Skip to main content
PMC home page
Journal of Clinical Laboratory Analysis logoLink to Journal of Clinical Laboratory Analysis
. 2003 Mar 7;17(2):66–72. doi: 10.1002/jcla.10070

Reticulocyte parameters and hemoglobin F production in sickle cell disease patients undergoing hydroxyurea therapy

R Borba 1, CSP Lima 1, HZW Grotto 1,✉
PMCID: PMC6807693  PMID: 12640630

Abstract

Hemoglobin F (HbF) is an effective inhibitor of HbS polymerization. Hydroxyurea (HU) is used to increase HbF synthesis and improve the clinical course of sickle cell disease (SCD) patients. We studied a series of laboratory parameters concerning HbF production and reticulocyte response, and compared data between two groups: 1) 13 SCD patients treated with HU, and 2) 33 untreated SCD patients. Higher values of Hb concentration, mean cell volume (MCV), mean cell hemoglobin (MCH), mean reticulocyte volume (MRV), HbF concentration, percentage of F‐cells, and amount of HbF/F‐cells were observed in the treated group of patients. There was no correlation between Hb and HbF elevations. The reticulocyte count, immature reticulocyte count, mean fluorescence index (MFI), and neutrophil count were significantly lower in treated patients. Taken together, these findings suggest that a decreased hemolytic process occurred in patients undergoing HU treatment. There was a significant correlation between MCV and HbF, between MRV and HbF, and between MRV and F‐cell in patients taking HU. These data indicate that macroreticulocytes correspond to F‐reticulocytes, and that an increase in MRV in SCD patients using HU may be an indirect signal of F‐cell production. The concentration of HbF/F‐cells was higher in patients treated with HU, but this increase apparently was independent of F‐cell production. Reticulocyte (RTC) parameters, as assessed by hematological analyzers, may be useful for following erythropoietic changes in patients receiving HU, and can indirectly indicate HbF and F‐cell production induced by HU therapy. J. Clin. Lab. Anal. 17:66–72, 2003. © 2003 Wiley‐Liss, Inc.

Keywords: sickle cell anemia, F‐cells, hydroxyurea, reticulocyte immaturity

REFERENCES

  • 1. Goldberg MA, Husson MA, Bunn HF. 1977. The participation of hemoglobins A and F in the polymerization of sickle hemoglobin. J Biol Chem 252:3414–3421. [PubMed] [Google Scholar]
  • 2. Yarbro JW. 1992. Mechanism of action of hydroxyurea. Semin Oncol 19:1–10. [PubMed] [Google Scholar]
  • 3. Charache S, Dover GJ, Moore RD, et al. 1992. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood 79:2555–2565. [PubMed] [Google Scholar]
  • 4. Lima CSP, Arruda VR, Costa FF, Saad STO. 1997. Minimal doses of hydroxyurea for sickle cell disease. Brazil J Med Biol Res 30:933–940. [DOI] [PubMed] [Google Scholar]
  • 5. Blau C, Constantoulakis P, Al‐Khatti A, et al. 1993. Fetal hemoglobin in acute and chronic states of erythroid expansion. Blood 81:227–233. [PubMed] [Google Scholar]
  • 6. Nagel RL, Vichhinsky E, Shah M, et al. 1993. F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: a double‐blind study. Blood 81:9–14. [PubMed] [Google Scholar]
  • 7. Steinberg MH, Nagel RL, Brugnara C. 1997. Cellular effects of hydroxyurea in Hb SC disease. Br J Haematol 98:838–844. [DOI] [PubMed] [Google Scholar]
  • 8. Brugnara C. 1998. Use of reticulocyte cellular indices in the diagnosis and treatment of hematological disorders. Int J Clin Lab Res 28:1–11. [DOI] [PubMed] [Google Scholar]
  • 9. Tsuda I, Tatsumi N. 1989. Maturity of reticulocytes in various hematological disorders. Eur J Haematol 43:252–254. [DOI] [PubMed] [Google Scholar]
  • 10. D'Onofrio G, Tichelli A, Foures C, Theodorsen L. 1996. Indicators of haematopoietic recovery after bone marrow transplantation: the role of reticulocyte measurements. Clin Lab Haematol 18:45–53. [PubMed] [Google Scholar]
  • 11. Cavill I. 1993. Annotation. The rejected reticulocyte. Br J Haematol 84:563–565. [DOI] [PubMed] [Google Scholar]
  • 12. Davies SV, Cavill I, Bentley N, Fegan CD, Poyton CH, Whittaker JA&!Aacute;. 1992. Evaluation of erythropoiesis after bone marrow transplantation: quantitative reticulocyte counting. Br J Haematol 81:12–17. [DOI] [PubMed] [Google Scholar]
  • 13. Grotto HZW, Vigoritto AC, Noronha JFA, Lima GALM. 1999. Immature reticulocyte fraction as a criterion for marrow engraftment. Evaluation of a semi‐automated reticulocyte counting method. Clin Lab Haematol 21:285–287. [DOI] [PubMed] [Google Scholar]
  • 14. Dacie JV, Lewis SM, editors. 1995. Practical hematology. Edinburgh: Churchill Livingstone: p 240–286. [Google Scholar]
  • 15. Weatherall DJ, Clegg JB, editors. 1972. The thalassemia syndrome. Oxford: Blackwell Scientific Publishing: p 744–769. [Google Scholar]
  • 16. Pembrey ME, MacWade P, Weatherall DJ. 1972. Reliable routine estimation of small amounts of foetal hemoglobin by alkali denaturation. J Clin Pathol 25:738–740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Marcus SJ, Ware RE. 1999. Physiologic decline in fetal hemoglobin parameters in infants with sickle cell disease: implications for pharmacological intervention. J Pediatr Hematol Oncol 21:407–411. [DOI] [PubMed] [Google Scholar]
  • 18. Rodgers GP. 1997. Overview of pathophysiology and rationale for treatment of sickle cell anemia. Semin Hematol 34:2–7. [PubMed] [Google Scholar]
  • 19. Pearson HA. 1996. Pharmacologic manipulation of fetal hemoglobin levels in sickle cell diseases and thalassemia: promise and reality. Adv Pediatr 43:309–334. [PubMed] [Google Scholar]
  • 20. Olivieri NF, Weatherall DJ. 1998. The therapeutic reactivation of fetal hemoglobin. Hum Mol Genet 7:1655–1658. [DOI] [PubMed] [Google Scholar]
  • 21. Brugnara C, Zelmanovic D, Sorette M, Ballas SK, Platt O. 1997. Reticulocyte hemoglobin. An integrated parameter for evaluation of erythropoietic activity. Am J Clin Pathol 108:133–142. [DOI] [PubMed] [Google Scholar]
  • 22. Torres A, Sânchez J, Lakomsky D, et al. 2001. Assessment of hematologic progenitor engraftment by complete reticulocyte maturation parameters after autologous and allogeneic hematopoietic stem cell transplantation. Haematologica 86:24–29. [PubMed] [Google Scholar]
  • 23. Chang C‐C, Kass L. 1997. Clinical significance of immature reticulocyte fraction determined by automated reticulocyte counting. Am J Clin Pathol 108:69–73. [PubMed] [Google Scholar]
  • 24. Grotto HZW, Noronha JFA. 2000. Evaluation of reticulocyte counting using the Pentra 120 Retic automated haematology analyzer: clinical application of mean fluorescence index (MFI) in bone marrow transplantation. J Bras Patol 36:234–240. [Google Scholar]
  • 25. Ballas SK, Dover GJ, Charache S. 1989. Effect of hydroxyurea on the rheological properties of sickle erythrocytes in vivo. Am J Hematol 32:104–111. [DOI] [PubMed] [Google Scholar]
  • 26. Ballas SK, Marcolina MJ, Dover GJ, Barton FB, Investigators of the Multicenter Study of HydroxyuAnemi Anemi. 1999. Erythropoietic activity in patients with sickle cell anaemia before and after treatment with hydroxyurea. Br J Haematol 105:491–496. [PubMed] [Google Scholar]
  • 27. Ohene‐Frempong K, Smith‐Whitley K. 1997. Use of hydroxyurea in children with sickle cell disease: what comes next?. Semin Hematol 34:30–41. [PubMed] [Google Scholar]
  • 28. Milner PF, Garbutt GJ, Nolan‐Davis LV, Jonah F, Wilson LB, Wilson JT. 1986. The effect of HbF and alpha‐thalassemia on the red cell indices in sickle‐cell anemia. Am J Hematol 21:383–395. [DOI] [PubMed] [Google Scholar]
  • 29. Miller MK, Zimmerman SA, Schultz WH, Ware RE. 2001. Hydroxyurea therapy for pediatric patients with hemoglobin SC disease. J Pediatr Hematol Oncol 23:306–308. [DOI] [PubMed] [Google Scholar]
  • 30. Dover GJ, Boyer SH, Charache S, Heintzelman K. 1978. Individual variation in the production and survival of F cells in sickle‐cell disease. N Engl J Med 299:1428–1435. [DOI] [PubMed] [Google Scholar]
  • 31. Maier‐Redelsperger M, Elion J, Girot R. 1998. F reticulocytes assay: a method to evaluate fetal hemoglobin production. Hemoglobin 22:419–425. [DOI] [PubMed] [Google Scholar]
  • 32. Wood WG, Stamatoyannopoulos G, Lim G, Nute PE. 1975. F‐cells in the adult: normal values and levels in individuals with hereditary and acquired elevations of HbF. Blood 46:671–682. [PubMed] [Google Scholar]
  • 33. Marcus ST, Kinney TR, Schultz WH, O'Branski EE, Ware RE. 1997. Quantitative analysis of erythrocytes containing fetal hemoglobin (F cells) in children with sickle cell disease. Am J Hematol 54:40–46. [DOI] [PubMed] [Google Scholar]
  • 34. Dover GG, Charache S. 1992. Hydroxyurea induction of fetal hemoglobin synthesis in sickle‐cell disease. Semin Oncol 19:61–66. [PubMed] [Google Scholar]
  • 35. Maier‐Redelsperger M, Noguchi CT, de Montalembert M, et al. 1994. Variation in fetal hemoglobin parameters and predicted hemoglobin S polymerization in sickle cell children in the first two years of life: Parisian prospective study on sickle cell disease. Blood 84:3182–3188. [PubMed] [Google Scholar]
  • 36. Bridges KR, Barabino GD, Brugnara C, et al. 1996. A multiparameter analysis of sickle erythrocytes in patients undergoing hydroxyurea therapy. Blood 88:4701–4710. [PubMed] [Google Scholar]
  • 37. Charache S. 1997. Mechanism of action of hydroxyurea in the management of sickle cell anemia in adults. Semin Hematol 34:15–21. [PubMed] [Google Scholar]

Articles from Journal of Clinical Laboratory Analysis are provided here courtesy of Wiley

RESOURCES