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Annals of Hematology

, Volume 98, Issue 10, pp 2257–2265 | Cite as

Association of plasma homocysteine level with vaso-occlusive crisis in sickle cell anemia patients of Odisha, India

  • Satyabrata Meher
  • Siris Patel
  • Kishalaya Das
  • Snehadhini Dehury
  • Bimal Prasad Jit
  • Mahendra M. Maske
  • Padmalaya Das
  • Bisnu Prasad DashEmail author
  • Pradeep Kumar MohantyEmail author
Original Article
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Abstract

Vascular complications of sickle cell anemia (SCA) are influenced by many factors. Elevated plasma homocysteine (Hcy) is supposed to be an independent risk factor and is either genetic or nutritional origin. The present study evaluated the plasma Hcy level, MTHFR C677T gene polymorphism, effect of folic acid (FA) supplementation‚ and hemato-biochemical parameters in SCA and their effect on the vaso-occlusive crisis (VOC) in SCA patients of an Asian-Indian haplotype population. One hundred twenty cases of SCA (HbSS) and 50 controls with normal hemoglobin(HbAA) were studied. It was found that the plasma Hcy level is significantly higher (p < 0.0001) in patients with SCA (22.41 ± 7.8 μmol/L) compared to controls (13.2 ± 4.4 μmol/L). Moreover, patients without FA supplementation had a significantly (p < 0.001) higher Hcy level (27 ± 7 μmol/L) compared to those with supplementation (17.75 ± 5.7 μmol/L). Turkey-Kramer multiple comparison tests show that there is a significant difference (p < 0.05) in HbF percent, hemoglobin (Hb), platelet count, serum bilirubin (direct:Bil-D and total:Bil-T), aspartate transaminase (AST), lactate dehydrogenase (LDH), and plasma Hcy levels between mild and severe VOC. Between moderate VOC and severe VOC, there was a significant difference (p < 0.05) in HbF%, Bil-D, AST, Hcy. Pearson correlation revealed that plasma Hcy had a significantly (p < 0.05) positive correlation with AST, serum bilirubin (indirect and total), LDH, jaundice, stroke, VOC per year, and hospitalization per year whereas it was inversely correlated with HbF percentage, Hb level, and FA treatment. In the study population, increased plasma Hcy level, hemolysis, and platelet activation were found to influence VOC in SCA.

Keywords

Sickle cell anemia Homocysteine Folic acid Vaso-occlusive crisis Hemolysis Methyltetrahydrofolate reductase 

Notes

Acknowledgments

We thank Prof. Manoj Kumar Mohapatra (Dean & Principal) and Director, V.S.S. Institute of Medical Sciences & Research, Burla, Sambalpur, Odisha, for permitting us to carry out this study. SM expresses his gratitude to the Hon’ble Vice Chancellor, Fakir Mohan University, for supporting the research work.

Author contributions

Conceptualization and design: SM, BPD, and PKM. Data collection: SM, SP, KD, SD, BPJ, MMM. Laboratory work: SM. Data analysis and interpretation: SM, SP, PD, BPD, PKM. Manuscript writing: all authors. Final approval of manuscript: all authors.

Funding information

The Odisha Sickle Cell Project, National Health Mission, Odisha, provided funding support.

Compliance with ethical standards

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional ethical committee of VIMSAR, Burla, Odisha (VIREC-No.2016/I-F-CT-01/008) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed written consent was obtained from all individual participants included in the study.

Financial relationship

The authors declare that they have no financial relationship with the organization that sponsored for the research work. The funding agencies had no involvement in study design, data collection, data analysis, and data interpretation.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

277_2019_3776_MOESM1_ESM.docx (12 kb)
Supplementary Table 4 Alleles and genotype frequency (%) of MTHFR C677T in SCA and control (DOCX 11 kb)
277_2019_3776_MOESM2_ESM.docx (13 kb)
Supplementary Table 5 Association between the clinical presentation of SCA and MTHFR C677T genotype (DOCX 12 kb)
277_2019_3776_Fig2_ESM.png (1 mb)
Supplementary Figure 1

Mutation detection by gel documentation for MTHFR (677 C > T) (PNG 1037 kb)

277_2019_3776_MOESM3_ESM.tif (749 kb)
High resolution image (TIF 748 kb)

References

  1. 1.
    Ingram VM (1956) A specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin. Nature. 178(4537):792–794CrossRefGoogle Scholar
  2. 2.
    Eaton WA, Hofrichter J (1987) Hemoglobin S gelation and sickle cell disease. Blood. 70(5):1245–1266Google Scholar
  3. 3.
    Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L et al (2018) Sickle cell disease. Nat Rev Dis Primers 4:18010.  https://doi.org/10.1038/nrdp.2018.10 CrossRefGoogle Scholar
  4. 4.
    Mohan IV, Jagroop IA, Mikhailidis DP, Stansby GP (2008) Homocysteine activates platelets in vitro. Clin Appl Thromb Hemost 14(1):8–18.  https://doi.org/10.1177/1076029607308390 CrossRefGoogle Scholar
  5. 5.
    Stuart MJ, Nagel RL (2004) Sickle-cell disease. Lancet 364(9442):1343–1360.  https://doi.org/10.1016/S0140-6736(04)17192-4 CrossRefGoogle Scholar
  6. 6.
    Kar BC (1991) Sickle cell disease in India. J Assoc Physicians India 39(12):954–960Google Scholar
  7. 7.
    Kato GJ, Steinberg MH, Gladwin MT (2017) Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest 127(3):750–760.  https://doi.org/10.1172/JCI89741 CrossRefGoogle Scholar
  8. 8.
    Wilcken DE, Wilcken B et al (1976) J Clin Invest 57(4):1079–1082.  https://doi.org/10.1172/JCI108350 CrossRefGoogle Scholar
  9. 9.
    Carey MC, Fennelly JJ, FitzGerald O, Homocystinuria II (1968) Homocystinuria. II. Subnormal serum folate levels increased folate clearance and effects of folic acid therapy. Am J Med 45(1):26–31. Available from: http://www.ncbi.nlm.nih.gov/pubmed/5658866.  https://doi.org/10.1016/0002-9343(68)90004-1 CrossRefGoogle Scholar
  10. 10.
    Kang SS, Wong PW, Norusis M (1987) Homocysteinemia due to folate deficiency. Metabolism 36(5):458–462.  https://doi.org/10.1016/0026-0495(87)90043-6 CrossRefGoogle Scholar
  11. 11.
    Pandey S, Pandey HR, Mishra RM, Pandey S, Saxena R (2012) Increased homocysteine level in Indian sickle cell anemia patients. Indian J Clin Biochem 27(1):103–104.  https://doi.org/10.1007/s12291-011-0158-7 CrossRefGoogle Scholar
  12. 12.
    Abby SL, Harris IM, Harris KM (1998) Homocysteine and cardiovascular disease. J Am Board Fam Pract 11(5):391–398.  https://doi.org/10.3122/15572625-11-5-391 CrossRefGoogle Scholar
  13. 13.
    Sati’Abbas S, Abul–Razak N, Mustafa N, Ali RA (2011) Homocysteine, folic acid, vitamin B12 and pyridoxine: effects on vaso-occlusive crisis in sickle cell anemia and sickle–thalassemia. Iraqi Acad Sci J 10(4):473–479 https://www.iasj.net/iasj?func=article&aId=43573 Google Scholar
  14. 14.
    Luo F, Liu X, Wang S, Chen H (2006) Effect of homocysteine on platelet activation induced by collagen. Nutrition 22(1):69–75.  https://doi.org/10.1016/j.nut.2005.04.012 CrossRefGoogle Scholar
  15. 15.
    Undas A, Stepień E, Plicner D, Zielinski L, Tracz W (2007) Elevated total homocysteine is associated with increased platelet activation at the site of microvascular injury: effects of folic acid administration. J Thromb Haemost 5(5):1070–1072.  https://doi.org/10.1111/j.1538-7836.2007.02459.x CrossRefGoogle Scholar
  16. 16.
    Lowenthal EA, Mayo MS, Cornwell PE, Thornley-Brown D (2000) Homocysteine elevation in sickle cell disease. J Am Coll Nutr 19(5):608–612.  https://doi.org/10.1080/07315724.2000.10718958 CrossRefGoogle Scholar
  17. 17.
    Raouf AA, Hamdy MM, Badr AM, Shalaan O, Sakr M, Rahman AR (2018) Effect of homocysteine and folic acid on vaso-occlusive crisis in children with sickle cell disease. Egypt J Haematol 43(3):115–118CrossRefGoogle Scholar
  18. 18.
    Graham IM, Daly LE, Refsum HM, Robinson K, Brattstr LE, Ueland PM et al (1997) Plasma homocysteine for vascular disease. JAMA 277(22):1775–1781.  https://doi.org/10.1001/jama.1997.03540460039030 CrossRefGoogle Scholar
  19. 19.
    Guthikonda S, Haynes WG (2006) Homocysteine: role and implications in atherosclerosis. Curr Atheroscler Rep 8(2):100–106.  https://doi.org/10.1007/s11883-006-0046-4 CrossRefGoogle Scholar
  20. 20.
    Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE (2001) Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 22(4):195–201. Available from: http://tips.trends.com.  https://doi.org/10.1016/S0165-6147(00)01675-8 CrossRefGoogle Scholar
  21. 21.
    Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10(1):111–113.  https://doi.org/10.1038/ng0595-111 CrossRefGoogle Scholar
  22. 22.
    Jit BP, Mohanty PK, Purohit P, Das K, Patel S, Meher S, Mohanty JR, Sinha S, Behera RK, Das P (2019) Association of fetal hemoglobin level with frequency of acute pain episodes in sickle cell disease (HbS-only phenotype) patients. Blood Cells Mol Dis 75:30–34CrossRefGoogle Scholar
  23. 23.
    Mashon RS, Dash PM, Khalkho J, Dash L, Mohanty PK, Patel S, Mohanty RC, Das BS, Das UK, Das PK, Patel DK (2009) Higher fetal hemoglobin concentration in patients with sickle cell disease in eastern India reduces frequency of painful crisis. Eur J Haematol 83(4):383–384CrossRefGoogle Scholar
  24. 24.
    Steinberg MH (2005) Predicting clinical severity in sickle cell anaemia. Br J Haematol 129(4):465–481CrossRefGoogle Scholar
  25. 25.
    Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW et al (1998) Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 91(1):288–294Google Scholar
  26. 26.
    Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, Kinney TR (1991) Pain in sickle cell disease: rates and risk factors. N Engl J Med 325(1):11–16CrossRefGoogle Scholar
  27. 27.
    Bailey K, Morris JS, Thomas P, Serjeant GR (1992) Fetal haemoglobin and early manifestations of homozygous sickle cell disease. Arch Dis Child 67(4):517–520CrossRefGoogle Scholar
  28. 28.
    Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Dewi M et al (2013) Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet 381(9861):142–151.  https://doi.org/10.1016/S0140-6736(12)61229-X CrossRefGoogle Scholar
  29. 29.
    Hockham C, Bhatt S, Colah R, Mukherjee MB, Penman BS, Gupta S et al (2018) The spatial epidemiology of sickle-cell anaemia in India. Sci Rep 8(1):17685.  https://doi.org/10.1038/s41598-018-36077-w CrossRefGoogle Scholar
  30. 30.
    Mohanty D, Mukherjee MB (2002) Sickle cell disease in India. Curr Opin Hematol 9(2):117–122CrossRefGoogle Scholar
  31. 31.
    Patel DK, Mashon RS, Patel S (2010) Epidemiology and clinical aspects of sickle cell disease in India. Orissa Phys J 6:19–23Google Scholar
  32. 32.
    Charache S, Terrin ML, Moore RD, Dover GJ, McMahon RP, Barton FB et al (1995) Investigators of the multicenter study of hydroxyurea. Design of the multicenter study of hydroxyurea in sickle cell anemia. Control Clin Trials 16(6):432–446.  https://doi.org/10.1016/S0197-2456(95)00098-4 CrossRefGoogle Scholar
  33. 33.
    Reid C, Davies A (2004) The World Health Organization three-step analgesic ladder comes of age. Palliat Med 18(3):175–176.  https://doi.org/10.1191/0269216304pm897ed CrossRefGoogle Scholar
  34. 34.
    Rees DC, Olujohungbe AD, Parker NE, Stephens AD, Telfer P, Wright J (2003) Guidelines for the management of the acute painful crisis in sickle cell disease. Br J Haematol 120(5):744–752CrossRefGoogle Scholar
  35. 35.
    Ballas SK, Bauserman RL, McCarthy WF, Castro OL, Smith WR, Waclawiw MA (2010) Investigators of the multicenter study of hydroxyurea in sickle cell anemia. Hydroxyurea and acute painful crises in sickle cell anemia: effects on hospital length of stay and opioid utilization during hospitalization, outpatient acute care contacts, and at home. J Pain Symptom Manag 40(6):870–882CrossRefGoogle Scholar
  36. 36.
    Kang SS, Wong PW, Malinow MR (1992) Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 12(1):279–298.  https://doi.org/10.1146/annurev.nu.12.070192.001431 CrossRefGoogle Scholar
  37. 37.
    Refsum H, Smith AD, Ueland PM, Nexo E, Clarke R, McPartlin J et al (2004) Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 50(1):3–2CrossRefGoogle Scholar
  38. 38.
    Old JM, Higgs DR (1983) Gene analysis. Methods in haematology. In: Weatherall DJ (ed) The Thalassemias. Churchill & Livingstone, Edinburgh, p 74Google Scholar
  39. 39.
    Solé X, Guinó E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies. Bioinformatics 22(15):1928–1929.  https://doi.org/10.1093/bioinformatics/btl268 CrossRefGoogle Scholar
  40. 40.
    Serjeant GR (2001) The emerging understanding of sickle cell disease. Br J Haematol 112(1):3–18.  https://doi.org/10.1046/j.1365-2141.2001.02557.x CrossRefGoogle Scholar
  41. 41.
    Phillips F (2005) Vegetarian nutrition. Nutr Bull 30(2):132–167.  https://doi.org/10.1111/j.1467-3010.2005.00467.x CrossRefGoogle Scholar
  42. 42.
    Brattström LE, Israelsson B, Jeppsson JO, Hultberg BL (1988) Folic acid—an innocuous means to reduce plasma homocysteine. Scand J Clin Lab Invest 48(3):215–221.  https://doi.org/10.3109/00365518809167487 CrossRefGoogle Scholar
  43. 43.
    Lin N, Qin S, Luo S, Cui S, Huang G, Zhang X (2014) Homocysteine induces cytotoxicity and proliferation inhibition in neural stem cells via DNA methylation in vitro. FEBS J 281(8):2088–2096.  https://doi.org/10.1111/febs.12764 CrossRefGoogle Scholar
  44. 44.
    García-Morin M, López-Sangüos C, Vázquez P, Alvárez T, Marañón R, Huerta J, Cela E (2016) Lactate dehydrogenase: a marker of the severity of vaso-occlusive crisis in children with sickle cell disease presenting at the emergency department. Hemoglobin. 40(6):388–391CrossRefGoogle Scholar
  45. 45.
    Najim OA, Hassan MK (2011) Lactate dehydrogenase and severity of pain in children with sickle cell disease. Acta Haematol 126(3):157–162CrossRefGoogle Scholar
  46. 46.
    Neely CL, Wajima T, Kraus AP, Diggs LW, Barreras L (1969) Lactic acid dehydrogenase activity and plasma hemoglobin elevations in sickle cell disease. Am J Clin Pathol 52(2):167–169CrossRefGoogle Scholar
  47. 47.
    Stojanovic KS, Steichen O, Lefevre G, Bachmeyer C, Avellino V, Grateau G et al (2012) High lactate dehydrogenase levels at admission for painful vaso-occlusive crisis is associated with severe outcome in adult SCA patients. Clin Biochem 45(18):1578–1582CrossRefGoogle Scholar
  48. 48.
    Ojuawo A, Adedoyin MA, Fagbule D (1994) Hepatic function tests in children with sickle cell anaemia during vaso occlusive crisis. Cent Afr J Med 40(12):342–345Google Scholar
  49. 49.
    Durand P, Lussier-Cacan S, Blache D (1997) Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. FASEB J 11(13):1157–1168CrossRefGoogle Scholar
  50. 50.
    Westwick J, Watson-Williams EJ, Krishnamurthi S, Marks G, Ellis V, Scully MF et al (1983) Platelet activation during steady state sickle cell disease. J Med 14(1):17–36Google Scholar
  51. 51.
    Gardner K, Thein SL (2015) Super-elevated LDH and thrombocytopenia are markers of a severe subtype of vaso-occlusive crisis in sickle cell disease. Am J Hematol 90(10):E206–E207CrossRefGoogle Scholar
  52. 52.
    Curtis SA, Danda N, Etzion Z, Cohen HW, Billett HH (2015) Elevated steady state WBC and platelet counts are associated with frequent emergency room use in adults with sickle cell anemia. PLoS One 10(8):e0133116.  https://doi.org/10.1371/journal.pone.0133116 CrossRefGoogle Scholar
  53. 53.
    Brzoska T, Kato GJ, Sundd P (2019) The role of platelets in sickle cell disease. InPlatelets, 4th edn, pp 563–580.  https://doi.org/10.1016/B978-0-12-813456-6.00031-X
  54. 54.
    Alhandalous CH, Han J, Hsu L, Gowhari M, Hassan J, Molokie R, Abbasi TA, Gordeuk VR (2015) Platelets decline during Vasoocclusive crisis as a predictor of acute chest syndrome in sickle cell disease. Am J Hematol 90(12):E228–E229CrossRefGoogle Scholar
  55. 55.
    Cronin S, Furie KL, Kelly PJ (2005) Dose-related association of MTHFR 677T allele with risk of ischemic stroke: evidence from a cumulative meta-analysis. Stroke 36(7):1581–1587.  https://doi.org/10.1161/01.STR.0000169946.31639.af CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Satyabrata Meher
    • 1
    • 3
  • Siris Patel
    • 1
  • Kishalaya Das
    • 1
  • Snehadhini Dehury
    • 1
  • Bimal Prasad Jit
    • 4
  • Mahendra M. Maske
    • 2
    • 5
  • Padmalaya Das
    • 6
  • Bisnu Prasad Dash
    • 3
    Email author
  • Pradeep Kumar Mohanty
    • 1
    • 2
    • 7
    Email author
  1. 1.Sickle Cell Clinic and Molecular Biology Laboratory, Odisha Sickle Cell Project (NHM)Veer Surendra Sai Institute of Medical Science and Research (VIMSAR)SambalpurIndia
  2. 2.Department of MedicineVeer Surendra Sai Institute of Medical Science & Research (VIMSAR)SambalpurIndia
  3. 3.Department of Bioscience and BiotechnologyFakir Mohan UniversityBalasoreIndia
  4. 4.School of Life SciencesSambalpur UniversitySambalpurIndia
  5. 5.Department of CardiologyGovt. Medical College and Super Specialty HospitalNagpurIndia
  6. 6.School of Life SciencesAIPH UniversityBhubaneswarIndia
  7. 7.Head of the Department of Medicine and Project Coordinator, Odisha Sickle Cell Project (NHM)Veer Surendra Sai Institute of Medical Science and Research (VIMSAR)SambalpurIndia

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