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Background: Some patients with sickle cell anemia (SS) experience significant decrease in their hemoglobin (Hb) level and significant increase in reticulocyte count during the progression of uncomplicated acute painful episodes. These changes have been attributed to, but not proven, hyperhemolysis. This study provides evidence of hyperhemolysis in this group of patients., Study Design and Methods: Hospitalized patients who met the above criteria were identified and followed prospectively, and the measures of red blood cell (RBC) survival were determined. The latter included 1) laboratory measures of hemolysis: Hb level, reticulocyte count, nucleated RBC count, RBC distribution width (RDW), total bilirubin, lactate dehydrogenase (LDH), and aspartate transaminase (AST); 2) determination of RBC survival in vivo by the (51)Cr method in selected patients; and 3) the determination of the RBC Hb:reticulocyte Hb ratio. Baseline values of these measures were also obtained and compared to the crisis data., Results: During the evolution of the painful episode in the selected patients, there was a significant increase in total bilirubin, LDH, AST, nucleated RBC count, and RDW that are indicative of hyperhemolysis. There was a significant decrease in RBC Hb:reticulocyte Hb and (51)Cr RBC survival, which is diagnostic of hyperhemolysis., Conclusion: Together, the data indicate that hyperhemolysis occurs during uncomplicated acute painful episodes in some patients with SS. The presence of free plasma Hb, consequent to hyperhemolysis, reduces nitric oxide bioavailability, promotes endothelial dysfunction, and contributes to the development of pulmonary hypertension and vasoocclusion.

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.

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.

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.