Hemolysis and Vaso-Occlusive Crisis in Sickle Cell Disease: A Review

Abstract

Sickle Cell Disease (SCD) is an inherited condition characterised by haemolysis and Vaso-occlusive crisis (VOC), resulting in considerable morbidity and organ impairment. These crises lead to consequences like stroke, splenic sequestration, and acute chest syndrome, significantly affecting patients quality of life. This review combines information on hemolysis and Vaso-occlusive crises in sickle cell disease, highlighting their aetiology, clinical implications, and prospective treatment approaches to alleviate disease severity. A systematic review was performed using PRISMA principles. Relevant publications from PubMed, Google Scholar, Web of Science, Scopus, and ScienceDirect were examined, focusing on research published between 2000 and 2024. A total of 68 research articles were included. Haemolysis in sickle cell disease leads to oxidative stress, endothelial dysfunction, and an increased risk of thrombosis. Volatile organic compounds (VOCs) exacerbate these effects, resulting in persistent discomfort, multi-organ impairment, and an increased healthcare burden. Although hydroxyurea remains a fundamental treatment, novel therapies, including voxelotor, crizanlizumab, and gene therapy, exhibit potential. Moreover, antioxidant supplementation, encompassing vitamins D, A, E, and C, has shown promise in mitigating oxidative damage, but clinical results are variable. Hemolysis and Vaso-occlusive crises are pivotal to the pathophysiology of sickle cell disease, substantially exacerbating consequences and patient distress. Progress in pharmacological and supportive therapy provides optimism for enhanced management. Further study is necessary to determine long-term effectiveness and accessibility.

Keywords

• Sickle Cell Disease
• Vaso-occlusive Crisis
• Haemolysis
• Antioxidants
• Gene Therapy

References

1. Chung SM AA, Russell MO. Management of osteonecrosis in sickle-cell, 1978:158-74. aaigvCORR.
2. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, Smith WR, Panepinto JA, Weatherall DJ, Costa FF: Sickle cell disease. Nature reviews Disease primers.(2018).4(1):1-22. doi.org/10.1038/nrdp.2018.10
3. Serjeant GR: The natural history of sickle cell disease. Cold Spring Harbor perspectives in medicine.(2013).3(10):a011783. doi: 10.1101/cshperspect.a011783
4. Steinberg MH: Genetic etiologies for phenotypic diversity in sickle cell anemia. The Scientific World Journal.(2009).9(1):46-67. doi.org/10.1100/tsw.2009.10
5. Steinberg MH, Sebastiani P: Genetic modifiers of sickle cell disease. American journal of hematology.(2012).87(8):795-803. doi.org/10.1002/ajh.23232
6. Rees DC, Williams TN, Gladwin MT: Sickle-cell disease. The Lancet.(2010).376(9757):2018-2031. DOI: 10.1016/S0140-6736(10)61029-X
7. Lee MT, Licursi M, McMahon DJ: Vitamin D deficiency and acute vaso‐occlusive complications in children with sickle cell disease. Pediatric Blood & Cancer.(2015).62(4):643-647. doi.org/10.1002/pbc.25399
8. Silva Junior GBd, Daher EDF, Rocha FACd: Osteoarticular involvement in sickle cell disease. Revista brasileira de hematologia e hemoterapia.(2012).34:156-164. doi.org/10.5581/1516-8484.20120036

9. Ballas SK, Darbari DS: Review/overview of pain in sickle cell disease. Complementary therapies in medicine.(2020).49:102327. doi.org/10.1016/j.ctim.2020.102327
10. Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN: Global burden of sickle cell anaemia in children under five, 2010–2050: modelling based on demographics, excess mortality, and interventions. PLoS medicine.(2013).10(7):e1001484. doi.org/10.1371/journal.pmed.1001484
11. Bonham VL, Smilan LE: Somatic genome editing in sickle cell disease: rewriting a more just future. NCL Rev.(2018).97:1093.
12. Alderson P: The Politics of Childhoods Real and Imagined: Practical application of critical realism and childhood studies, vol. 2: Routledge; 2015. doi.org/10.4324/9781315669380
13. Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW, Wethers DL, Pegelow CH, Gill FM, Sickle Cell Disease tCSo: Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood, The Journal of the American Society of Hematology.(1998).91(1):288-294. doi.org/10.1182/blood.V91.1.288
14. Kiriza N: A Comprehensive Review of Sickle Cell Disease Treatment and Research Centers in the United States and Their Implication on Healthcare Access. University of Pittsburgh; 2021.
15. Naik RP, Streiff MB, Haywood Jr C, Segal JB, Lanzkron S: Venous thromboembolism incidence in the cooperative study of sickle cell disease. Journal of Thrombosis and Haemostasis.(2014).12(12):2010-2016. doi.org/10.1111/jth.12744
16. Brunson A, Lei A, Rosenberg AS, White RH, Keegan T, Wun T: Increased incidence of VTE in sickle cell disease patients: risk factors, recurrence and impact on mortality. British journal of haematology.(2017).178(2):319-326. doi.org/10.1111/bjh.14655
17. Lizarralde-Iragorri MA, Shet AS: Sickle cell disease: a paradigm for venous thrombosis pathophysiology. International journal of molecular sciences.(2020).21(15):5279. doi.org/10.3390/ijms21155279
18. Ashwell E: The basics of blood and associated disorders. British Journal of Nursing.(2022).31(21):1096-1102. doi.org/10.12968/bjon.2022.31.21.1096
19. Obeagu EI: Influence of Hemoglobin Variants on Vaso-Occlusive Phenomena in Sickle Cell Anemia: A Review. International Journal of Medical Sciences and Pharma Research.(2024).10(2):54-59. doi.org/10.22270/ijmspr.v10i2.104
20. Alnaqbi KA: A Rare Case of Multiple Bone Infarctions and Abnormal Pulmonary Function Tests in a Patient With Compound Heterozygous Hemoglobin S and Type 2 Hereditary Persistence of Fetal Hemoglobin. Cureus.(2024).16(8). DOI: 10.7759/cureus.66395
21. Nelson M, Noisette L, Pugh N, Gordeuk V, Hsu L, Wun T, Shah N, Glassberg J, Kutlar A, Hankins J: The clinical spectrum of HbSC sickle cell disease‐not a benign condition. British Journal of Haematology.(2024).205(2):653-663. doi.org/10.1111/bjh.19523
22. Mian UK, Tang J, Allende AP, Heo M, Bernstein N, Vattappally L, Schoenfeld D, Minniti CP: Elevated fetal haemoglobin levels are associated with decreased incidence of retinopathy in adults with sickle cell disease. British journal of haematology.(2018).183(5):807-811. doi.org/10.1111/bjh.15617
23. Sathi BK, Yoshida Y, Weaver MR, Nolan LS, Gruner B, Balasa V, Altes T, Leiva-Salinas C: Unusually high prevalence of stroke and cerebral vasculopathy in hemoglobin SC Disease: a Retrospective Single Institution Study. Acta Haematologica.(2022).145(2):160-169. doi.org/10.1159/000519360
24. Petigas L, Seck N, Doupa D, Diagne I, Roth-Kleiner M: Findings supporting neonatal screening for sickle cell disease: an observational study in Senegal. Frontiers in pediatrics.(2025).13:1578570. doi.org/10.3389/fped.2025.1578570
25. Jeremiah Z, Neenwi EM: Expression of major haemoglobin haplotypes in the first twenty-four months of life suggests a gradual decline of normal haemoglobin A among infants of African descent. Medicinska istraživanja.(2025).58(1). doi.org/10.5937/medi58-52808
26. Kohne E: Hemoglobinopathies: clinical manifestations, diagnosis, and treatment. Deutsches Ärzteblatt International.(2011).108(31-32):532. doi: 10.3238/arztebl.2011.0532
27. Uçucu S, Karabıyık T, Azik F: Difficulties in the diagnosis of HbS/beta thalassemia: Really a mild disease? Journal of Medical Biochemistry.(2022).41(1):32. doi: 10.5937/jomb0-30420
28. Adams RJ, Kutlar A, McKie V, Carl E, Nichols FT, Liu JC, McKie K, Clary A: Alpha thalassemia and stroke risk in sickle cell anemia. American journal of hematology.(1994).45(4):279-282. doi.org/10.1002/ajh.2830450402
29. Ataga KI, Gordeuk VR, Agodoa I, Colby JA, Gittings K, Allen IE: Low hemoglobin increases risk for cerebrovascular disease, kidney disease, pulmonary vasculopathy, and mortality in sickle cell disease: A systematic literature review and meta-analysis. PLoS One.(2020).15(4):e0229959. doi.org/10.1371/journal.pone.0229959
30. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, Abboud M, Gallagher D, Kutlar A, Nichols FT: Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. New England Journal of Medicine.(1998).339(1):5-11. DOI: 10.1056/NEJM199807023390102
31. Hebbel RP, Eaton J, Balasingam M, Steinberg MH: Spontaneous oxygen radical generation by sickle erythrocytes. The Journal of clinical investigation.(1982).70(6):1253-1259. doi.org/10.1172/JCI110724.
32. Hebbel RP, Morgan WT, Eaton JW, Hedlund BE: Accelerated autoxidation and heme loss due to instability of sickle hemoglobin. Proceedings of the National Academy of Sciences.(1988).85(1):237-241. doi.org/10.1073/pnas.85.1.237
33. Kanias T, Acker JP: Biopreservation of red blood cells–the struggle with hemoglobin oxidation. The FEBS journal.(2010).277(2):343-356. doi.org/10.1111/j.1742-4658.2009.07472.x
34. Srivastava NK, Mukherjee S, Mishra VN: One advantageous reflection of iron metabolism in context of normal physiology and pathological phases. Clinical Nutrition ESPEN.(2023). doi.org/10.1016/j.clnesp.2023.10.006
35. Alayash AI: Oxidative pathways in the sickle cell and beyond. Blood Cells, Molecules, and Diseases.(2018).70:78-86. doi.org/10.1016/j.bcmd.2017.05.009
36. Demirci-Cekic S, Özkan G, Avan AN, Uzunboy S, Çapanoğlu E, Apak R: Biomarkers of oxidative stress and antioxidant defense. Journal of pharmaceutical and biomedical analysis.(2022).209:114477. doi.org/10.1016/j.jpba.2021.114477
37. Pisoschi AM, Pop A: The role of antioxidants in the chemistry of oxidative stress: A review. European journal of medicinal chemistry.(2015).97:55-74. doi.org/10.1016/j.ejmech.2015.04.040
38. Azzi A: The role of α-tocopherol in preventing disease. European journal of nutrition.(2004).43:i18-i25. doi.org/10.1007/s00394-004-1105-7
39. Esterbauer H, Dieber-Rotheneder M, Striegl G, Waeg G: Role of vitamin E in preventing the oxidation of low-density lipoprotein. The American journal of clinical nutrition.(1991).53(1):S314-S321. DOI: 10.1093/ajcn/53.1.314S
40. Berridge MJ: Vitamin D cell signalling in health and disease. Biochemical and biophysical research communications.(2015).460(1):53-71. doi.org/10.1016/j.bbrc.2015.01.008
41. Liu Y, Hyde AS, Simpson MA, Barycki JJ: Emerging regulatory paradigms in glutathione metabolism. Advances in cancer research.(2014).122:69-101. doi.org/10.1016/B978-0-12-420117-0.00002-5
42. Vašková J, Kočan L, Vaško L, Perjési P: Glutathione-Related Enzymes and Proteins: A Review. Molecules.(2023).28(3):1447. doi.org/10.3390/molecules28031447
43. Liu X, Zhang Y, Zhuang L, Olszewski K, Gan B: NADPH debt drives redox bankruptcy: SLC7A11/xCT-mediated cystine uptake as a double-edged sword in cellular redox regulation. Genes & diseases.(2021).8(6):731-745. doi.org/10.1016/j.gendis.2020.11.010
44. Gammoh NZ, Rink L: Zinc in infection and inflammation. Nutrients.(2017).9(6):624. doi.org/10.3390/nu9060624
45. Pisoschi AM, Iordache F, Stanca L, Gajaila I, Ghimpeteanu OM, Geicu OI, Bilteanu L, Serban AI: Antioxidant, anti-inflammatory, and immunomodulatory roles of nonvitamin antioxidants in anti-SARS-CoV-2 therapy. Journal of Medicinal Chemistry.(2022).65(19):12562-12593. doi.org/10.1021/acs.jmedchem.2c01134
46. Hama AH, Shakiba E, Rahimi Z, Karimi M, Mozafari H, Abdulkarim OA: Vitamin D level, lipid profile, and vitamin D receptor and transporter gene variants in sickle cell disease patients from Kurdistan of Iraq. Journal of clinical laboratory analysis.(2021).35(9):e23908. doi.org/10.1002/jcla.23908
47. Singh P, Shukla AK, Behera SK, Tiwari PK: Zinc application enhances superoxide dismutase and carbonic anhydrase activities in zinc-efficient and zinc-inefficient wheat genotypes. Journal of Soil Science and Plant Nutrition.(2019).19:477-487.
48. Yalcinkaya A, Unal S, Oztas Y: Altered HDL particle in sickle cell disease: decreased cholesterol content is associated with hemolysis, whereas decreased Apolipoprotein A1 is linked to inflammation. Lipids in health and disease.(2019).18:1-7.
49. Serjeant GR, Ceulaer CD, Lethbridge R, Morris J, And AS, Thomas PW: The painful crisis of homozygous sickle cell disease: clinical features. British journal of haematology.(1994).87(3):586-591. doi.org/10.1111/j.1365-2141.1994.tb08317.x
50. PETERSDORF RG, BEESON PB: Fever of unexplained origin: report on 100 cases. Medicine.(1961).40(1):1-30.
51. Bainbridge R, Higgs DR, Maude GH, Serjeant GR: Clinical presentation of homozygous sickle cell disease. The Journal of pediatrics.(1985).106(6):881-885. doi.org/10.1016/S0022-3476(85)80230-4
52. Onalo R: Cardiovascular changes in sickle cell crises and impact of arginine supplementation in vaso-occlusive crisis and acute chest syndrome. Faculty of Health Sciences, University of the Witwatersrand, Johannesburg; 2020.
53. Michaels LA, Maraventano MF, Drachtman RA: Thrombosis and gangrene in a patient with sickle cell disease and dactylitis. The Journal of pediatrics.(2003).142(4):449. DOI: 10.1067/mpd.2003.102
54. Santos LFOd, Guimarães MW, Baptista AF, Sá KN: Impact of neuropathic pain on quality of life in adults with sickle cell disease: observational study. Hematology, Transfusion and Cell Therapy.(2021).43:263-267. doi.org/10.1016/j.htct.2020.03.010
55. Takaoka K, Cyril AC, Jinesh S, Radhakrishnan R: Mechanisms of pain in sickle cell disease. British Journal of Pain.(2021).15(2):213-220. doi.org/10.1177/2049463720920682
56. Hama AH, Qadir AM: Detection of Sickle Cell Disease in Kurdistan, Iraq. doi.org/10.1007/s00192-017-3536-8. DOI:10.48309/IJABBR.2025.2035372.1525
57. Berghmans B: Physiotherapy for pelvic pain and female sexual dysfunction: an untapped resource. International urogynecology journal.(2018).29:631-638. doi.org/10.1007/s00192-017-3536-8
58. Kassim MAK, Pantazi AC, Nori W, Tuta LA, Balasa AL, Mihai CM, Mihai L, Frecus CE, Lupu VV, Lupu A: Non-pharmacological interventions for pain management in hemodialysis: a narrative review. Journal of Clinical Medicine.(2023).12(16):5390. doi.org/10.3390/jcm12165390
59. Lorente L, Vera M, Peiró T: Nurses stressors and psychological distress during the COVID‐19 pandemic: The mediating role of coping and resilience. Journal of advanced nursing.(2021).77(3):1335-1344. doi.org/10.1111/jan.14695
60. Berzon R, Hays R, Shumaker S: International use, application and performance of health-related quality of life instruments. Quality of Life Research.(1993).2(6):367-368. doi.org/10.1007/BF00422214
61. Yawn BP, John-Sowah J: Management of sickle cell disease: recommendations from the 2014 expert panel report. American family physician.(2015).92(12):1069-1076.
62. Palm N, Floroff C, Hassig TB, Boylan A, Kanter J: Low-dose ketamine infusion for adjunct management during vaso-occlusive episodes in adults with sickle cell disease: a case series. Journal of pain & palliative care pharmacotherapy.(2018).32(1):20-26. doi.org/10.1080/15360288.2018.1468383
63. Brandow AM, Panepinto JA: Clinical interpretation of quantitative sensory testing as a measure of pain sensitivity in patients with sickle cell disease. Journal of pediatric hematology/oncology.(2016).38(4):288. DOI: 10.1097/MPH.0000000000000532
64. Darbari DS, Sheehan VA, Ballas SK: The vaso‐occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management. European journal of haematology.(2020).105(3):237-246. doi.org/10.1111/ejh.13430
65. Edwards CL, Scales MT, Loughlin C, Bennett GG, Harris-Peterson S, Castro LMD, Whitworth E, Abrams M, Feliu M, Johnson S: A brief review of the pathophysiology, associated pain, and psychosocial issues in sickle cell disease. International journal of behavioral medicine.(2005).12:171-179. doi.org/10.1207/s15327558ijbm1203_6
66. Pope M, Albo C, Kidwell KM, Xu H, Bowman L, Wells L, Barrett N, Fields S, Bora P, Clay ELJ: Evolution of chronic pain in sickle cell disease. Blood.(2016).128(22):1297. doi.org/10.1182/blood.V128.22.1297.1297
67. Tawfic QA, Faris AS, Kausalya R: The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease. Journal of pain and symptom management.(2014).47(2):334-340. doi.org/10.1016/j.jpainsymman.2013.03.012
68. Neri CM, Pestieau SR, Darbari DS: Low‐dose ketamine as a potential adjuvant therapy for painful vaso‐occlusive crises in sickle cell disease. Pediatric Anesthesia.(2013).23(8):684-689. doi.org/10.1111/pan.12172
69. Anie KA, Green J: Psychological therapies for sickle cell disease and pain. Cochrane Database of Systematic Reviews.(2015).(5). doi.org/10.1002/14651858.CD001916
70. Shah N, Bhor M, Xie L, Paulose J, Yuce H: Medical resource use and costs of treating sickle cell-related vaso-occlusive crisis episodes: a retrospective claims study. Journal of health economics and outcomes research.(2020).7(1):52. doi: 10.36469/jheor.2020.12852
71. Shapiro BS, Dinges DF, Orne EC, Bauer N, Reilly LB, Whitehouse WG, Ohene-Frempong K, Orne MT: Home management of sickle cell-related pain in children and adolescents: natural history and impact on school attendance. Pain.(1995).61(1):139-144. doi.org/10.1016/0304-3959(94)00164-A
72. Smith WR, Penberthy LT, Bovbjerg VE, McClish DK, Roberts JD, Dahman B, Aisiku IP, Levenson JL, Roseff SD: Daily assessment of pain in adults with sickle cell disease. Annals of internal medicine.(2008).148(2):94-101. doi.org/10.7326/0003-4819-148-2-200801150-00004
73. Holdford D, Vendetti N, Sop DM, Johnson S, Smith WR: Indirect economic burden of sickle cell disease. Value in Health.(2021).24(8):1095-1101. doi.org/10.1016/j.jval.2021.02.014
74. Mvundura M, Amendah D, Kavanagh PL, Sprinz PG, Grosse SD: Health care utilization and expenditures for privately and publicly insured children with sickle cell disease in the United States. Pediatric blood & cancer.(2009).53(4):642-646. doi.org/10.1002/pbc.22069
75. Kanter J, Kruse-Jarres R: Management of sickle cell disease from childhood through adulthood. Blood reviews.(2013).27(6):279-287. doi.org/10.1016/j.blre.2013.09.001
76. Kapur A: Economic analysis of diabetes care. Indian Journal of Medical Research.(2007).125(3):473-482.
77. Kauf TL, Coates TD, Huazhi L, Mody‐Patel N, Hartzema AG: The cost of health care for children and adults with sickle cell disease. American journal of hematology.(2009).84(6):323-327. doi.org/10.1002/ajh.21408
78. Kumar A, Avishay DM, Jones CR, Shaikh JD, Kaur R, Aljadah M, Kichloo A, Shiwalkar N, Keshavamurthy S: Sudden cardiac death: epidemiology, pathogenesis and management. Reviews in Cardiovascular Medicine.(2021).22(1):147-158. DOI: 10.31083/j.rcm.2021.01.207
79. Sethi S: Approaches to Anti Infective Therapies. Bentham Sci.(2021).5:120. doi.org/10.2174/97898149983901210501
80. Chou ST: Transfusion therapy for sickle cell disease: a balancing act. Hematology 2013, the American Society of Hematology Education Program Book.(2013).2013(1):439-446. doi.org/10.1182/asheducation-2013.1.439
81. Kutlar A, Kanter J, Liles DK, Alvarez OA, Cançado RD, Friedrisch JR, Knight‐Madden JM, Bruederle A, Shi M, Zhu Z: Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: a SUSTAIN study analysis. American journal of hematology.(2019).94(1):55-61. doi.org/10.1002/ajh.25308
82. Simeone JC, Shah S, Ganz ML, Sullivan S, Koralova A, LeGrand J, Bushman J: Healthcare resource utilization and cost among patients with type 1 diabetes in the United States. Journal of Managed Care & Specialty Pharmacy.(2020).26(11):1399-1410. doi.org/10.18553/jmcp.2020.26.11.139
83. Smith WR, Scherer M: Sickle-cell pain: advances in epidemiology and etiology. Hematology 2010, the American Society of Hematology Education Program Book.(2010).2010(1):409-415. doi.org/10.1182/asheducation-2010.1.409
84. Gueguen A, Mahevas M, Nzouakou R, Hosseini H, Habibi A, Bachir D, Brugière P, Lionnet F, Ribeil JA, Godeau B: Sickle‐cell disease stroke throughout life: A retrospective study in an adult referral center. American Journal of Hematology.(2014).89(3):267-272. doi.org/10.1002/ajh.23625
85. Adams RJ, McKie VC, Brambilla D, Carl E, Gallagher D, Nichols FT, Roach S, Abboud M, Berman B, Driscoll C: Stroke prevention trial in sickle cell anemia. Controlled clinical trials.(1998).19(1):110-129. doi.org/10.1002/ajh.23625
86. Oluwole O, Brunson AM, Adesina OO, Willen SM, Keegan TH, Fertrin KY, Wun T: Rates of strokes in Californians with sickle cell disease in the post-STOP era. Blood.(2024).144(24):2517-2527. doi.org/10.1182/blood.2023023031
87. Fox CK, Leykina L, Hills NK, Kwiatkowski JL, Kanter J, Strouse JJ, Voeks JH, Fullerton HJ, Adams RJ, Group P-SS: Hemorrhagic stroke in children and adults with sickle cell anemia: the Post-STOP Cohort. Stroke.(2022).53(11):e463-e466. doi.org/10.1161/STROKEAHA.122.038651
88. Bolarinwa AB, Oduwole O, Okebe J, Ogbenna AA, Otokiti OE, Olatinwo AT: Antioxidant supplementation for sickle cell disease. Cochrane Database of Systematic Reviews.(2024).(5). doi.org/10.1161/STROKEAHA.122.038651
89. Delesderrier E, Curioni C, Omena J, Macedo CR, Cople-Rodrigues C, Citelli M: Antioxidant nutrients and hemolysis in sickle cell disease. Clinica Chimica Acta.(2020).510:381-390. doi.org/10.1016/j.cca.2020.07.020
90. Ibrahim A, Muhammad SA: Antioxidant-rich nutraceutical as a therapeutic strategy for sickle cell disease. Journal of the american nutrition association.(2023).42(6):588-597. doi.org/10.1080/27697061.2022.2108930
91. Alabi OJ, Adegboyega FN, Olawoyin DS, Babatunde OA: Functional foods: promising therapeutics for Nigerian Children with sickle cell diseases. Heliyon.(2022).8(6). DOI: 10.1016/j.heliyon.2022.e09630
92. Huang H-Y, Appel LJ, Croft KD, Miller III ER, Mori TA, Puddey IB: Effects of vitamin C and vitamin E on in vivo lipid peroxidation: results of a randomized controlled trial. The American journal of clinical nutrition.(2002).76(3):549-555. doi.org/10.1093/ajcn/76.3.549
93. Arruda MM, Mecabo G, Rodrigues CA, Matsuda SS, Rabelo IB, Figueiredo MS: 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.(2013).160(5):688-700. doi.org/10.1111/bjh.12185
94. Wang S-W, Zhang X-W, Qu J-X, Rao Y-Z, Lu S, Wang B, He J, Zhao Y, Rao B-Q: Hemolysis attributed to high dose vitamin C: Two case reports. World Journal of Clinical Cases.(2024).12(17):3168. doi: 10.12998/wjcc.v12.i17.3168
95. Evans VA, O’Neill LA: Lessons from Glucocorticoids, Metformin, and Dimethyl Fumarate: Could Targeting Immunometabolism Lead to Better Anti-Inflammatory Therapies? Annual Review of Pharmacology and Toxicology.(2025).66. doi.org/10.1146/annurev-pharmtox-062624-013520
96. Luo M, Zhou L, Huang Z, Li B, Nice EC, Xu J, Huang C: Antioxidant therapy in cancer: rationale and progress. Antioxidants.(2022).11(6):1128. doi.org/10.3390/antiox11061128
97. Manivasagam T, Arunadevi S, Essa MM, SaravanaBabu C, Borah A, Thenmozhi AJ, Qoronfleh MW: Role of oxidative stress and antioxidants in autism. Personalized food intervention and therapy for autism spectrum disorder management.(2020).193-206. doi.org/10.1007/978-3-030-30402-7_7
98. Hsu T-J, Hsieh R-H, Huang C-H, Chen C-S, Lin W-Y, Huang Y-C, Lin J-H, Huang K-T, Liu Y-L, Tsai H-M: Efficacy of zinc supplementation in the management of primary dysmenorrhea: A systematic review and meta-analysis. Nutrients.(2024).16(23):4116. doi: 10.3390/nu16234116
99. Veljović M, Mihajlović I, Subota V, Antunović M, Jevđić J, Udovičić I, Popadić A, Vulović T: Effect of pretreatment with omega-3 polyunsaturated fatty acids (PUFAs) on hematological parameters and platelets aggregation in patients during elective coronary artery bypass grafting. Vojnosanitetski pregled.(2013).70(4):396-402. doi.org/10.2298/VSP1304396V
100. Doaei S, Gholami S, Rastgoo S, Gholamalizadeh M, Bourbour F, Bagheri SE, Samipoor F, Akbari ME, Shadnoush M, Ghorat F: The effect of omega-3 fatty acid supplementation on clinical and biochemical parameters of critically ill patients with COVID-19: a randomized clinical trial. Journal of translational medicine.(2021).19(1):128. doi.org/10.1186/s12967-021-02795-5
101. Gharekhani A, Khatami M-R, Dashti-Khavidaki S, Razeghi E, Abdollahi A, Hashemi-Nazari S-S, Mansournia M-A: Potential effects of omega-3 fatty acids on anemia and inflammatory markers in maintenance hemodialysis patients. DARU Journal of Pharmaceutical Sciences.(2014).22(1):11. doi.org/10.1186/2008-2231-22-11
102. Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR, Anemia IotMSoHiSC: Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. New England Journal of Medicine.(1995).332(20):1317-1322. DOI: 10.1056/NEJM199505183322001
103. Nevitt SJ, Jones AP, Howard J: Hydroxyurea (hydroxycarbamide) for sickle cell disease. Cochrane Database of Systematic Reviews.(2017).(4). doi.org/10.1002/14651858.CD002202.pub2
104. Rankine-Mullings AE, Nevitt SJ: Hydroxyurea (hydroxycarbamide) for sickle cell disease. Cochrane Database of Systematic Reviews.(2022).(9). doi.org/10.1002/14651858.CD002202.pub3
105. Goldberg MA, Brugnara C, Dover GJ, Schapira L, Charache S, Bunn HF: Treatment of sickle cell anemia with hydroxyurea and erythropoietin. New England Journal of Medicine.(1990).323(6):366-372. DOI: 10.1056/NEJM199008093230602
106. López Rubio M, Argüello Marina M: The Current Role of Hydroxyurea in the Treatment of Sickle Cell Anemia. Journal of Clinical Medicine.(2024).13(21):6404. doi.org/10.3390/jcm13216404
107. Steinberg MH, McCarthy WF, Castro O, Ballas SK, Armstrong FD, Smith W, Ataga K, Swerdlow P, Kutlar A, DeCastro L: The risks and benefits of long‐term use of hydroxyurea in sickle cell anemia: a 17.5 year follow‐up. American journal of hematology.(2010).85(6):403-408. doi.org/10.1002/ajh.21699
108. Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, Hassab H, Achebe MM, Alkindi S, Brown RC: A phase 3 randomized trial of voxelotor in sickle cell disease. New England Journal of Medicine.(2019).381(6):509-519. DOI: 10.1056/NEJMoa1903212
109. Howard J, Ataga KI, Brown RC, Achebe M, Nduba V, El-Beshlawy A, Hassab H, Agodoa I, Tonda M, Gray S: Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Haematology.(2021).8(5):e323-e333. DOI: 10.1016/S2352-3026(21)00059-4
110. Estepp JH, Kalpatthi R, Woods G, Trompeter S, Liem RI, Sims K, Inati A, Inusa BP, Campbell A, Piccone C: Safety and efficacy of voxelotor in pediatric patients with sickle cell disease aged 4 to 11 years. Pediatric blood & cancer.(2022).69(8):e29716. doi.org/10.1002/pbc.29716
111. White SL, Hart K, Kohn DB: Diverse approaches to gene therapy of sickle cell disease. Annual review of medicine.(2023).74(1):473-487. doi.org/10.1146/annurev-med-042921-021707
112. Esrick EB, Bauer DE: Genetic therapies for sickle cell disease. In: Seminars in Hematology: 2018. Elsevier: 76-86. doi.org/10.1053/j.seminhematol.2018.04.014
113. Ballantine J, Tisdale JF: Gene Therapy for Sickle Cell Disease: Recent Advances, Clinical Trials, and Future directions. Cytotherapy.(2024). doi.org/10.1016/j.jcyt.2024.11.006
114. Alshammari S: Sickle cell disease associated lipid changes and their relevance towards the disease pathogenesis And Lipid Biomarkers and Embryo Quality in In Vitro Fertilization; Pregnancy Success Differentially Expressed by Body Weight. 2021). doi.org/10.25772/FNS0-X122
115. Almashjary MN: The Impact of Dietary Iron Restriction on Sickling Kinetics and Hemolysis in a Transgenic Model of Sickle Cell Disease: The Catholic University of America; 2020.
116. Glaros AK, Razvi R, Shah N, Zaidi AU: Voxelotor: alteration of sickle cell disease pathophysiology by a first-in-class polymerization inhibitor. Therapeutic advances in hematology.(2021).12:20406207211001136. doi.org/10.1177/20406207211001
117. Ikawa Y, Miccio A, Magrin E, Kwiatkowski JL, Rivella S, Cavazzana M: Gene therapy of hemoglobinopathies: progress and future challenges. Human Molecular Genetics.(2019).28(R1):R24-R30. doi.org/10.1093/hmg/ddz172
118. Salcedo J, Bulovic J, Young CM: Cost-effectiveness of a hypothetical cell or gene therapy cure for sickle cell disease. Scientific Reports.(2021).11(1):10838. doi.org/10.1038/s41598-021-90405-1
119. Nader E, Romana M, Connes P: The red blood cell—inflammation vicious circle in sickle cell disease. Frontiers in immunology.(2020).11:454. doi.org/10.3389/fimmu.2020.00454
120. Jagadeeswaran R, Rivers A: Evolving treatment paradigms in sickle cell disease. Hematology 2014, the American Society of Hematology Education Program Book.(2017).2017(1):440-446. doi.org/10.1182/asheducation-2017.1.440
121. Vona R, Sposi NM, Mattia L, Gambardella L, Straface E, Pietraforte D: Sickle cell disease: role of oxidative stress and antioxidant therapy. Antioxidants.(2021).10(2):296. doi.org/10.3390/antiox10020296
122. Treadwell MJ, Du L, Bhasin N, Marsh AM, Wun T, Bender M, Wong TE, Crook N, Chung JH, Norman S: Barriers to hydroxyurea use from the perspectives of providers, individuals with sickle cell disease, and families: report from a US regional collaborative. Frontiers in genetics.(2022).13:921432. doi.org/10.3389/fgene.2022.921432
123. Abraham AA, Tisdale JF: Gene therapy for sickle cell disease: moving from the bench to the bedside. Blood, The Journal of the American Society of Hematology.(2021).138(11):932-941. doi.org/10.1182/blood.2019003776