Antioxidant vitamins C and E supplementation increases markers of haemolysis in sickle cell anaemia patients: A randomized, double-blind, placebo-controlled trial

British Journal of Haematology

Volumn 160, Issue 5, 2013, Pages 688-700

  Arruda, Martha M ^a   Mecabo, Grazielle ^a   Rodrigues, Celso A ^a   Matsuda, Sandra S ^a   Rabelo, Iara B ^a   Figueiredo, Maria S ^a  

^a FEDERAL UNIVERSITY OF SÃO PAULO   (Brazil)

Author keywords

Haemolysis; Oxidative stress; Sickle cell anaemia; Vitamin C; Vitamin E

Indexed keywords

ALPHA TOCOPHEROL; ASCORBIC ACID; HEMOGLOBIN; PLACEBO;

ACUTE CHEST SYNDROME; ADULT; AGED; ALPHA TOCOPHEROL DEFICIENCY; ANEMIA; ANTIOXIDANT ACTIVITY; ARTICLE; ASCORBIC ACID DEFICIENCY; CEREBROVASCULAR ACCIDENT; CONTROLLED STUDY; DIARRHEA; DISEASE MARKER; DOUBLE BLIND PROCEDURE; EPIGASTRIC PAIN; FATIGUE; FEMALE; HEADACHE; HEMOGLOBIN BLOOD LEVEL; HEMOLYSIS; HUMAN; LABORATORY TEST; MAJOR CLINICAL STUDY; MALE; NAUSEA; PRIAPISM; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; SICKLE CELL ANEMIA; SICKLE CELL BETA THALASSEMIA; TREATMENT DURATION; VITAMIN BLOOD LEVEL; VITAMIN SUPPLEMENTATION;

ADOLESCENT; ADULT; AGED; ANEMIA, SICKLE CELL; ANTIOXIDANTS; ASCORBIC ACID; BIOLOGICAL MARKERS; DIETARY SUPPLEMENTS; DOUBLE-BLIND METHOD; DRUG UTILIZATION; FEMALE; HEMOLYSIS; HOSPITALIZATION; HUMANS; INFLAMMATION; MALE; MIDDLE AGED; OXIDATIVE STRESS; QUALITY OF LIFE; REACTIVE OXYGEN SPECIES; SICKLE CELL TRAIT; THALASSEMIA; VITAMIN E; YOUNG ADULT;

EID: 84873999285     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/bjh.12185     Document Type: Article

References (97)

1. Amer, J. & Fibach, E. (2004) Oxidative status of platelets in normal and thalassemic blood. Thrombosis and Haemostasis, 92, 1052-1059.
2. Amer, J., Ghoti, H., Rachmilewitz, E., Koren, A., Levin, C. & Fibach, E. (2006) Red blood cells, platelets and polymorphonuclear neutrophils of patients with sickle cell disease exhibit oxidative stress that can be ameliorated by antioxidants. British Journal of Haematology, 132, 108-113.
3. Amer, J., Zelig, O. & Fibach, E. (2008a) Oxidative status of red blood cells, neutrophils, and platelets in paroxysmal nocturnal hemoglobinuria. Experimental Hematology, 36, 369-377.
4. Amer, J., Atlas, D. & Fibach, E. (2008b) N-acetylcysteine amide (AD4) attenuates oxidative stress in beta-thalassemia blood cells. Biochimica et Biophysica Acta, 1780, 249-255.
5. Amer, J., Goldfarb, A., Rachmilewitz, E.A. & Fibach, E. (2008c) Fermented papaya preparation as redox regulator in blood cells of beta-thalassemic mice and patients. Phytotheraphy Research, 22, 820-828.
6. Andreassi, M.G. (2008) DNA damage, vascular senescence and atherosclerosis. Journal of Molecular Medicine, 86, 1033-1043.
7. Ballas, S.K., Lieff, S., Benjamin, L.J., Dampier, C.D., Heeney, M.M., Hoppe, C., Johnson, C.S., Rogers, Z.R., Smith-Whitley, K., Wang, W.C. & Telen, M.J. (2011) Definitions of the phenotypic manifestations of sickle cell disease. American Journal of Hematology, 85, 6-13.
8. Banerjee, T. & Kuypers, F.A. (2004) Reactive oxygen species and phosphatidylserine externalization in murine sickle red cells. British Journal of Haematology, 124, 391-402.
9. Bao, B., Prasad, A.S., Beck, F.W., Snell, D., Suneja, A., Sarkar, F.H., Doshi, N., Fitzgerald, J.T. & Swerdlow, P. (2008) Zinc supplementation decreases oxidative stress, incidence of infection, and generation of inflammatory cytokines in sickle cell disease patients. Translational Research, 152, 67-80.
10. Barabino, G.A., Platt, M.O. & Kaul, D.K. (2010) Sickle cell biomechanics. Annual Review of Biomedical Engineering, 12, 345-367.
11. Candan, F. & Gultekin, F. (2002) Effect of vitamin C and zinc on osmotic fragility and lipid peroxidation in zinc-deficient haemodialysis patients. Cell Biochemistry and Function, 20, 95-98.
12. Cella, D. (1997) The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: a new tool for the assessment of outcomes in cancer anemia and fatigue. Seminars in Hematology, 34, 13-19.
13. Cesquini, M., Torsoni, M.A., Stoppa, G.R. & Ogo, S.H. (2003) t-BOOH-induced oxidative damage in sickle red blood cells and the role of flavonoids. Biomedicine & Pharmacotherapy, 57, 124-129.
14. Chan, A.C., Chow, C.K. & Chiu, D. (1999) Interaction of antioxidants and their implication in genetic anemia. Proceedings of the Society for Experimental Biology and Medicine, 222, 274-282.
15. Chappell, L.C., Seed, P.T., Briley, A.L., Kelly, F.J., Lee, R., Hunt, B.J., Parmar, K., Bewley, S.J., Shennan, A.H., Steer, P.J. & Poston, L. (1999) Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet, 354, 810-816.
16. Chiu, D., Vichinsky, E., Ho, S.L., Liu, T. & Lubin, B.H. (1990) Vitamin C deficiency in patients with sickle cell anemia. The American Journal of Pediatric Hematology/Oncology, 12, 262-267.
17. Claster, S., Wood, J.C., Noetzli, L., Carson, S.M., Hofstra, T.C., Khanna, R. & Coates, T.D. (2009) Nutritional deficiencies in iron overloaded patients with hemoglobinopathies. American Journal of Hematology, 84, 344-348.
18. Das, N., Das Chowdhury, T., Chattopadhyay, A. & Datta, A.G. (2004) Attenuation of oxidative stress-induced changes in thalassemic erythrocytes by vitamin E. Polish Journal of Pharmacology, 56, 85-96.
19. Dissayabutra, T., Tosukhowong, P. & Seksan, P. (2005) The benefits of vitamin C and vitamin E in children with beta-thalassemia with high oxidative stress. Journal of the Medical Association of Thailand, 88(Suppl 4), S317-S321.
20. Eldamhougy, S., Elhelw, Z., Yamamah, G., Hussein, L., Fayyad, I. & Fawzy, D. (1988) The vitamin E status among glucose-6 phosphate dehydrogenase deficient patients and effectiveness of oral vitamin E. International Journal for Vitamin and Nutrition Research, 58, 184-188.
21. Fibach, E. & Rachmilewitz, E. (2008) The role of oxidative stress in hemolytic anemia. Current Molecular Medicine, 8, 609-619.
22. Freikman, I., Amer, J., Ringel, I. & Fibach, E. (2009) A flow cytometry approach for quantitative analysis of cellular phosphatidylserine distribution and shedding. Analytical Biochemistry, 393, 111-116.
23. Giardini, O., Cantani, A., Donfrancesco, A., Martino, F., Mannarino, O., D'Eufemia, P., Miano, C., Ruberto, U. & Lubrano, R. (1985) Biochemical and clinical effects of vitamin E administration in homozygous beta-thalassemia. Acta Vitaminologica et Enzymologica, 7, 55-60.
24. Gomperts, E.D., Zail, S.S., Christensen, D. & Metz, J. (1975) The effect of vitamin E on haemolysis in paroxysmal nocturnal haemoglobinuria: in vitro and in vivo studies. Scandinavian Journal of Haematology, 14, 81-85.
25. Halliwell, B. & Gutteridge, J.M. (1984) Lipid peroxidation, oxygen radicals, cell damage, and antioxidant therapy. Lancet, 1, 1396-1397.
26. Halliwell, B.G. & Gutteridge, J.M. (2007) Free Radicals in Biology and Medicine. Oxford University Press, New York.
27. Hasanato, R.M. (2006) Zinc and antioxidant vitamin deficiency in patients with severe sickle cell anemia. Annals of Saudi Medicine, 26, 17-21.
28. Haymann, J.P., Stankovic, K., Levy, P., Avellino, V., Tharaux, P.L., Letavernier, E., Grateau, G., Baud, L., Girot, R. & Lionnet, F. (2010) Glomerular hyperfiltration in adult sickle cell anemia: a frequent hemolysis associated feature. Clinical Journal of the American Society of Nephrology, 5, 756-761.
29. Hebbel, R.P., Eaton, J.W., Balasingam, M. & Steinberg, M.H. (1982) Spontaneous oxygen radical generation by sickle erythrocytes. Journal of Clinical Investigation, 70, 1253-1259.
30. Helewa, M.E., Burrows, R.F., Smith, J., Williams, K., Brain, P. & Rabkin, S.W. (1997) Report of the Canadian Hypertension Society Consensus Conference: 1. Definitions, evaluation and classification of hypertensive disorders in pregnancy. CMAJ, 157, 715-725.
31. Ibraheem, N.K., Ahmed, J.H. & Hassan, M.K. (2010) The effect of fixed oil and water extracts of Nigella sativa on sickle cells: an in vitro study. Singapore Medical Journal, 51, 230-234.
32. Institute of Medicine (U.S.). Panel on Dietary Antioxidants and Related Compounds (2000) Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids: A Report of the Panel on Dietary Antioxidants and Related Compounds. Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine, Vol. 1, pp. 529. National Academy Press, Washington, DC.
33. Ishikawa, N.M., Thuler, L.C., Giglio, A.G., Baldotto, C.S., de Andrade, C.J. & Derchain, S.F. (2010) Validation of the Portuguese version of functional assessment of cancer therapy-fatigue (FACT-F) in Brazilian cancer patients. Supportive Care in Cancer, 18, 481-490.
34. Jaja, S.I., Ikotun, A.R., Gbenebitse, S. & Temiye, E.O. (2002) Blood pressure, hematologic and erythrocyte fragility changes in children suffering from sickle cell anemia following ascorbic acid supplementation. Journal of Tropical Pediatrics, 48, 366-370.
35. Jaja, S.I., Aigbe, P.E., Gbenebitse, S. & Temiye, E.O. (2005) Changes in erythrocytes following supplementation with alpha-tocopherol in children suffering from sickle cell anaemia. The Nigerian Postgraduate Medical Journal, 12, 110-114.
36. Kahane, I. & Rachmilewitz, E.A. (1976) Alterations in the red blood cell membrane and the effect of vitamin E on osmotic fragility in beta-thalassemia major. Israel Journal of Medical Sciences, 12, 11-15.
37. Kalpravidh, R.W., Wichit, A., Siritanaratkul, N. & Fucharoen, S. (2005) Effect of coenzyme Q10 as an antioxidant in beta-thalassemia/Hb E patients. BioFactors, 25, 225-234.
38. Kappus, H. & Diplock, A.T. (1992) Tolerance and safety of vitamin E: a toxicological position report. Free Radical Biology & Medicine, 13, 55-74.
39. Kato, G.J., Gladwin, M.T. & Steinberg, M.H. (2007) Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Reviews, 21, 37-47.
40. Krajewski, M.L., Hsu, L.L. & Gladwin, M.T. (2008) The proverbial chicken or the egg? Dissection of the role of cell-free hemoglobin versus reactive oxygen species in sickle cell pathophysiology. American Journal of Physiology. Heart and Circulatory Physiology, 295, H4-H7.
41. Krukoski, D.W., Comar, S.R., Claro, L.M., Leonart, M.S. & do Nascimento, A.J. (2009) Effect of vitamin C, deferoxamine, quercetin and rutin against tert-butyl hydroperoxide oxidative damage in human erythrocytes. Hematology, 14, 168-172.
42. Langlois, M.R. & Delanghe, J.R. (1996) Biological and clinical significance of haptoglobin polymorphism in humans. Clinical Chemistry, 42, 1589-1600.
43. Liu, X., Miller, M.J., Joshi, M.S., Sadowska-Krowicka, H., Clark, D.A. & Lancaster, J.R. Jr (1998) Diffusion-limited reaction of free nitric oxide with erythrocytes. Journal of Biological Chemistry, 273, 18709-18713.
44. Martindale, J.L. & Holbrook, N.J. (2002) Cellular response to oxidative stress: signaling for suicide and survival. Journal of Cellular Physiology, 192, 1-15.
45. Martins, V.D., Manfredini, V., Peralba, M.C. & Benfato, M.S. (2009) Alpha-lipoic acid modifies oxidative stress parameters in sickle cell trait subjects and sickle cell patients. Clinical Nutrition, 28, 192-197.
46. McCall, M.R. & Frei, B. (1999) Can antioxidant vitamins materially reduce oxidative damage in humans? Free Radical Biology & Medicine, 26, 1034-1053.
47. McCance, D.R., Holmes, V.A., Maresh, M.J., Patterson, C.C., Walker, J.D., Pearson, D.W. & Young, I.S. (2010) Vitamins C and E for prevention of pre-eclampsia in women with type 1 diabetes (DAPIT): a randomised placebo-controlled trial. Lancet, 376, 259-266.
48. ® evaluations: vitamina C. In: Micromedex 2.0. Online database, Thomson Reuters, URL http://www.thomsonhc.com/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/CB5BD5/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/D3B450/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/evidencexpert.IntermediateToDocumentLink?docId=47&contentSetId=51.
49. ® evaluations: vitamina E. In: Micromedex 2.0. Online database, Thomson Reuters, URL http://www.thomsonhc.com/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/FAC9F0/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/C054C2/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/evidencexpert.IntermediateToDocumentLink?docId=3123&contentSetId=51. Thomson Reuters.
50. Mukherjee, A.K., Ghosal, S.K. & Maity, C. (1998) Effect of oral supplementation of vitamin E on the hemolysis and erythrocyte phospholipid-splitting action of cobra and viper venoms. Toxicon, 36, 657-664.
51. Muskiet, F.A., Muskiet, F.D., Meiborg, G. & Schermer, J.G. (1991) Supplementation of patients with homozygous sickle cell disease with zinc, alpha-tocopherol, vitamin C, soybean oil, and fish oil. American Journal of Clinical Nutrition, 54, 736-744.
52. Natta, C.L., Chen, L.C. & Chow, C.K. (1990) Selenium and glutathione peroxidase levels in sickle cell anemia. Acta Haematologica, 83, 130-132.
53. Naziroglu, M., Akkus, S., Soyupek, F., Yalman, K., Celik, O., Eris, S. & Uslusoy, G.A. (2010a) Vitamins C and E treatment combined with exercise modulates oxidative stress markers in blood of patients with fibromyalgia: a controlled clinical pilot study. Stress, 13, 498-505.
54. Naziroglu, M., Kilinc, F., Uguz, A.C., Celik, O., Bal, R., Butterworth, P.J. & Baydar, M.L. (2010b) Oral vitamin C and E combination modulates blood lipid peroxidation and antioxidant vitamin levels in maximal exercising basketball players. Cell Biochemistry and Function, 28, 300-305.
55. Nemeth, I., Turi, S., Haszon, I. & Bereczki, C. (2000) Vitamin E alleviates the oxidative stress of erythropoietin in uremic children on hemodialysis. Pediatric Nephrology (Berlin, Germany), 14, 13-17.
56. Nur, E., Biemond, B.J., Otten, H.M., Brandjes, D.P. & Schnog, J.J. (2011a) Oxidative stress in sickle cell disease; pathophysiology and potential implications for disease management. American Journal of Hematology, 86, 484-489.
57. Nur, E., Verwijs, M., de Waart, D.R., Schnog, J.J., Otten, H.M., Brandjes, D.P., Biemond, B.J. & Elferink, R.P. (2011b) Increased efflux of oxidized glutathione (GSSG) causes glutathione depletion and potentially diminishes antioxidant defense in sickle erythrocytes. Biochimica et Biophysica Acta, 1812, 1412-1417.
58. Ohnishi, S.T. & Ohnishi, T. (2001) In vitro effects of aged garlic extract and other nutritional supplements on sickle erythrocytes. Journal of Nutrition, 131, 1085S-1092S.
59. Ohnishi, S.T., Ohnishi, T. & Ogunmola, G.B. (2000) Sickle cell anemia: a potential nutritional approach for a molecular disease. Nutrition, 16, 330-338.
60. Okpala, I., Ibegbulam, O., Duru, A., Ocheni, S., Emodi, I., Ikefuna, A., Umar, G., Asinobi, I., Madu, A., Okoye, A., Nwagha, T., Oguonu, U., Uamai, I., Agwu, O., Nonyelu, C., Anike, U., Agu, K., Anigbo, C., Chukwura, A., Ugwu, O. & Herrada, S. (2004) Pilot study of omega-3 fatty acid supplements in sickle cell disease. APMIS, 119, 442-448.
61. Ono, K. (1985) Effects of large dose vitamin E supplementation on anemia in hemodialysis patients. Nephron, 40, 440-445.
62. Pace, B.S., Shartava, A., Pack-Mabien, A., Mulekar, M., Ardia, A. & Goodman, S.R. (2003) Effects of N-acetylcysteine on dense cell formation in sickle cell disease. American Journal of Hematology, 73, 26-32.
63. Palasuwan, A., Soogarun, S., Wiwanitkit, V., Luechapudiporn, R., Pradniwat, P. & Lertlum, T. (2006) Preliminary study of the effect of vitamin E supplementation on the antioxidant status of hemoglobin-E carriers. Southeast Asian Journal of Tropical Medicine and Public Health, 37(Suppl 3), 184-189.
64. Palasuwan, A., Sriprapun, M., Dahlan, W., Luechapudiporn, R. & Soogarun, S. (2008) Antioxidant protection in hemoglobin E trait subjects after vitamin E supplementation. Southeast Asian Journal of Tropical Medicine and Public Health, 39, 82-89.
65. Pamplona, R. (2008) Membrane phospholipids, lipoxidative damage and molecular integrity: a causal role in aging and longevity. Biochimica et Biophysica Acta, 1777, 1249-1262.
66. Pfeifer, W.P., Degasperi, G.R., Almeida, M.T., Vercesi, A.E., Costa, F.F. & Saad, S.T. (2008) Vitamin E supplementation reduces oxidative stress in beta thalassaemia intermedia. Acta Haematologica, 120, 225-231.
67. Poston, L., Briley, A.L., Seed, P.T., Kelly, F.J. & Shennan, A.H. (2006) Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet, 367, 1145-1154.
68. Pryor, W.A. (2000) Vitamin E and heart disease: basic science to clinical intervention trials. Free Radical Biology & Medicine, 28, 141-164.
69. Rahman, K. (2007) Studies on free radicals, antioxidants, and co-factors. Clinical Interventions in Aging, 2, 219-236.
70. Ray, D., Deshmukh, P., Goswami, K. & Garg, N. (2007) Antioxidant vitamin levels in sickle cell disorders. National Medical Journal of India, 20, 11-13.
71. Ren, H., Ghebremeskel, K., Okpala, I., Lee, A., Ibegbulam, O. & Crawford, M. (2008) Patients with sickle cell disease have reduced blood antioxidant protection. International Journal for Vitamin and Nutrition Research, 78, 139-147.
72. Repka, T. & Hebbel, R.P. (1991) Hydroxyl radical formation by sickle erythrocyte membranes: role of pathologic iron deposits and cytoplasmic reducing agents. Blood, 78, 2753-2758.
73. Rizzo, M.R., Abbatecola, A.M., Barbieri, M., Vietri, M.T., Cioffi, M., Grella, R., Molinari, A., Forsey, R., Powell, J. & Paolisso, G. (2008) Evidence for anti-inflammatory effects of combined administration of vitamin E and C in older persons with impaired fasting glucose: impact on insulin action. Journal of the American College of Nutrition, 27, 505-511.
74. Roberts, J.M., Myatt, L., Spong, C.Y., Thom, E.A., Hauth, J.C., Leveno, K.J., Pearson, G.D., Wapner, R.J., Varner, M.W., Thorp, J.M. Jr, Mercer, B.M., Peaceman, A.M., Ramin, S.M., Carpenter, M.W., Samuels, P., Sciscione, A., Harper, M., Smith, W.J., Saade, G., Sorokin, Y. & Anderson, G.B. (2010) Vitamins C and E to prevent complications of pregnancy-associated hypertension. New England Journal of Medicine, 362, 1282-1291.
75. Rodrigo, R., Prat, H., Passalacqua, W., Araya, J. & Bachler, J.P. (2008) Decrease in oxidative stress through supplementation of vitamins C and E is associated with a reduction in blood pressure in patients with essential hypertension. Clinical Science (London), 114, 625-634.
76. Rother, R.P., Bell, L., Hillmen, P. & Gladwin, M.T. (2005) The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA, 293, 1653-1662.
77. Ruiz-Ramos, M., Vargas, L.A., Fortoul Van der Goes, T.I., Cervantes-Sandoval, A. & Mendoza-Nunez, V.M. (2010) Supplementation of ascorbic acid and alpha-tocopherol is useful to preventing bone loss linked to oxidative stress in elderly. The Journal of Nutrition, Health & Aging, 14, 467-472.
78. Rumbold, A.R., Crowther, C.A., Haslam, R.R., Dekker, G.A. & Robinson, J.S. (2006) Vitamins C and E and the risks of preeclampsia and perinatal complications. New England Journal of Medicine, 354, 1796-1806.
79. Saeian, K., Bajaj, J.S., Franco, J., Knox, J.F., Daniel, J., Peine, C., McKee, D., Varma, R.R. & Ho, S. (2004) High-dose vitamin E supplementation does not diminish ribavirin-associated haemolysis in hepatitis C treatment with combination standard alpha-interferon and ribavirin. Alimentary Pharmacology & Therapeutics, 20, 1189-1193.
80. Saltman, P. (1989) Oxidative stress: a radical view. Seminars in Hematology, 26, 249-256.
81. Sibai, B.M. (1998) Prevention of preeclampsia: a big disappointment. American Journal of Obstetrics and Gynecology, 179, 1275-1278.
82. Son, S.M. (2007) Role of vascular reactive oxygen species in development of vascular abnormalities in diabetes. Diabetes Research and Clinical Practice, 77(Suppl 1), S65-S70.
83. Spielberg, S.P., Boxer, L.A., Corash, L.M. & Schulman, J.D. (1979) Improved erythrocyte survival with high-dose vitamin E in chronic hemolyzing G6PD and glutathione synthetase deficiencies. Annals of Internal Medicine, 90, 53-54.
84. Spinnato, J.A. 2nd, Freire, S., Pinto, E.S.J.L., Cunha Rudge, M.V., Martins-Costa, S., Koch, M.A., Goco, N., Santos Cde, B., Cecatti, J.G., Costa, R., Ramos, J.G., Moss, N. & Sibai, B.M. (2007) Antioxidant therapy to prevent preeclampsia: a randomized controlled trial. Obstetrics and Gynecology, 110, 1311-1318.
85. Steinberg, M.H. (2005) Predicting clinical severity in sickle cell anaemia. British Journal of Haematology, 129, 465-481.
86. Sultana, N., Begum, N., Akhter, S., Begum, S., Quraishi, S.B., Ferdousi, S. & Ali, T. (2008) Role of vitamin E supplementation on serum levels of copper and zinc in hemolytic anemic patients with G6PD deficiency. Mymensingh Medical Journal, 17, S84-S90.
87. Suthutvoravut, U., Hathirat, P., Sirichakwal, P., Sasanakul, W., Tassaneeyakul, A. & Feungpean, B. (1993) Vitamin E status, glutathione peroxidase activity and the effect of vitamin E supplementation in children with thalassemia. Journal of the Medical Association of Thailand, 76(Suppl 2), 146-152.
88. Talaulikar, V. (2010) Vitamin C and E to prevent pre-eclampsia in diabetic women. Lancet, 376, 1642-1643; author reply 1643.
89. Talaulikar, V. & Manyonda, I. (2010) The myth of vitamins C and E for the prevention of preeclampsia: just when will the penny drop? American Journal of Obstetrics and Gynecology, 203, e7-e8; author reply e8.
90. Tesoriere, L., D'Arpa, D., Butera, D., Allegra, M., Renda, D., Maggio, A., Bongiorno, A. & Livrea, M.A. (2001) Oral supplements of vitamin E improve measures of oxidative stress in plasma and reduce oxidative damage to LDL and erythrocytes in beta-thalassemia intermedia patients. Free Radical Research, 34, 529-540.
91. Theodorou, A.A., Nikolaidis, M.G., Paschalis, V., Koutsias, S., Panayiotou, G., Fatouros, I.G., Koutedakis, Y. & Jamurtas, A.Z. (2011) No effect of antioxidant supplementation on muscle performance and blood redox status adaptations to eccentric training. American Journal of Clinical Nutrition, 93, 1373-1383.
92. Traber, M.G. & Stevens, J.F. (2011) Vitamins C and E: beneficial effects from a mechanistic perspective. Free Radical Biology & Medicine, 51, 1000-1013.
93. Unchern, S., Laoharuangpanya, N., Phumala, N., Sipankapracha, P., Pootrakul, P., Fucharoen, S., Wanachivanawin, W. & Chantharaksri, U. (2003) The effects of vitamin E on platelet activity in beta-thalassaemia patients. British Journal of Haematology, 123, 738-744.
94. Villar, J., Purwar, M., Merialdi, M., Zavaleta, N., Thi Nhu Ngoc, N., Anthony, J., De Greeff, A., Poston, L. & Shennan, A. (2009) World Health Organisation multicentre randomised trial of supplementation with vitamins C and E among pregnant women at high risk for pre-eclampsia in populations of low nutritional status from developing countries. BJOG, 116, 780-788.
95. Wood, K.C. & Granger, D.N. (2007) Sickle cell disease: role of reactive oxygen and nitrogen metabolites. Clinical and Experimental Pharmacology and Physiology, 34, 926-932.
96. Wun, T. (2001) The role of inflammation and leukocytes in the pathogenesis of sickle cell disease; haemoglobinopathy. Hematology, 5, 403-412.
97. Xu, H., Perez-Cuevas, R., Xiong, X., Reyes, H., Roy, C., Julien, P., Smith, G., von Dadelszen, P., Leduc, L., Audibert, F., Moutquin, J.M., Piedboeuf, B., Shatenstein, B., Parra-Cabrera, S., Choquette, P., Winsor, S., Wood, S., Benjamin, A., Walker, M., Helewa, M., Dube, J., Tawagi, G., Seaward, G., Ohlsson, A., Magee, L.A., Olatunbosun, F., Gratton, R., Shear, R., Demianczuk, N., Collet, J.P., Wei, S. & Fraser, W.D. (2010) An international trial of antioxidants in the prevention of preeclampsia (INTAPP). American Journal of Obstetrics and Gynecology, 202, 239.e1-239.e10.