Hydroxyurea increases hemoglobin F levels and improves the effectiveness of erythropoiesis in beta-thalassemia/hemoglobin E disease.

Hydroxyurea (HU) is one of several agents that have been shown to enhance hemoglobin (Hb) F levels in patients with sickle cell disease and may be useful as a therapy for beta-globinopathies. However, limited information exists on the effects of HU in patients with thalassemia. Accordingly, we examined the hematologic effects of orally administered HU in 13 patients with beta-thalassemia/Hb E, including four patients who had been splenectomized. These patients were treated with escalating doses (final range, 10 to 20 mg/kg/d) for 5 months and were observed in the outpatient hematology clinic every 2 to 4 weeks. Complete blood counts including reticulocyte counts, amounts of Hb E and Hb F, G gamma:A gamma and alpha:non-alpha globin biosynthetic ratios were evaluated before and during treatment. Almost all patients responded with an average increase of 33% in Hb F levels, from a mean (+/- SD) of 42% +/- 11% to 56% +/- 8% (P < .0001), and a reciprocal decline in the percentage of Hb E from 59% +/- 9% to 49% +/- 8% (P < .001). Reticulocytosis was decreased from a mean (+/- SD) of 18.0% +/- 15.6% to 11.7% +/- 9.1% (P < .05); there was also a slight (10%) but statistically significant increase in hemoglobin levels and an improved balance in alpha:non-alpha globin chains ratios. The side effects were minimal in most patients, although these patients tended to tolerate a lower dose of HU before significant myelosuppression than has been our previous experience in sickle cell disease. One splenectomized patient died of sepsis during the trial. We conclude that increased Hb F production in beta-thalassemia/Hb E patients, with an improvement in the alpha:non-alpha globin ratios and, probably, the effectiveness of erythropoiesis, can be achieved using HU. Longer trials of HU in this population, including at other doses and in combination with other agents, appear warranted.

The thalassemic red cell membrane.

The underlying cause of pathology in thalassemia is the premature destruction of red cells, both in the bone marrow and by the reticuloendothelial system. It is generally accepted that the presence of unpaired excess globin chains is the primary circumstance leading to such membrane alterations as oxidation of phospholipids, modification of cytoskeletal proteins and their interactions, reduced membrane-associated ATPase activities, and enhanced permeability of cations. Such perturbations in turn result in the exposure of outer surface neoantigens, enhanced binding of autoantibodies and complement fixation to the outer red cell surface. These factors contribute to the observed distinctive morphologies, increased rigidity and decreased deformability of the thalassemic red cells. In alpha-thalassemic red cells, excess beta-globin chains form homotetramers, Hb H, which are relatively stable and will only damage red cell membrane when precipitated as inclusion bodies, whereas excess alpha-globin chains cannot form such homotetramers and upon synthesis rapidly bind to the cytoplasmic side of the beta-thalassemic red cell membrane, even in young erythroblasts. This difference in properties of the excess globin chains may offer an explanation for the variation in clinical severity observed between these two forms of thalassemia.

Different molecular defects of G gamma (A gamma delta beta)o-thalassaemia in Thailand.

DNA from members of 2 Thai families with conditions considered to be delta beta-thalassaemia were studied by using restriction endonuclease DNA mapping. The propositus in family A is a double heterozygote for beta-thalassaemia and delta beta-thalassaemia. DNA analysis reveals a deletion of the beta-globin gene cluster starting at the area between the Sac I and Eco RI sites near the 3' end of the G gamma-gene and extending through the A gamma-, delta- and beta-genes to an unknown extent downstream. In family B, the propositus is delta beta-thalassaemia/Hb E. Deletion of the beta-globin gene cluster begins in the large intervening sequence of the A gamma-gene and removes both delta- and beta-genes downstream.