Is Hemoglobin Instability Important in the Interaction Between Hemoglobin E and ß Thalassemia?

Hemoglobin E (HbE; ?2ß226glu-lys), globally the commonest hemoglobin variant, is synthesized at a slightly reduced rate and has a homozygous phenotype similar to heterozygous ß thalassemia. Yet, when it is inherited together with a ß thalassemia allele, the resulting condition, HbE/ß thalassemia, is sometimes characterized by a severe, transfusion-dependent thalassemia major. The severity of this interaction has not been explained. We have explored the possibility that it may reflect the instability of HbE consequent upon globin chain imbalance imposed by the ß thalassemia allele. Time-course and pulse-chase globin chain synthesis studies at 37°C on peripheral blood and bone marrow suggest that hemoglobin instability is not significant in steady-state HbE/ß thalassemia; this is confirmed by density-gradient centrifugation studies that show no decrease in HbE levels relative to HbA as HbE/ß+ thalassemia red blood cells age. Globin binding to membranes was assessed and only ? globin chains were found, in contrast to other unstable hemoglobins in which both ? and ß chains were present. However, in experiments performed on blood from HbE/ß thalassemics in the temperature range 39°C to 41°C, there was evidence of instability of HbE, a finding that was also observed in homozygous HbE. These findings suggest that the phenotype of HbE/ß thalassemia is primarily the result of the interaction of two ß thalassemia alleles; however, hemoglobin instability may be important during febrile episodes, contributing to worsening anemia. © 1998 by The American Society of Hematology.