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740 Part VI: The Erythrocyte Chapter 48: The Thalassemias: Disorders of Globin Synthesis 741

survival of red cells consequent to their damage in the microvasculature rapidly in the spleen and elsewhere, cells with a much longer survival
of the spleen as a result of the presence of the inclusions. In addition, that contain relatively more hemoglobin F, and populations of interme-
because of the defect in hemoglobin synthesis, the cells are hypochro- diate age and hemoglobin constitution. 7,182
mic and microcytic. Hemoglobin Bart’s is more stable than hemoglobin Although cell selection is probably the main reason for the
H and does not form large inclusions. increased levels of hemoglobin F in the red cells in β-thalassemia,
Although, as is the case in β-thalassemia, excess globin chains other mechanisms may also be involved. In any form of “stress erythro-
cause damage to the red cell membrane, the mechanisms are different poiesis,” that is, rapid erythroid proliferation, there is a tendency for a
in the two forms of the disease. As described in “Etiology and Pathogen- relative increase in γ-chain production. Furthermore, as discussed in
esis” above, in β-thalassemia, excess α chains result in mechanical insta- “Hereditary Persistence of Fetal Hemoglobin” above, several genes or
bility and oxidative damage to a variety of membrane proteins, notably chromosomal locations have been defined in which polymorphisms are
protein 4.1. However, in α-thalassemia, the membranes are hyperstable, involved in the increased basal production of γ chains and a relative
and no evidence of oxidation or dysfunction of this protein is present. increase in the number of F cells in the blood. The interaction of these
Furthermore, the state of red cell hydration is different in α-thalassemia. different loci appear to be responsible for high levels of hemoglobin F
Accumulation of excess β chains results in increased hydration. These production in β-thalassemia and sickle cell anemia with the production
differences in the pathophysiology of membrane damage between α- of milder phenotypes. 125–128,184 However, biosynthesis studies indicate
and β-thalassemia are discussed in detail in references 7 and 174 to 176. that marrow expansion and the selective survival of F-cell precursors
Another factor exacerbates the tissue hypoxia of the anemia of the and their progeny are the major factors in hemoglobin F production in
α-thalassemias. Both hemoglobin Bart’s and hemoglobin H show no hemoglobin E/β-thalassemia. 183
heme–heme interaction and have almost hyperbolic oxygen dissocia- Because a reciprocal relation exists between γ- and δ-chain syn-
tion curves with very high oxygen affinities. Thus, they are not able to thesis, the red cells of β-thalassemia homozygotes containing large
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liberate oxygen at physiologic tissue tensions; in effect, they are useless amounts of hemoglobin F have relatively low hemoglobin A levels.
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as oxygen carriers. 7 Thus, the measured percent hemoglobin A in these individuals is the
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As a consequence, infants with high levels of hemoglobin Bart’s average of a very heterogeneous cell population. This finding probably
have severe intrauterine hypoxia. This is the major basis for the clini- accounts for the extreme variability in hemoglobin A levels found in
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cal picture of homozygous α -thalassemia, which results in the stillbirth homozygotes for this disorder. A further consequence of the persistence
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of hydropic infants late in pregnancy or at term. Oxygen deprivation of hemoglobin F in β-thalassemia is the high oxygen affinity of the red
is reflected by the grossly hydropic state of the infant, presumably as cells.
a result of increased capillary permeability, and by severe erythrob-
lastosis. Deficient fetal oxygenation probably is responsible for the
enormously hypertrophied placentas and possibly for the associated CONSEQUENCES OF COMPENSATORY
developmental abnormalities that occur with the severe forms of intra-
uterine α-thalassemia. 7 MECHANISMS FOR THE ANEMIA OF
THALASSEMIA
PERSISTENT FETAL HEMOGLOBIN The profound anemia of homozygous β-thalassemia and the relatively
PRODUCTION AND CELLULAR high oxygen affinity of hemoglobin F combine to cause severe tissue
hypoxia. Because of the high oxygen affinity of hemoglobins Bart’s and
HETEROGENEITY H, a similar defect in tissue oxygenation occurs in the more severe
Children with severe thalassemia have an increased level of hemoglobin forms of α-thalassemia. The major adaptive response to hypoxia is
F that persists into childhood and later. In the β -thalassemias, hemo- increased erythropoietin production. It has been found that in severely
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7,10
globin F is the only hemoglobin produced, except for small amounts anemic children with hemoglobin E β-thalassemia, age and hemoglobin
of hemoglobin A . Examination of the blood using staining methods levels are independent variables in erythropoietin response and that for
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specific for hemoglobin F shows that it is heterogeneously distributed a given hemoglobin level there is a relatively high erythropoietin in very
among the red cells. Persistent hemoglobin F production is not a major young children. These observations provide an explanation for the
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185
feature of the more severe forms of α-thalassemia. rather unstable phenotype of many intermediate forms of β-thalassemia
The mechanism of persistent γ-chain synthesis in the thalassemias during early childhood. The major effect of these very high levels of ery-
is incompletely understood. Normal adults have small quantities of thropoietin production is expansion of the dyserythropoietic marrow.
hemoglobin F that are heterogeneously distributed among the red cells. The results are deformities of the skull and face and porosity of the long
Cells with demonstrable hemoglobin F are called F cells. One impor- bones. Extramedullary hematopoietic tumors may develop in extreme
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tant mechanism for high hemoglobin F levels in the blood of patients cases. Apart from the production of severe skeletal deformities, mar-
with β-thalassemia is cell selection. 7,180–183 The major cause of ineffec- row expansion may cause pathologic fractures and sinus and middle ear
tive erythropoiesis and shortened red cell survival in β-thalassemia is infection as a result of ineffective drainage.
the deleterious effect of excess α chains on erythroid maturation in the Another important effect of the enormous expansion of the mar-
marrow and on the survival of red cells in the blood. Therefore, red cell row mass is the diversion of calories required for normal development
precursors that produce γ chains are at a selective advantage. Excess α to the ineffective red cell precursors. Thus, patients severely affected by
chains combine with γ chains to produce hemoglobin F; therefore, the thalassemia show poor development and wasting. The massive turnover
magnitude of α-chain precipitation is less. Differential centrifugation of erythroid precursors may result in secondary hyperuricemia and
experiments 181–183 and in vivo labeling studies have shown that pop- gout and severe folate deficiency.
180
ulations of red cells with relatively large amounts of hemoglobin F are The effects of gross intrauterine hypoxia in homozygous α -
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more efficiently produced and survive longer in the blood. The blood thalassemia have been described. In the symptomatic forms of α-
of patients with homozygous β-thalassemia shows remarkable cellular thalassemia (e.g., hemoglobin H disease) that are compatible with
heterogeneity with respect to red cell survival, such as populations of survival into adult life, bone changes and other consequences of erythroid
cells containing predominantly hemoglobin A that are destroyed very expansion are seen, although less commonly than in β-thalassemia.

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