Aggiornamento monografico
L'anemia falciforme
SICKLE CELL DISEASE
MARZIA LAZZERINI1, MARCO RABUSIN2
1UOC di Pronto Soccorso e Primo Accoglimento, 2UO di Emato - Oncologia, Dipartimento di Pediatria, IRCCS “Burlo Garofolo”, Università di Trieste
Aprile 2006 - pagg. 223 -234
Abstract
Sickle cell disease (SCD) is one of the most prevalent haemoglobinopathies in the world, being related to areas where malaria is or was endemic. In Italy the majority of patients still live in Sicily, where the overall HbS gene frequency is 2%. Domestic migration and recent immigration from foreign countries, in particular from Africa, has contributed to the further diffusion of SCD in Central and Northern Italy. With the global scope of SCD, paediatricians need to be familiar with the knowledge of its clinical presentations and treatment. Much progress has been made during the past decades in understanding its natural history and management. This review addresses the current knowledge on SCD epidemiology, pathophysiology, diagnosis, clinical features, prognosis, treatment and prevention. Guidelines of the management of its most serious complications, as acute chest syndrome, stroke, priapism, pain episodes and indication to transfusion therapy, hydroxyurea, bone marrow transplantation are discussed.
Parole chiave
Suggerite dall'AI
Classificazione MeSH
Bibliografia
1. Stuart MJ, Nagel RL. Sickle-cell disease.
Lancet 2004;364(9442):1343-60.
2. Ragusa A, Lombardo M, Sortino G, et al. Beta S gene in Sicily is in linkage disequilibrium with the Benin haplotype: implications for gene flow. Am J Hematol 1988;27(2):139-41.
3. Sammarco P, Giambona A, Lo Gioco P, et al. Evidence of the African origin of sickle cell hemoglobin in western Sicily. Hemoglobin 1988; 12(2):193-6.
4. Martins MC, Olim G, Melo J, et al. Hereditary anaemias in Portugal: epidemiology, public health significance, and control. J Med Genet 1993;30(3):235-9.
5. Steinberg MH. Management of sickle cell disease. N Engl J Med 1999;340(13):1021-30.
6. Alvares Filho F, Naoum PC, Moreira HW, Cruz R, Manzato AJ, Domingos CR. Age and racial geographic distribution of S hemoglobin in Brazil. Sangre (Barc) 1995;40(2):97-102.
7. Athanassiou-Metaxa M, Kirkos J, Koussi A, Hatzipantelis E, Tsatra I, Economou M. Aascular necrosis of the femoral head among children and adolescents with sickle cell disease in Greece. Haematologica 2002; 87(7): 771-2.
8. Kocak R, Alparslan ZN, Agridag G, Baslamisli F, Aksungur PD, Koltas S. The frequency of anaemia, iron deficiency, hemoglobin S and beta thalassemia in the south of Turkey. Eur J Epidemiol 1995;11(2):181-4.
9. Schiliro G, Spena M, Giambelluca E, Maggio A. Sickle hemoglobinopathies in Sicily. Am J Hematol 1990;33(2):81-5.
10. Fournier C, Benkerrou M, Vilmer E, et al. Development of care activities for children with sickle cell disease at the Robert-Debre Hospital (Paris), between 1992 and 1996. Arch Pediatr 2000;7(5):465-73.
11. Dulin Inigueza E, Cantalejo Lopez MA, et al. Early detection of sickle cell anemia and other hemoglobinopathies in neonates in the Autonomous Community of Madrid. A pilot study An Pediatr (Barc) 2003;58(2):146-55.
12. Hickman M, Modell B, Greengross P, et al. Mapping the prevalence of sickle cell and beta thalassaemia in England: estimating and validating ethnic-specific rates. Br J Haematol 1999;104(4):860-7.
13. Russo-Mancuso G, La Spina M, Schiliro G. The changing profile of sickle cell disease in Italy. Eur J Epidemiol 2003;18(9):923-4.
14. Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997;337 (11):762-9
15. McMahon L EC, Mark EJ. Case 34-1997 - A 22 - Year-Old Man with a Sickle Cell Crisis and Sudden Death. N Engl J Med 1997;337:1293- 301.
16. Claster S, Vichinsky EP. Managing sickle cell disease. BMJ 2003;327(7424):1151-5.
17. Schiliro G, Samperi P, Testa R, et al. Cinical, hematological, and molecular features in Sicilians with Hb S-beta-thalassemia. Am J Hematol 1992;41(4):264-9.
18. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med 2000;342(25):1855-65.
19. Maitre B, Habibi A, Roudot-Thoraval F, et al. Acute chest syndrome in adults with sickle cell disease. Chest 2000;117(5):1386-92.
20. Juwah AI, Nlemadim EU, Kaine W. Types of anaemic crises in paediatric patients with sickle cell anaemia seen in Enugu, Nigeria. Arch Dis Child 2004;89(6):572-6.
21. Wigfall DR, Ware RE, Burchinal MR, et al. Prevalence and clinical correlates of glomerulopathy in children with sickle cell disease. J Pediatr 2000;136(6):749-53.
22. Foucan L, Bourhis V, Bangou J, et al. A randomized trial of captopril for microalbuminuria in normotensive adults with sickle cell anemia. Am J Med 1998;104(4):339-42.
23. Falk RJ, Scheinman J, Phillips G, et al. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin- converting enzyme. N Engl J Med 1992;326(14):910-5.
24. Adams RJ, Ohene-Frempong K, Wang W. Sickle cell and the brain.Hematology (Am Soc Hematol Educ Program) 2001;31-46.
25. Maunoury C, Acar P, de Montalembert M, et al. Myocardial perfusion in children with sickle cell disease. Am J Cardiol 2003;91(3): 374-6.
26. Sylvester KP, Patey RA, Milligan P, et al. A.Pulmonary function abnormalities in children with sickle cell disease. Thorax 2004;59 (1):67-70.
27. Gladwin MT, Sachdev V, Jison ML, et al. Plmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 2004;350(9):886-95.
28. Vichinsky EP. Pulmonary hypertension in sickle cell disease. N Engl J Med 2004; 350 (9):857-9.
29. Samperi P, Consalvo C, Romano V, Gelardi S, Du Bella D, Schilliro G. Liver involvement in white patients with sickle-cell disease. Arch Pediatr Adolesc Med 1996; 150(11):1177-80.
30. Kark JA, Ward FT. Exercise and hemoglobin S. Semin Hematol 1994;31(3):181-225.
31. Thiriet P, Le Hesran JY, Wouassi D, et al. Sickle cell trait performance in a prolonged race at high altitude. Med Sci Sports Exerc 1994;26(7):914-8.
32. Quinn CT, Rogers ZR, Buchanan GR. Survival of children with sickle cell disease. Blood 2004;103(11):4023-7.
33. Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood 1995;86 (2):776-83.
34. Lee A, Thomas P, Cupidore L, et al. Improved survival in homozygous sickle cell disease: lessons from a cohort study. BMJ 1995; 311(7020):1600-2.
35. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994;330(23):1639-44.
36. Diallo D, Tchernia G. Sickle cell disease in Africa. Curr Opin Hematol 2002;9(2):111-6.
37. Miller ST, Sleeper LA, Pegelow CH, et al. Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med 2000; 342(2):83-9.
38. Lees CM, Davies S, Dezateux C. Neonatal screening for sickle cell disease. Cochrane Database Syst Rev 2000;(2):CD001913.
39. Yang YM, Andrews S, Peterson R, et al. Prenatal sickle cell screening education effect on the follow-up rates of infants with sickle cell trait. Patient Educ Couns 2000;39(2-3):185-9.
40. Gil KM, Anthony KK, Carson JW, et al. Daily coping practice predicts treatment effects in children with sickle cell disease. J Pediatr Psychol 2001;26(3):163-73.
41. Zemel BS, Kawchak DA, Fung EB, et al. Effect of zinc supplementation on growth and body composition in children with sickle cell disease. Am J Clin Nutr 2002;75(2):300-7.
42. Prasad AS, Beck FW, Kaplan J, et al. Effect of zinc supplementation on incidence of infections and hospital admissions in sickle cell disease (SCD). Am J Hematol 1999;61(3):194- 202.
43. Riddington C, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease. Cochrane Database Syst Rev 2002;(3):CD003427.
44. Woods GM, Jorgensen JH, Waclawiw M, et al. Influence of penicillin prophylaxis on antimicrobial resistance in nasopharyngeal S. pneumoniae among children with sickle cell anemia. The Ancillary Nasopharyngeal Culture Study of Prophylactic Penicillin Study II. Pediatr Hematol Oncol 1997;19(4):327-33.
45. Davies EG, Riddington C, Lottenberg R, et al. Pneumococcal vaccines for sickle cell disease. Cochrane Database Syst Rev 2004;(1): CD003885.
46. American Academy of Pediatrics. Vaccinations. In: Pickering LK (ed). Red Book 2003. Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2003.
47. Oniyangi O, Omari AA. Malaria chemoprophylaxis in sickle cell disease. Cochrane Database Syst Rev 2003;(3):CD003489.
48. Riddington C, Williamson L. Preoperative blood transfusions for sickle cell disease. Cochrane Database Syst Rev 2001;(3):CD003149.
49. Owusu-Ofori S, Riddington C. Splenectomy versus conservative management for acute sequestration crises in people with sickle cell disease. Cochrane Database Syst Rev 2002;(4):CD003425.
50. Koshy M, Burd L, Wallace D, Moawad A, et al. Prophylactic red-cell transfusions in pregnant patients with sickle cell disease. A randomized cooperative study. N Engl J Med 1988;319(22):1447-52.
51. Riddington C, Wang W. Blood transfusion for preventing stroke in people with sickle cell disease. Cochrane Database Syst Rev 2002; (1):CD003146.
52. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339(1):5-11.
53. Adams RJ, Brambilla DJ, Granger S, et al. Impact of chronic transfusion on incidence of pain and acute chest syndrome during the Stroke Prevention Trial (STOP) in sickle-cell anemia. J Pediatr 2001;139(6):785-9.
54. Harmatz P, Butensky E, Quirolo K, et al. Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy. Blood 2000;96(1):76- 9.
55. Silliman CC, Peterson VM, Mellman DL, et al. Iron chelation by deferoxamine in sickle cell patients with severe transfusion-induced hemosiderosis: a randomized, doubleblind study of the dose-response relationship. J Lab Clin Med 1993;122(1):48-54.
56. Hoffbrand AV, AL-Refaie F, Davis B, et al. Long-term trial of deferiprone in 51 transfusion- dependent iron overloaded patients. Blood 1998;91(1):295-300.
57. Hilliard LM, Williams BF, Lounsbury AE, et al. Erythrocytapheresis limits iron accumulation in chronically transfused sickle cell patients. Am J Hematol 1998;59(1):28-35.
58. Davies S, Olujohungbe A. Hydroxyurea for sickle cell disease. Cochrane Database Syst Rev 2001;(2):CD002202.
59. Steinberg MH, Barton F, Castro O, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA 2003;289(13):1645-51.
60. Halsey C, Roberts IA. The role of hydroxyurea in sickle cell disease. Br J Haematol 2003;120(2):177-86.
61. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995; 332 (20):1317-22.
62. Charache S, Barton FB, Moore RD, et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive “switching” agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore) 1996;75(6):300-26.
63. Zimmerman SA, Schultz WH, Davis JS, et al. Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Blood 2004; 103(6):2039-45.
64. Wang WC, Wynn LW, Rogers ZR, et al. A two-year pilot trial of hydroxyurea in very young children with sickle-cell anemia. J Pediatr 2001;139(6):790-6.
65. Rigano P, Rodgers GP, Renda D, et al. Clinical and hematological responses to hydroxyurea in Sicilian patients with Hb S/betathalassemia. Hemoglobin 2001;25(1):9-17.
66. Amrolia PJ, Almeida A, Halsey C, Roberts IA, Davies SC. Therapeutic challenges in childhood sickle cell disease. Part 1: Current and future treatment options. Br J Haematol 2003;120(5):725-36.
67. Walters MC, Storb R, Patience M, et al. Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease. Blood 2000;95(6):1918-24.
68. Walters MC, Patience M, Leisenring W, et al. Multicenter Investigation of Bone Marrow Transplantation for Sickle Cell Disease. Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia. Biol Blood Marrow Transplant 2001;7 (12):665-73.
69. Locatelli F, Rocha V, Reed W, et al. Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood 2003;101(6):2137-43.
70. Orringer EP, Casella JF, Ataga KI, et al. Purified Poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: a randomized controlled trial. JAMA 2001;286 (17):2099-106.
71. Schnog JB, Kater AP, Mac Gillavry MR, et al. Low adjusted-dose acenocoumarol therapy in sickle cell disease: a pilot study. Am J Hematol 2001;68(3):179-83.
72. Semple MJ, Al-Hasani SF, Kioy P, et al. A double-blind trial of ticlopidine in sickle cell disease. Thromb Haemost 1984;51(3):303-6.
73. Zago MA, Costa FF, Ismael SJ, et al. Treatment of sickle cell diseases with aspirin. Acta Haematol 1984;72(1):61-4.
74. Greenberg J, Ohene-Frempong K, Halus J, Way C, Schwartz E. Trial of low doses of aspirin as prophylaxis in sickle cell disease. J Pediatr 1983;102(5):781-4.
75. Rodgers GP, Roy MS, Noguchi CT, et al. Is there a role for selective vasodilation in the management of sickle cell disease? Blood 1988;71(3):597-602.
76. Morris CR, Morris SM Jr, Hagar W, et al. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med 2003;168(1):63-9.
77. Weiner DL, Hibberd PL, Betit P, et al. Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease. JAMA 2003; 289(9): 1136-42.
2. Ragusa A, Lombardo M, Sortino G, et al. Beta S gene in Sicily is in linkage disequilibrium with the Benin haplotype: implications for gene flow. Am J Hematol 1988;27(2):139-41.
3. Sammarco P, Giambona A, Lo Gioco P, et al. Evidence of the African origin of sickle cell hemoglobin in western Sicily. Hemoglobin 1988; 12(2):193-6.
4. Martins MC, Olim G, Melo J, et al. Hereditary anaemias in Portugal: epidemiology, public health significance, and control. J Med Genet 1993;30(3):235-9.
5. Steinberg MH. Management of sickle cell disease. N Engl J Med 1999;340(13):1021-30.
6. Alvares Filho F, Naoum PC, Moreira HW, Cruz R, Manzato AJ, Domingos CR. Age and racial geographic distribution of S hemoglobin in Brazil. Sangre (Barc) 1995;40(2):97-102.
7. Athanassiou-Metaxa M, Kirkos J, Koussi A, Hatzipantelis E, Tsatra I, Economou M. Aascular necrosis of the femoral head among children and adolescents with sickle cell disease in Greece. Haematologica 2002; 87(7): 771-2.
8. Kocak R, Alparslan ZN, Agridag G, Baslamisli F, Aksungur PD, Koltas S. The frequency of anaemia, iron deficiency, hemoglobin S and beta thalassemia in the south of Turkey. Eur J Epidemiol 1995;11(2):181-4.
9. Schiliro G, Spena M, Giambelluca E, Maggio A. Sickle hemoglobinopathies in Sicily. Am J Hematol 1990;33(2):81-5.
10. Fournier C, Benkerrou M, Vilmer E, et al. Development of care activities for children with sickle cell disease at the Robert-Debre Hospital (Paris), between 1992 and 1996. Arch Pediatr 2000;7(5):465-73.
11. Dulin Inigueza E, Cantalejo Lopez MA, et al. Early detection of sickle cell anemia and other hemoglobinopathies in neonates in the Autonomous Community of Madrid. A pilot study An Pediatr (Barc) 2003;58(2):146-55.
12. Hickman M, Modell B, Greengross P, et al. Mapping the prevalence of sickle cell and beta thalassaemia in England: estimating and validating ethnic-specific rates. Br J Haematol 1999;104(4):860-7.
13. Russo-Mancuso G, La Spina M, Schiliro G. The changing profile of sickle cell disease in Italy. Eur J Epidemiol 2003;18(9):923-4.
14. Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997;337 (11):762-9
15. McMahon L EC, Mark EJ. Case 34-1997 - A 22 - Year-Old Man with a Sickle Cell Crisis and Sudden Death. N Engl J Med 1997;337:1293- 301.
16. Claster S, Vichinsky EP. Managing sickle cell disease. BMJ 2003;327(7424):1151-5.
17. Schiliro G, Samperi P, Testa R, et al. Cinical, hematological, and molecular features in Sicilians with Hb S-beta-thalassemia. Am J Hematol 1992;41(4):264-9.
18. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med 2000;342(25):1855-65.
19. Maitre B, Habibi A, Roudot-Thoraval F, et al. Acute chest syndrome in adults with sickle cell disease. Chest 2000;117(5):1386-92.
20. Juwah AI, Nlemadim EU, Kaine W. Types of anaemic crises in paediatric patients with sickle cell anaemia seen in Enugu, Nigeria. Arch Dis Child 2004;89(6):572-6.
21. Wigfall DR, Ware RE, Burchinal MR, et al. Prevalence and clinical correlates of glomerulopathy in children with sickle cell disease. J Pediatr 2000;136(6):749-53.
22. Foucan L, Bourhis V, Bangou J, et al. A randomized trial of captopril for microalbuminuria in normotensive adults with sickle cell anemia. Am J Med 1998;104(4):339-42.
23. Falk RJ, Scheinman J, Phillips G, et al. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin- converting enzyme. N Engl J Med 1992;326(14):910-5.
24. Adams RJ, Ohene-Frempong K, Wang W. Sickle cell and the brain.Hematology (Am Soc Hematol Educ Program) 2001;31-46.
25. Maunoury C, Acar P, de Montalembert M, et al. Myocardial perfusion in children with sickle cell disease. Am J Cardiol 2003;91(3): 374-6.
26. Sylvester KP, Patey RA, Milligan P, et al. A.Pulmonary function abnormalities in children with sickle cell disease. Thorax 2004;59 (1):67-70.
27. Gladwin MT, Sachdev V, Jison ML, et al. Plmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 2004;350(9):886-95.
28. Vichinsky EP. Pulmonary hypertension in sickle cell disease. N Engl J Med 2004; 350 (9):857-9.
29. Samperi P, Consalvo C, Romano V, Gelardi S, Du Bella D, Schilliro G. Liver involvement in white patients with sickle-cell disease. Arch Pediatr Adolesc Med 1996; 150(11):1177-80.
30. Kark JA, Ward FT. Exercise and hemoglobin S. Semin Hematol 1994;31(3):181-225.
31. Thiriet P, Le Hesran JY, Wouassi D, et al. Sickle cell trait performance in a prolonged race at high altitude. Med Sci Sports Exerc 1994;26(7):914-8.
32. Quinn CT, Rogers ZR, Buchanan GR. Survival of children with sickle cell disease. Blood 2004;103(11):4023-7.
33. Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood 1995;86 (2):776-83.
34. Lee A, Thomas P, Cupidore L, et al. Improved survival in homozygous sickle cell disease: lessons from a cohort study. BMJ 1995; 311(7020):1600-2.
35. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994;330(23):1639-44.
36. Diallo D, Tchernia G. Sickle cell disease in Africa. Curr Opin Hematol 2002;9(2):111-6.
37. Miller ST, Sleeper LA, Pegelow CH, et al. Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med 2000; 342(2):83-9.
38. Lees CM, Davies S, Dezateux C. Neonatal screening for sickle cell disease. Cochrane Database Syst Rev 2000;(2):CD001913.
39. Yang YM, Andrews S, Peterson R, et al. Prenatal sickle cell screening education effect on the follow-up rates of infants with sickle cell trait. Patient Educ Couns 2000;39(2-3):185-9.
40. Gil KM, Anthony KK, Carson JW, et al. Daily coping practice predicts treatment effects in children with sickle cell disease. J Pediatr Psychol 2001;26(3):163-73.
41. Zemel BS, Kawchak DA, Fung EB, et al. Effect of zinc supplementation on growth and body composition in children with sickle cell disease. Am J Clin Nutr 2002;75(2):300-7.
42. Prasad AS, Beck FW, Kaplan J, et al. Effect of zinc supplementation on incidence of infections and hospital admissions in sickle cell disease (SCD). Am J Hematol 1999;61(3):194- 202.
43. Riddington C, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease. Cochrane Database Syst Rev 2002;(3):CD003427.
44. Woods GM, Jorgensen JH, Waclawiw M, et al. Influence of penicillin prophylaxis on antimicrobial resistance in nasopharyngeal S. pneumoniae among children with sickle cell anemia. The Ancillary Nasopharyngeal Culture Study of Prophylactic Penicillin Study II. Pediatr Hematol Oncol 1997;19(4):327-33.
45. Davies EG, Riddington C, Lottenberg R, et al. Pneumococcal vaccines for sickle cell disease. Cochrane Database Syst Rev 2004;(1): CD003885.
46. American Academy of Pediatrics. Vaccinations. In: Pickering LK (ed). Red Book 2003. Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2003.
47. Oniyangi O, Omari AA. Malaria chemoprophylaxis in sickle cell disease. Cochrane Database Syst Rev 2003;(3):CD003489.
48. Riddington C, Williamson L. Preoperative blood transfusions for sickle cell disease. Cochrane Database Syst Rev 2001;(3):CD003149.
49. Owusu-Ofori S, Riddington C. Splenectomy versus conservative management for acute sequestration crises in people with sickle cell disease. Cochrane Database Syst Rev 2002;(4):CD003425.
50. Koshy M, Burd L, Wallace D, Moawad A, et al. Prophylactic red-cell transfusions in pregnant patients with sickle cell disease. A randomized cooperative study. N Engl J Med 1988;319(22):1447-52.
51. Riddington C, Wang W. Blood transfusion for preventing stroke in people with sickle cell disease. Cochrane Database Syst Rev 2002; (1):CD003146.
52. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339(1):5-11.
53. Adams RJ, Brambilla DJ, Granger S, et al. Impact of chronic transfusion on incidence of pain and acute chest syndrome during the Stroke Prevention Trial (STOP) in sickle-cell anemia. J Pediatr 2001;139(6):785-9.
54. Harmatz P, Butensky E, Quirolo K, et al. Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy. Blood 2000;96(1):76- 9.
55. Silliman CC, Peterson VM, Mellman DL, et al. Iron chelation by deferoxamine in sickle cell patients with severe transfusion-induced hemosiderosis: a randomized, doubleblind study of the dose-response relationship. J Lab Clin Med 1993;122(1):48-54.
56. Hoffbrand AV, AL-Refaie F, Davis B, et al. Long-term trial of deferiprone in 51 transfusion- dependent iron overloaded patients. Blood 1998;91(1):295-300.
57. Hilliard LM, Williams BF, Lounsbury AE, et al. Erythrocytapheresis limits iron accumulation in chronically transfused sickle cell patients. Am J Hematol 1998;59(1):28-35.
58. Davies S, Olujohungbe A. Hydroxyurea for sickle cell disease. Cochrane Database Syst Rev 2001;(2):CD002202.
59. Steinberg MH, Barton F, Castro O, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA 2003;289(13):1645-51.
60. Halsey C, Roberts IA. The role of hydroxyurea in sickle cell disease. Br J Haematol 2003;120(2):177-86.
61. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995; 332 (20):1317-22.
62. Charache S, Barton FB, Moore RD, et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive “switching” agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore) 1996;75(6):300-26.
63. Zimmerman SA, Schultz WH, Davis JS, et al. Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Blood 2004; 103(6):2039-45.
64. Wang WC, Wynn LW, Rogers ZR, et al. A two-year pilot trial of hydroxyurea in very young children with sickle-cell anemia. J Pediatr 2001;139(6):790-6.
65. Rigano P, Rodgers GP, Renda D, et al. Clinical and hematological responses to hydroxyurea in Sicilian patients with Hb S/betathalassemia. Hemoglobin 2001;25(1):9-17.
66. Amrolia PJ, Almeida A, Halsey C, Roberts IA, Davies SC. Therapeutic challenges in childhood sickle cell disease. Part 1: Current and future treatment options. Br J Haematol 2003;120(5):725-36.
67. Walters MC, Storb R, Patience M, et al. Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease. Blood 2000;95(6):1918-24.
68. Walters MC, Patience M, Leisenring W, et al. Multicenter Investigation of Bone Marrow Transplantation for Sickle Cell Disease. Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia. Biol Blood Marrow Transplant 2001;7 (12):665-73.
69. Locatelli F, Rocha V, Reed W, et al. Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood 2003;101(6):2137-43.
70. Orringer EP, Casella JF, Ataga KI, et al. Purified Poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: a randomized controlled trial. JAMA 2001;286 (17):2099-106.
71. Schnog JB, Kater AP, Mac Gillavry MR, et al. Low adjusted-dose acenocoumarol therapy in sickle cell disease: a pilot study. Am J Hematol 2001;68(3):179-83.
72. Semple MJ, Al-Hasani SF, Kioy P, et al. A double-blind trial of ticlopidine in sickle cell disease. Thromb Haemost 1984;51(3):303-6.
73. Zago MA, Costa FF, Ismael SJ, et al. Treatment of sickle cell diseases with aspirin. Acta Haematol 1984;72(1):61-4.
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