Blood Reviews
Volume 21, Issue 1 , Pages 37-47 , January 2007

Deconstructing sickle cell disease: Reappraisal of the role of hemolysis in the development of clinical subphenotypes

  • Gregory J. Kato

      Affiliations

    • Vascular Medicine Branch, National Heart, Lung and Blood Institute; Critical Care Medicine Department, Clinical Center, National Institutes of Health, 10 Center Drive, Building 10CRC 5-5140, Bethesda, MD 20892-1476, U.S.A.
    • Corresponding Author InformationCorresponding author. Tel.: +1 301 451 8497; fax: +1 301 451 7091.
    • ,
  • Mark T. Gladwin

      Affiliations

    • Vascular Medicine Branch, National Heart, Lung and Blood Institute; Critical Care Medicine Department, Clinical Center, National Institutes of Health, 10 Center Drive, Building 10CRC 5-5140, Bethesda, MD 20892-1476, U.S.A.
    • ,
  • Martin H. Steinberg

      Affiliations

    • Center of Excellence in Sickle Cell Disease, E248, Boston Medical Center, 88 E Newton St, Boston, MA 02118, U.S.A.

References 

  1. Ohene-Frempong K, Steinberg MH. Clinical Aspects of Sickle Cell Anemia in Adults and Children. In:  Steinberg MH,  Forget BG,  Higgs DR,  Nagel RL editor. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge: Cambridge University Press; 2001;p. 611–670
  2. De Ceulaer K, Higgs DR, Weatherall DJ, Hayes RJ, Serjeant BE, Serjeant GR. Alpha thalassemia reduces the hemolytic rate in homozygous sickle-cell disease. N Engl J Med. 1983;309:189–190
  3. Ballas SK, Marcolina MJ. Hyperhemolysis during the evolution of uncomplicated acute painful episodes in patients with sickle cell anemia. Transfusion. 2006;46:105–110
  4. Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO, Schechter AN, et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nature Medicine. 2002;8:1383–1389
  5. Gladwin MT, Kato GJ. Cardiopulmonary complications of sickle cell disease: role of nitric oxide and hemolytic anemia. Hematology (Am Soc Hematol Educ Program). 2005;51–57
  6. Hebbel RP. Auto-oxidation and a membrane-associated ‘Fenton reagent’: a possible explanation for development of membrane lesions in sickle erythrocytes. Clinics in Haematology. 1985;14:129–140
  7. Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, et al. Dysregulated Arginine Metabolism, Hemolysis-Associated Pulmonary Hypertension and Mortality in Sickle Cell Disease. JAMA. 2005;294:81–90
  8. Aslan M, Freeman BA. Oxidant-mediated impairment of nitric oxide signaling in sickle cell disease–mechanisms and consequences. Cell Mol Biol (Noisy.-le-grand). 2004;50:95–105
  9. Wood KC, Hebbel RP, Granger DN. Endothelial cell NADPH oxidase mediates the cerebral microvascular dysfunction in sickle cell transgenic mice. FASEB J. 2005;19:989–991
  10. Atichartakarn V, Angchaisuksiri P, Aryurachai K, Onpun S, Chuncharunee S, Thakkinstian A, et al. Relationship between hypercoagulable state and erythrocyte phosphatidylserine exposure in splenectomized haemoglobin E/beta-thalassaemic patients. Br J Haematol. 2002;118:893–898
  11. Atichartakarn V, Angchaisuksiri P, Aryurachai K, Chuncharunee S, Thakkinstian A. In vivo platelet activation and hyperaggregation in hemoglobin E/beta-thalassemia: a consequence of splenectomy. Int J Hematol. 2003;77:299–303
  12. Chou R, DeLoughery TG. Recurrent thromboembolic disease following splenectomy for pyruvate kinase deficiency. Am J Hematol. 2001;67:197–199
  13. Hayag-Barin JE, Smith RE, Tucker FC. Hereditary spherocytosis, thrombocytosis, and chronic pulmonary emboli: a case report and review of the literature. Am J Hematol. 1998;57:82–84
  14. Aessopos A, Farmakis D, Deftereos S, Tsironi M, Polonifi A, Moyssakis I, et al. Cardiovascular effects of splenomegaly and splenectomy in beta-thalassemia. Annals of Hematology. 2005;84:353–357
  15. Stewart GW, Amess JA, Eber SW, Kingswood C, Lane PA, Smith BD, et al. Thrombo-embolic disease after splenectomy for hereditary stomatocytosis. Br J Haematol. 1996;93:303–310
  16. Setty BN, Kulkarni S, Stuart MJ. Role of erythrocyte phosphatidylserine in sickle red cell-endothelial adhesion. Blood. 2002;99:1564–1571
  17. Setty BN, Rao AK, Stuart MJ. Thrombophilia in sickle cell disease: the red cell connection. Blood. 2001;98:3228–3233
  18. Stuart MJ, Setty BN. Hemostatic alterations in sickle cell disease: relationships to disease pathophysiology. Pediatr Pathol Mol Med. 2001;20:27–46
  19. Semenza GL. Involvement of hypoxia-inducible factor 1 in pulmonary pathophysiology. Chest. 2005;128:592S–594S
  20. Wang J, Weigand L, Lu W, Sylvester JT, Semenza GL, Shimoda LA. Hypoxia inducible factor 1 mediates hypoxia-induced TRPC expression and elevated intracellular Ca2+ in pulmonary arterial smooth muscle cells. Circulation Research. 2006;98:1528–1537
  21. Castro O, Gladwin MT. Pulmonary hypertension in sickle cell disease: mechanisms, diagnosis, and management. Hematology/Oncology Clinics of North America. 2005;19:881–896vii
  22. Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. New England Journal of Medicine. 2004;350:886–895
  23. Ataga KI, Sood N, De Gent G, Kelly E, Henderson AG, Jones S, et al. Pulmonary hypertension in sickle cell disease. The American Journal of Medicine. 2004;117:665–669
  24. De Castro LM, Jonassaint JC, Graham FL, Ashley-Koch A, Telen MJ. Pulmonary Hypertension in SS, SC and S-beta Thalassemia: Prevalence, Associated Clinical Syndromes, and Mortality. ASH Annual Meeting Abstracts. 2004;104:1663
  25. Jardine DL, Laing AD. Delayed pulmonary hypertension following splenectomy for congenital spherocytosis. Intern Med J. 2004;34:214–216
  26. Aessopos A, Farmakis D, Deftereos S, Tsironi M, Tassiopoulos S, Moyssakis I, et al. Thalassemia heart disease: a comparative evaluation of thalassemia major and thalassemia intermedia. Chest. 2005;127:1523–1530
  27. Atichartakarn V, Likittanasombat K, Chuncharunee S, Chandanamattha P, Worapongpaiboon S, Angchaisuksiri P, et al. Pulmonary arterial hypertension in previously splenectomized patients with beta-thalassemic disorders. Int J Hematol. 2003;78:139–145
  28. Aessopos A, Stamatelos G, Skoumas V, Vassilopoulos G, Mantzourani M, Loukopoulos D. Pulmonary hypertension and right heart failure in patients with beta-thalassemia intermedia. Chest. 1995;107:50–53
  29. Chotivittayatarakorn P, Seksarn P, Pathmanand C, Thisyakorn C, Sueblinvong V. Cardiac dysfunction in beta-thalassemic children. J Med Assoc Thai. 1993;76:591–596
  30. Derchi G, Fonti A, Forni GL, Galliera EO, Cappellini MD, Turati F, et al. Pulmonary hypertension in patients with thalassemia major. Am Heart J. 1999;138:384
  31. Du ZD, Roguin N, Milgram E, Saab K, Koren A. Pulmonary hypertension in patients with thalassemia major. Am Heart J. 1997;134:532–537
  32. Grisaru D, Rachmilewitz EA, Mosseri M, Gotsman M, Lafair JS, Okon E, et al. Cardiopulmonary assessment in beta-thalassemia major. Chest. 1990;98:1138–1142
  33. Hahalis G, Manolis AS, Apostolopoulos D, Alexopoulos D, Vagenakis AG, Zoumbos NC. Right ventricular cardiomyopathy in beta-thalassaemia major. Eur Heart J. 2002;23:147–156
  34. Koren A, Garty I, Antonelli D, Katzuni E. Right ventricular cardiac dysfunction in beta-thalassemia major. Am J Dis Child. 1987;141:93–96
  35. Hayag-Barin JE, Smith RE, Tucker FC. Hereditary spherocytosis, thrombocytosis, and chronic pulmonary emboli: a case report and review of the literature. American Journal of Hematology. 1998;57:82–84
  36. Verresen D, De Backer W, Van Meerbeeck J, Neetens I, Van Marck E, Vermeire P. Spherocytosis and pulmonary hypertension coincidental occurrence or causal relationship?. Eur Respir J. 1991;4:629–631
  37. Adedeji MO, Cespedes J, Allen K, Subramony C, Hughson MD. Pulmonary thrombotic arteriopathy in patients with sickle cell disease. Arch Pathol Lab Med. 2001;125:1436–1441
  38. Taher A, Abou-Mourad Y, Abchee A, Zalouaa P, Shamseddine A. Pulmonary thromboembolism in beta-thalassemia intermedia: are we aware of this complication?. Hemoglobin. 2002;26:107–112
  39. Hoeper MM, Niedermeyer J, Hoffmeyer F, Flemming P, Fabel H. Pulmonary hypertension after splenectomy?. Annals of Internal Medicine. 1999;130:506–509
  40. Robinette CD, Fraumeni JF. Splenectomy and subsequent mortality in veterans of the 1939-45 war. Lancet. 1977;2:127–129
  41. Westerman MP, Pizzey A, Hirschmann JV, Cerino M, Eze A, Ramoton P, et al. Plasma ‘free’ Hb is related to red cell derived vesicle numbers in sickle cell anemia and thalassemia intermedia: Implications for nitric oxide (NO) scavenging and pulmonary hypertension. Blood. 2004;104(11):465a
  42. Kuypers FA, de JK. The role of phosphatidylserine in recognition and removal of erythrocytes. Cell Mol Biol (Noisy.-le-grand). 2004;50:147–158
  43. Kato GJ, McGowan VR, Machado RF, Little JA, Taylor VJ, Morris CR, et al. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension and death in patients with sickle cell disease. Blood. 2006;107:2279–2285
  44. Kato GJ, Martyr S, Blackwelder WC, Nichols JS, Coles WA, Hunter LA, et al. Levels of soluble endothelium-derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality. Br J Haematol. 2005;130:943–953
  45. Gladwin MT, Schechter AN, Ognibene FP, Coles WA, Reiter CD, Schenke WH, et al. Divergent nitric oxide bioavailability in men and women with sickle cell disease. Circulation. 2003;107:271–278
  46. Morris CR, Kuypers FA, Kato GJ, Lavrisha L, Larkin S, Singer T, et al. Hemolysis-associated pulmonary hypertension in thalassemia. Annals of the New York Academy of Sciences. 2005;1054:481–485
  47. Nolan VG, Wyszynski DF, Farrer LA, Steinberg MH. Hemolysis-associated priapism in sickle cell disease. Blood. 2005;106:3264–3267
  48. Dore F, Bonfigli S, Pardini S, Pirozzi F, Longinotti M. Priapism in thalassemia intermedia. Haematologica. 1991;76:523
  49. Edney MT, Schned AR, Cendron M, Chaffee S, Ellsworth PI. Priapism in a 15-year-old boy with congenital dyserythropoietic anemia type II (hereditary erythroblastic multinuclearity with positive acidified serum lysis test). J Urol. 2002;167:309–310
  50. Goulding FJ. Priapism caused by glucose phosphate isomerase deficiency. Journal of Urology. 1976;116:819–820
  51. Jackson N, Franklin IM, Hughes MA. Recurrent priapism following splenectomy for thalassaemia intermedia. Br J Surg. 1986;73:678
  52. Macchia P, Massei F, Nardi M, Favre C, Brunori E, Barba V. Thalassemia intermedia and recurrent priapism following splenectomy. Haematologica. 1990;75:486–487
  53. Montalban J, Lozano P, Lu L, Gonzalez A. Paroxysmal nocturnal hemoglobinuria and priapism. Med Clin (Barc.). 1986;87:394
  54. Rao KR, Patel AR. Priapism and thalassaemia intermedia. British Journal of Surgery. 1986;73:1048
  55. Thuret I, Bardakdjian J, Badens C, Wajcman H, Galacteros F, Vanuxem D, et al. Priapism following splenectomy in an unstable hemoglobin: hemoglobin Olmsted beta 141 (H19) Leu–>Arg. American Journal of Hematology. 1996;51:133–136
  56. Champion HC, Bivalacqua TJ, Takimoto E, Kass DA, Burnett AL. Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism. Proc Natl Acad Sci USA. 2005;102:1661–1666
  57. Bialecki ES, Bridges KR. Sildenafil relieves priapism in patients with sickle cell disease. Am J Med. 2002;113:252
  58. Burnett AL, Bivalacqua TJ, Champion HC, Musicki B. Long-term oral phosphodiesterase 5 inhibitor therapy alleviates recurrent priapism. Urology. 2006;67:1043–1048
  59. Nolan VG, Adewoye A, Baldwin C, Wang L, Ma Q, Wyszynski DF, et al. Sickel cell leg ulcers: associations with haemolysis and SNPs in Klotho, TEK and genes of the TGF-beta/BMP pathway. Br J Haematol. 2006;133:570–578
  60. Bordi B, Rosaria DM, Guariglia R, Capobianco G, Bordi E, Tirelli A. A case of congenital dyserythropoietic anemia type II, Gilbert’s syndrome and malleolar trophic ulcers. Hematology. 2002;7:197–199
  61. Gimmon Z, Wexler MR, Rachmilewitz EA. Juvenile leg ulceration in beta-thalassemia major and intermedia. Plastic and Reconstructive Surgery. 1982;69:320–325
  62. Giraldi S, Abbage KT, Marinoni LP, Oliveira V, Pianowski MA, Lehmkuhl AE, et al. Leg ulcer in hereditary spherocytosis. Pediatric Dermatology. 2003;20:427–428
  63. Muller-Soyano A, Tovar dR, Duke PR, De Acquatella GC, Arends T, Guinto E, et al. Pyruvate kinase deficiency and leg ulcers. Blood. 1976;47:807–813
  64. Peachey RD. Leg ulceration and haemolytic anaemia: an hypothesis. British Journal of Dermatology. 1978;98:245–249
  65. Pope FM, Hodgson GA. Leg ulceration and thalassaemia. British Journal of Dermatology. 1968;80:840
  66. Stevens DM, Shupack JL, Javid J, Silber R. Ulcers of the leg in thalassemia. Archives of Dermatology. 1977;113:1558–1560
  67. Tanaka KR, Paglia DE. Pyruvate kinase deficiency. Seminars in Hematology. 1971;8:367–396
  68. Vanscheidt W, Leder O, Vanscheidt E, Wokalek H, Wilmer J, Hofmann E, et al. Leg ulcers in a patient with spherocytosis: a clinicopathological report. Dermatologica. 1990;181:56–59
  69. Lawrence P, Aronson I, Saxe N, Jacobs P. Leg ulcers in hereditary spherocytosis. Clinical and Experimental Dermatology. 1991;16:28–30
  70. Ballas SK. Sickle cell anemia with few painful crises is characterized by decreased red cell deformability and increased number of dense cells. American Journal of Hematology. 1991;36:122–130
  71. Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91:288–294
  72. Adams RJ, Kutlar A, McKie V, Carl E, Nichols FT, Liu JC, et al. Alpha thalassemia and stroke risk in sickle cell anemia. American Journal of Hematology. 1994;45:279–282
  73. Hsu LL, Miller ST, Wright E, Kutlar A, McKie V, Wang W, et al. Alpha Thalassemia is associated with decreased risk of abnormal transcranial Doppler ultrasonography in children with sickle cell anemia. J Pediatr Hematol Oncol. 2003;25:622–628
  74. Lezcano NE, Odo N, Kutlar A, Brambilla D, Adams RJ. Regular transfusion lowers plasma free hemoglobin in children with sickle-cell disease at risk for stroke. Stroke. 2006;37:1424–1426
  75. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, 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;339:5–11
  76. Kinney TR, Sleeper LA, Wang WC, Zimmerman RA, Pegelow CH, Ohene-Frempong K, et al. Silent cerebral infarcts in sickle cell anemia: a risk factor analysis. The Cooperative Study of Sickle Cell Disease. Pediatrics. 1999;103:640–645
  77. Kato GJ, Hsieh M, Machado RF, Taylor JG, Butman JA, Lehky T, et al. Cerebrovascular disease associated with sickle cell pulmonary hypertension. American Journal of Hematology. 2006;81:503–510
  78. Hawker H, Neilson H, Hayes RJ, Serjeant GR. Haematological factors associated with avascular necrosis of the femoral head in homozygous sickle cell disease. British Journal of Haematology. 1982;50:29–34
  79. Castro O, Brambilla DJ, Thorington B, Reindorf CA, Scott RB, Gillette P, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood. 1994;84:643–649
  80. Bailey K, Morris JS, Thomas P, Serjeant GR. Fetal haemoglobin and early manifestations of homozygous sickle cell disease. Arch Dis Child. 1992;67:517–520
  81. Steinberg MH. Predicting clinical severity in sickle cell anaemia. Br J Haematol. 2005;129:465–481
  82. Franco RS, Yasin Z, Palascak MB, Ciraolo P, Joiner CH, Rucknagel DL. The effect of fetal hemoglobin on the survival characteristics of sickle cells. Blood. 2006;108:1073–1076
  83. Sebastiani P, Ramoni MF, Nolan V, Baldwin CT, Steinberg MH. Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nature Genetics. 2005;37:435–440
  84. Embury SH, Dozy AM, Miller J, Davis JR, Kleman KM, Preisler H, et al. Concurrent sickle-cell anemia and alpha-thalassemia: effect on severity of anemia. N Engl J Med. 1982;306:270–274
  85. Steinberg MH, Rosenstock W, Coleman MB, Adams JG, Platica O, Cedeno M, et al. Effects of thalassemia and microcytosis on the hematologic and vasoocclusive severity of sickle cell anemia. Blood. 1984;63:1353–1360
  86. Koshy M, Entsuah R, Koranda A, Kraus AP, Johnson R, Bellvue R, et al. Leg ulcers in patients with sickle cell disease. Blood. 1989;74:1403–1408
  87. Higgs DR, Aldridge BE, Lamb J, Clegg JB, Weatherall DJ, Hayes RJ, et al. The interaction of alpha-thalassemia and homozygous sickle-cell disease. N Engl J Med. 1982;306:1441–1446
  88. Neonato MG, Guilloud-Bataille M, Beauvais P, Begue P, Belloy M, Benkerrou M, et al. Acute clinical events in 299 homozygous sickle cell patients living in France. French Study Group on Sickle Cell Disease. Eur J Haematol. 2000;65:155–164
  89. Gill FM, Sleeper LA, Weiner SJ, Brown AK, Bellevue R, Grover R, 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;86:776–783
  90. Billett HH, Nagel RL, Fabry ME. Paradoxical increase of painful crises in sickle cell patients with alpha-thalassemia. Blood. 1995;86:4382
  91. Billett HH, Kim K, Fabry ME, Nagel RL. The percentage of dense red cells does not predict incidence of sickle cell painful crisis. Blood. 1986;68:301–303
  92. Bailey S, Higgs DR, Morris J, Serjeant GR. Is the painful crisis of sickle-cell disease due to sickling?. Lancet. 1991;337:735
  93. Milner PF, Kraus AP, Sebes JI, Sleeper LA, Dukes KA, Embury SH, et al. Sickle cell disease as a cause of osteonecrosis of the femoral head. N Engl J Med. 1991;325:1476–1481
  94. Ballas SK, Talacki CA, Rao VM, Steiner RM. The prevalence of avascular necrosis in sickle cell anemia: correlation with alpha-thalassemia. Hemoglobin. 1989;13:649–655
  95. Hebbel RP, Mohandas N. Cell Adhesion and Microrheaology in Sickle Cell Disease. In:  Steinberg MH,  Forget BG,  Higgs DR,  Nagel RL editor. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge: Cambridge University Press; 2001;p. 527–549
  96. Hebbel RP, Boogaerts MA, Eaton JW, Steinberg MH. Erythrocyte adherence to endothelium in sickle-cell anemia. A possible determinant of disease severity. N Engl J Med. 1980;302:992–995
  97. Hoover R, Rubin R, Wise G, Warren R. Adhesion of normal and sickle erythrocytes to endothelial monolayer cultures. Blood. 1979;54:872–876
  98. Hebbel RP. Perspectives series: cell adhesion in vascular biology. Adhesive interactions of sickle erythrocytes with endothelium. J Clin Invest. 1997;99:2561–2564
  99. Matsui NM, Borsig L, Rosen SD, Yaghmai M, Varki A, Embury SH. P-selectin mediates the adhesion of sickle erythrocytes to the endothelium. Blood. 2001;98:1955–1962
  100. De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA, et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. Journal of Clinical Investigation. 1995;96:60–68
  101. Khan BV, Harrison DG, Olbrych MT, Alexander RW, Medford RM. Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proceedings of the National Academy of Sciences of the United States of America. 1996;93:9114–9119
  102. Spiecker M, Darius H, Kaboth K, Hubner F, Liao JK. Differential regulation of endothelial cell adhesion molecule expression by nitric oxide donors and antioxidants. Journal of Leukocyte Biology. 1998;63:732–739
  103. Spiecker M, Peng HB, Liao JK. Inhibition of endothelial vascular cell adhesion molecule-1 expression by nitric oxide involves the induction and nuclear translocation of I-kappa Balpha. Journal of Biological Chemistry. 1997;272:30969–30974
  104. Shin WS, Hong YH, Peng HB, De Caterina R, Libby P, Liao JK. Nitric oxide attenuates vascular smooth muscle cell activation by interferon-gamma. The role of constitutive NF-kappa B activity. Journal of Biological Chemistry. 1996;271:11317–11324
  105. Lee SK, Kim JH, Yang WS, Kim SB, Park SK, Park JS. Exogenous nitric oxide inhibits VCAM-1 expression in human peritoneal mesothelial cells. Role of cyclic GMP and NF-kappaB. Nephron. 2002;90:447–454
  106. Christakis J, Vavatsi N, Hassapopoulou H, Papadopoulou M, Mandraveli K, Loukopoulos D, et al. Comparison of homozygous sickle cell disease in northern Greece and Jamaica. Lancet. 1990;335:637–640
  107. Kar BC, Satapathy RK, Kulozik AE, Kulozik M, Sirr S, Serjeant BE, et al. Sickle cell disease in Orissa State, India. Lancet. 1986;2:1198–1201
  108. Dash BP, Kar BC. Priapism is rare in sickle cell disease in India. J Assoc Physicians India. 2000;48:255
  109. Quinn CT, Ahmad N. Clinical correlates of steady-state oxyhaemoglobin desaturation in children who have sickle cell disease. Br J Haematol. 2005;131:129–134
  110. Homi J, Levee L, Higgs D, Thomas P, Serjeant G. Pulse oximetry in a cohort study of sickle cell disease. Clin Lab Haematol. 1997;19:17–22
  111. Rackoff WR, Kunkel N, Silber JH, Asakura T, Ohene-Frempong K. Pulse oximetry and factors associated with hemoglobin oxygen desaturation in children with sickle cell disease. Blood. 1993;81:3422–3427
  112. Setty BN, Stuart MJ, Dampier C, Brodecki D, Allen JL. Hypoxaemia in sickle cell disease: biomarker modulation and relevance to pathophysiology. Lancet. 2003;362:1450–1455
  113. Milner PF. Oxygen transport in sickle cell anemia. Archives of Internal Medicine. 1974;133:565–572
  114. Minneci PC, Deans KJ, Zhi H, Yuen PS, Star RA, Banks SM, et al. Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin. J Clin Invest. 2005;115:3409–3417
  115. Weiner DL, Hibberd PL, Betit P, Cooper AB, Botelho CA, Brugnara C. Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease. JAMA. 2003;289:1136–1142
  116. Morris CR, Morris SM, Hagar W, Van Warmerdam J, Claster S, Kepka-Lenhart D, et al. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease?. American Journal of Critical Care and Respiratory Medicine. 2003;168:63–69
  117. Machado RF, Martyr S, Kato GJ, Barst RJ, Anthi A, Robinson MR, et al. Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension. Br J Haematol. 2005;130:445–453
  118. Derchi G, Forni GL, Formisano F, Cappellini MD, Galanello R, D’Ascola G, et al. Efficacy and safety of sildenafil in the treatment of severe pulmonary hypertension in patients with hemoglobinopathies. Haematologica. 2005;90:452–458
  119. Gordeuk VR. Efficacy and safety of sildenafil in the treatment of severe pulmonary hypertension in patients with hemoglobinopathies. Haematologica. 2005;90:433b–4434
  120. Mack AK, Kato GJ. Sickle cell disease and nitric oxide: A paradigm shift?. International Journal of Biochemistry and Cell Biology. 2005;38:1237–1243
  121. Alexander N, Higgs D, Dover G, Serjeant GR. Are there clinical phenotypes of homozygous sickle cell disease?. British Journal of Haematology. 2004;126:606–611
  122. Machado RF, Gladwin MT. Chronic sickle cell lung disease: new insights into the diagnosis, pathogenesis and treatment of pulmonary hypertension. Br J Haematol. 2005;129:449–464
  123. De Franceschi L, Bachir D, Galacteros F, Tchernia G, Cynober T, Alper S, et al. Oral magnesium supplements reduce erythrocyte dehydration in patients with sickle cell disease. J Clin Invest. 1997;100:1847–1852
  124. Stocker JW, De Franceschi L, McNaughton-Smith GA, Corrocher R, Beuzard Y, Brugnara C. ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice. Blood. 2003;101:2412–2418
  125. Quinn CT, Miller ST. Risk factors and prediction of outcomes in children and adolescents who have sickle cell anemia. Hematology/Oncology Clinics of North America. 2004;18:1339–1354ix

PII: S0268-960X(06)00041-5

doi: 10.1016/j.blre.2006.07.001

Blood Reviews
Volume 21, Issue 1 , Pages 37-47 , January 2007

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