Determinants of red cell survival and erythropoietic activity in patients with sickle cell anemia in the steady state.

We have studied 26 patients with sickle cell anemia to determine the factors that affect red blood cell (RBC) survival and other parameters of erythropoietic activity in the steady state. Determinants of erythropoietic activity included RBC survival by the 51Cr method, RBC production/destruction rate, alpha genotype, beta(s) haplotype, plasma 59Fe clearance, plasma iron turnover, erythron transferrin uptake), RBC Fe utilization, reticulocyte count, and erythropoietin levels. The alpha genotype was the most significant determinant of RBC survival followed, to a lesser extent, by the beta(s) haplotype. Hb F showed no correlation with RBC survival due to patient selection bias - the patients studied had comparable Hb F levels to start with. Other determinants of erythropoietic activity (hemoglobin level, mean corpuscular volume, reticulocyte count, RBC mass, RBC production/destruction rate, and erythropoietin level) were most likely secondary determinants associated with the alpha genotype, and not independent determinants in themselves. The data suggest that the alpha genotype and, and to a lesser extent, the beta(s) haplotype, might be determinants of the severity of the anemia of sickle cell disease, and should be considered in genetic counseling and patient selection for aggressive therapeutic interventions.

Erythropoietic activity in patients with sickle cell anaemia before and after treatment with hydroxyurea.

In this project we have prospectively studied the erythropoietic activity in patients with sickle cell anaemia (SS) before and after treatment with hydroxyurea (HU). Some of the patients were enrolled in a double-blind placebo controlled trial of HU in patients with SS and others were enrolled in an open label study. Determinants of erythropoietic activity included the reticulocyte count, red blood cell (RBC) survival by the 51Cr method, plasma 59Fe clearance, plasma iron turnover (PIT), erythron transferrin uptake (ETU), RBC production/destruction rate, and RBC Fe utilization. Therapy with HU increased the mean corpuscular volume (MCV), haemoglobin (Hb)F, RBC survival and t1/2 59Fe clearance; it decreased the reticulocyte count, the white blood cell (WBC) count, ETU, and the PIT. Most of the changes in parameters of erythropoiesis could be explained by the increase in 51Cr RBC survival after therapy with HU. Together the data showed that in selected patients the net effect of HU on Hb level was a function of the difference between the suppressive effect of HU (decreased RBC production) and the increase in RBC survival. In the majority of patients who responded to HU, there was a preferential effect on RBC survival.

In vitro storage and in vivo survival studies of red cells from persons with the In(Lu) gene.

Red cells (RBCs) of individuals with the In(Lu) gene are characterized by suppression of the Lutheran, P1, i, and other blood group antigens, acanthocytosis, and abnormal electrolyte metabolism. To determine the clinical significance of these abnormalities, the survival of autologous RBCs was determined by 51Cr in two siblings with the dominant Lu(a-b-) [In(Lu)] phenotype. Both subjects studied had normal hemoglobin, hematocrit, reticulocyte count, haptoglobin, and ferritin values. RBC indices were mildly hypochromic. Examination of the peripheral smear showed mild acanthocytosis in one individual. Analysis of RBC distribution on discontinuous density gradients showed a shift to lighter fractions than normal control RBCs. Storage of these Lu (a-b-) RBCs at 4 degrees C showed significant hemolysis within a few days; this was confirmed by increased autohemolysis, which was reduced by glucose and ATP. RBC cation content (sodium and potassium) was higher than that in control cells, which indicated increased cell hydration, which explains the lighter density and mild hypochromia of the Lu(a-b-) RBCs. 51Cr survival of autologous Lu(a-b-) RBCs was normal in both subjects studied. The data indicate that the morphologic and cation abnormalities of RBCs of persons with the In(Lu) gene are clinically insignificant, as these cells have normal in vivo survival. Such RBCs, however, are susceptible to increased hemolysis in vitro under standard blood banking storage conditions. Individuals of the Lu(a-b-) phenotype, associated with In(Lu), may not be suitable candidates for routine blood donation.

A clinically significant anti-N in a patient whose red cells were negative for N and U antigens.

A patient with sickle cell anemia had M+N-S-s-U-phenotype and developed anti-E, anti-U, and anti-N after multiple transfusions. The anti-N was IgG, showed positive red cell mononuclear phagocyte assay, caused shortened survival of 51Cr-labeled N+ red cells, and incited a delayed hemolytic transfusion reaction. The anti-U also caused decreased survival of U+ cells. The serological findings indicated that the anti-N recognized both N and 'N' antigens.