The pathophysiology and clinical features of α thalassemia

© Cambridge University Press 2009. Introduction: The primary abnormality in patients with α thalassemia is the underproduction of α-globin chains. Important secondary effects occur because of the continued production of excess γ chains in fetal life, which form the γ4 tetramer (Hb Bart's) and excess β-chains in adult life producing a β4 tetramer (HbH). Excess, unmatched non-α-globin chains damage the developing erythroid precursors, giving rise to intramedullary hemolysis or ineffective erythropoiesis. In addition, the presence of Hb Bart's and HbH cause premature destruction of mature red cells, giving rise to the predominant pathophysiology of α thalassemia that involves extravascular hemolysis. As set out in Chapter 13 and http://globin.bx.psu.edu/hbvar/we currently know of approximately 80 mutations associated with α+ thalassemia and approximately 40 that cause α0 thalassemia. There are potentially several hundred different interactions that could take place between the large numbers of determinants described. Phenotypically, these interactions result in one of three broad categories; α thalassemia trait, in which there are mild hematological changes but no major clinical abnormalities, HbH disease, and the Hb Bart's hydrops fetalis syndrome. We shall consider each of these in this chapter. The information set out in Chapter 13 suggests that the α thalassemia determinants can be arranged in the order of their severity (from αα to --) as shown in Table 14.1. In general the phenotypes resulting from their interactions correlate well with the reduction in α-chain synthesis predicted for each mutation.