormality is quantitative.

Let’s look at this a little closer. Remember the structure of hemoglobin? It has that protoporphyrin ring (with the iron in it) and four globin chains. In the adult, the globin chains consist of two alpha chains and two beta chains (that’s called hemoglobin A). In the fetus, there are two alpha chains and two gamma chains (hemoglobin F). Around 6 months of age, the hemoglobin changes from being mostly Hb F to mostly Hb A. There’s another hemoglobin form, too, that has two alpha chains and two delta chains; this is called hemoglobin A2, and it’s present in small amounts in normal adults.

In thalassemia, the patient has a genetic defect in either the alpha chain genes or the beta chain genes. If the defect is in one or more of the alpha chain genes (you have four alpha chain genes), then the patient won’t be able to make the alpha chain of hemoglobin. That’s called alpha thalassemia. Likewise, if the defect is in one or both of the beta chain genes, then the patient won’t be able to make beta chains; that is called beta thalassemia.

The degree of the defect varies from patient to patient in both types of thalassemia. If you just have one gene that’s defective/missing (in alpha thalassemia, the genetic “defect” is really a gene deletion, whereas in beta thalassemia, the genetic defect is one that affects gene transcription, translation, or processing), you’ll have a mild thalassemia (either alpha or beta).  If the genetic defect/deletion affects most or all of the alpha or beta chain genes, then the thalassemia is more severe, and possibly incompatible with life.

If you think about the different kinds of hemoglobin, you can see that it’s generally better to have a beta thalassemia than an alpha thalassemia. That’s because there are multiple things to pair with an alpha chain (beta chains, gamma chains, delta chains). If you’re making less beta chain, you can substitute gamma or delta chains and at least you’ll have some hemoglobin. However, there is only one thing that pairs with a beta chain, and that’s an alpha chain. So if you’re making less alpha chain, there’s nothing you can substitute in its place.

So – how does this relate to the actual anemia? Well, if you’re making insufficient alpha or beta chain, you’re not going to be able to make a normal amount of hemoglobin, and you’re going to be anemic (some patients are only mildly anemic – and some patients, if the defect is very mild, will not be anemic at all). Also, if you’re making insufficient alpha or beta chain, the partner chains will be sitting there unpaired. So in alpha thalassemia, you’ll have excess unpaired beta chains, and in beta thalassemia, you’ll have (at least some) unpaired alpha chains. These excess unpaired chains aggregate in the red cell, and the macrophages in the spleen see these aggregates and bite them out, leading to premature destruction of that red cell. Which only makes the anemia worse.

What does thalassemia look like on a blood smear? That depends on whether it’s a mild case of thalassemia (in which case the blood smear will look normal) or a severe case of thalassemia (in which the blood smear will look terrible, with a decreased number of red cells, a lot of abnormally shaped red cells, and some nucleated red cells as the bone marrow is desperately trying to get red cells into the circulation as fast as possible).

Many cases of thalassemia are mild to moderate. In these cases, the anemia is microcytic and hypochromic, just like iron deficiency anemia. It can sometimes be hard to tell these two disorders apart, in fact. There are a few things to look for, though. In iron deficiency anemia, there is a lot of anisocytosis (cells of varying sizes), whereas in a mild-moderate thalassemia, the red cells are all pretty much the same size. Also, in iron deficiency anemia, there is a decreased number of red cells, whereas in thalassaemia, the red cell number is actually increased, for some reason. Finally, in thalassemia, you often see target cells (as in the image above), which are absent in iron deficiency anemia.

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