Ij

Figure 5.10 Erythroid hyperplasia: the bone marrow's response to anemic stress.

Figure 5.11 Thalassemia major, showing a high degree of poikilocytosis and nRBCs.

inheritance for this disorder was described by Dr. W N. Valentine in 1944, and since 1960, the genetic interactions and the cloning of the thalassemic genes have been accomplished. Yet there has been no cure.

The Pathophysiology of the Thalassemias

Unlike the other microcytic processes discussed, the thalassemias have nothing to do with iron. The thal-assemias are globin chain disorders that are concerned with the lack of production of alpha or beta globin chains. The thalassemias are hemoglobin synthesis defects. Failure to synthesize either the alpha or the beta chain impairs the production of the normal physiological adult hemoglobin, hemoglobin A (a2,P2), hemoglobin A2 (a2,52), and hemoglobin F (a2,52). The construction of each of these normal hemoglobins depends on alpha and beta chains being synthesized as part of their normal tetramer. When this synthesis is impaired, the hemoglobins are formed as a result of the unbalanced chain production that negatively affects red cell life span. Additionally, there are multiorgan complications, the development of a microcytic anemia, and a peripheral smear with many red cell morphological abnormalities. There are two major types of thalassemias: alpha thalassemia and beta thalassemian. Put simply, the alpha thalassemias result from gene deletions. Each individual inherits four alpha genes, two maternal and two paternal. Each of the four clinical presentations of alpha thalassemia results from one or more of the alpha genes being deleted. The beta thalassemias revolve around the inheritance of a defective beta gene, either from one parent (heterozygously) or from both parents (homozygously). To date, 200 mutations of the beta gene have been described, and these mutations have been broadly divided into the B0 or the B+ gene. In the B0 individuals, there is a complete lack of synthesis of the beta chain, and in B+ individuals, a limited amount of the beta chain is synthesized. Both of these mutations affect specific populations (Table 5.10). On the molecular level, beta chain defects result from faulty transcription of messenger RNA.

The Alpha Thalassemias

Symptomatology

The alpha thalassemias have a high incidence in the Asian populations (e.g., Thailand, Vietnam, Cambodia, Indonesia, and Laos).15 They are also seen in Saudi Arabian and Filipino populations. As you may recall, the alpha chain is the critical building block for construction of all normal adult physiological hemoglobins, because each adult hemoglobin depends on the production of the alpha chain. The alpha chain is also critical in the development of hemoglobin in the fetus; without alpha chain development, there is no Hgb F formed. There are four clinical states of alpha thal-assemia that are related to the number of alpha genes deleted (Fig. 5.12).

Gene States of Alpha Hemoglobin

The most severe state is Barts hydrops fetalis, in which there is a total absence of alpha chain synthesis: no hemoglobin A is formed, only hemoglobin Barts (y 4), a high oxygen affinity hemoglobin. Because this hemoglobin is an abnormal tetramer and oxygen loving (hemoglobin Barts holds onto oxygen and resists delivering oxygen to the tissues), the anemia that develops is severe and usually leads to stillbirth or spontaneous abortion. Hemoglobin H disease is the next most severe condition. Here, there is only one functional alpha gene, and the other three genes are deleted. Little hemoglobin A is produced; instead, a new hemoglobin H is formed, which is also a fairly unstable tetramer (^4) and repre-

Table 5.10

Gene Expression in Population

Northern Italy Greece Algeria Saudi Arabia

Mediterranean region Southeast Asia Middle East Indian subcontinent West Africa

76 Part II • Red Cell Disorders

Normal chromosome 16

— Alpha chain loci

Clinical Conditions of Alpha Thalassemia Hydrops Barts fetalis Hemoglobin H Disease

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