Main Article Content

Adekunle Emmanuel Alagbe
John Ayodele Olaniyi
Oladapo Wale Aworanti


Sickle cell anemia, Cytokines, Bone pain crisis, Severity, Steady state


Background and Objective: Inflammatory markers that influence bone pain crisis (BPC) and other complications of sickle cell anaemia (SCA) are numerous and play various roles. This study determined the plasma levels of tumour necrosis factor (TNF) - ?, interleukin - 8 (IL-8), and endothelin - 1 (ET-1) in adult SCA patients during BPC and in steady state. In addition, the plasma levels of these cytokines were correlated with the severity of BPC of the patients.

Methods and Materials: Sixty adult SCA patients (30 during BPC and 30 during steady state) and 30 haemoglobin A controls were enrolled for this cross-sectional study. The severity of BPC was assessed clinically, and questionnaires were filled. Plasma levels of TNF- ?, IL-8 and ET-1 were quantified by ELISA, and haematological parameters were determined using a 5-part auto-analyzer. Plasma levels were correlated with the severity of bone pain crisis. Results were considered statistically significant if p<0.05.

Results: Plasma TNF-?, IL-8, and ET-1 were significantly elevated in the BPC group than in the steady state group and the controls. Plasma TNF-?, IL-8 and ET-1 were markedly higher in the severe BPC groups than the steady state and control groups, There was a positive correlation between TNF-? and ET-1 in the bone pain crisis group.

Conclusion: Elevated levels of plasma TNF-?, IL-8, and ET-1 further establish the chronic inflammatory state in SCA and equally affirm their significant contribution, not only to pathogenesis but also to the severity of pain in SCA.


Keywords: Sickle cell anaemia, Cytokines, Bone pain crisis, Severity, Steady state.




Download data is not yet available.
Abstract 2172 | PDF Downloads 482 HTML Downloads 292


Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, Kinney TR. Pain in Sickle Cell Disease. New England Journal of Medicine. 1991;325 (1):11-6.
2. Delicou S, Maragkos K. Pain Management in Patients with Sickle Cell Disease-A Review. Hematology. 2013.
3. Steinberg MH, Rodgers GP, editors. Pathophysiology of sickle cell disease: role of cellular and genetic modifiers. Seminars in hematology; 2001: Elsevier.
4. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. Jama. 2005;293(13):1653-62.
5. Setty BNY, Betal SG, Zhang J, Stuart MJ. Heme induces endothelial tissue factor expression: potential role in hemostatic activation in patients with hemolytic anemia. Journal of Thrombosis and Haemostasis. 2008;6(12):2202-9.
6. Embury SH, Matsui NM, Ramanujam S, Mayadas TN, Noguchi CT, Diwan BA, Mohandas N, Cheung AT. The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo. Blood. 2004;104(10):3378-85.
7. Belcher JD, Mahaseth H, Welch TE, Vilback AE, Sonbol KM, Kalambur VS, Bowlin PR,Bischof JC, Hebbel RP, Vercellotti GM. Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice. American Journal of Physiology-Heart and Circulatory Physiology. 2005;288(6):H2715-H25.
8. Ikram N, Hassan K, Tufail S. Classes of Cytokines (Table. International Journal of Pathology. 2004;2(1):47-58.
9. Popa C, Netea MG, Van Riel PL, van der Meer JW, Stalenhoef AF. The role of TNF-? in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. Journal of lipid research. 2007;48(4):751-62.
10. Pitanga TN, Vilas-Boas W, Cerqueira BAnV, Seixas MO, Barbosa CG, Adorno EV, Goncalves MS. Cytokine profiles in sickle cell anemia: Pathways to be unraveled. Advances in Bioscience and Biotechnology. 2013;Vol.04No.07:7.
11. Pathare A, Al Kindi S, Alnaqdy AA, Daar S, Knox-Macaulay H, Dennison D. Cytokine profile of sickle cell disease in Oman. American Journal of Hematology. 2004;77(4):323-8.
12. Tavakkoli F, Nahavandi M, Wyche MQ, Perlin E. Plasma Levels of TNF-? in Sickle Cell Patients Receiving Hydroxyurea. Hematology. 2004;9(1):61-4.
13. Cajado C, Cerqueira BAV, Couto FD, Moura-Neto JP, Vilas-Boas W, Dorea MJ, et al. TNF-alpha and IL-8: Serum levels and gene polymorphisms (?308G>A and ?251A>T) are associated with classical biomarkers and medical history in children with sickle cell anemia. Cytokine. 2011;56(2):312-7.
14. Goncalves MS, Queiroz IL, Cardoso SA, Zanetti A, Strapazoni AC, Adorno E, Lyra, IM, Barbosa CG, Reis MG, Goncalves MS. Interleukin 8 as a vaso-occlusive marker in Brazilian patients with sickle cell disease. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica [et al]. 2001;34(10):1309-13.
15. Lanaro C, Franco-Penteado CF, Albuqueque DM, Saad STO, Conran N, Costa FF. Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy. Journal of Leukocyte Biology. 2009;85(2):235-42.
16. Qari MH, Dier U, Mousa SA. Biomarkers of Inflammation, Growth Factor, and Coagulation Activation in Patients With Sickle Cell Disease. Clinical and Applied Thrombosis/Hemostasis. 2012;18(2):195-200.
17. Keikhaei B, Mohseni AR, Norouzirad R, Alinejadi M, Ghanbari S, Shiravi F, et al. Altered levels of pro-inflammatory cytokines in sickle cell disease patients during vaso-occlusive crises and the steady state condition. European cytokine network. 2013;24(1):45-52.
18. Musa BO, Onyemelukwe GC, Hambolu JO, Mamman AI, Isa AH. Pattern of serum cytokine expression and T-cell subsets in sickle cell disease patients in vaso-occlusive crisis. Clinical and vaccine immunology : CVI. 2010;17(4):602-8.
19. Graido-Gonzalez E, Doherty JC, Bergreen EW, Organ G, Telfer M, McMillen MA. Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso-occlusive sickle crisis. Blood. 1998;92(7):2551-5.
20. van der Land V, Peters M, Biemond BJ, Heijboer H, Harteveld CL, Fijnvandraat K. Markers of endothelial dysfunction differ between subphenotypes in children with sickle cell disease. Thrombosis Research.132(6):712-7.
21. Groves D, Jiang Y. Chemokines, a family of chemotactic cytokines. Critical Reviews in Oral Biology & Medicine. 1995;6(2):109-18.
22. Su S-B, Mukaida N, Matsushima K. Rapid secretion of intracellularly pre-stored interleukin-8 from rabbit platelets upon activation. Journal of leukocyte biology. 1996;59(3):420-6.
23. Etienne-Julan M, Belloy M-S, Decastel M, Dougaparsad S, Ravion S, Hardy-Dessources M-D. Childhood sickle cell crises: clinical severity, inflammatory markers and the role of interleukin-8. Haematologica. 2004;89(7):863-4.
24. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411-5.
25. Bori? MP, Donoso V, Fournier A, Pierre SS, Huidobro-Toro JP. Endothelin reduces microvascular blood flow by acting on and venules of the hamster cheek pouch. European journal of pharmacology. 1990;190(1):123-33.
26. Makis AC, Hatzimichael EC, Bourantas KL. The role of cytokines in sickle cell disease. Ann Hematol. 2000;79(8):407-13.
27. Akingbola TS, Kolude B, Aneni EC, Raji AA, Iwara KU, Aken'Ova YA, Soyannwo, O. A. Abdominal pain in adult sickle cell disease patients: a nigerian experience. Ann Ib Postgrad Med. 2011;9(2):100-4.
28. De Nucci G, Thomas R, D'Orleans-Juste P, Antunes E, Walder C, Warner TD, Vane, JR. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proceedings of the National Academy of Sciences. 1988;85(24):9797-800.
29. McMillen MA, Huribal M, Cunningham ME, Kumar R, Sumpio BE. Endothelin-1 increases intracellular calcium in human monocytes and causes production of interleukin-6. Critical care medicine. 1995;23(1):34-40.
30. Cunningham ME, Huribal M, Bala R, McMillen MA. Endothelin-1 and endothelin-4 stimulate monocyte production of cytokines. Critical care medicine. 1997;25(6):958-64.
31. Wright CD, Cody WL, Dunbar JB, Doherty AM, Hingorani GP, Rapundalo ST. Characterization of endothelins as chemoattractants for human neutrophils. Life sciences. 1994;55(21):1633-41.
32. McCarron RM, Wang L, Stanimirovic DB, Spatz M. Endothelin induction of adhesion molecule expression on human brain microvascular endothelial cells. Neuroscience letters. 1993;156(1):31-4.
33. Sessa WC, Kaw S, Hecker M, Vane JR. The biosynthesis of endothelin-1 by human polymorphonuclear leukocytes. Biochemical and biophysical research communications. 1991;174(2):613-8.
34. Johnson C. Measuring pain. Visual analog scale versus numeric pain scale: what is the difference? Journal of chiropractic medicine. 2006;4(1):43-4.
35. McMaffery M, Pasero C. Pain: Clinical Manual. St. Louis, MO: Mosby. Inc; 1999.
36. Vargas-Schaffer G. Is the WHO analgesic ladder still valid? Twenty-four years of experience. Canadian Family Physician. 2010;56(6):514-7.
37. Zhang J-M, An J. Cytokines, Inflammation and Pain. International anesthesiology clinics. 2007;45(2):27-37.
38. Kasschau MR, Barabino GA, Bridges KR, Golan DE. Adhesion of sickle neutrophils and erythrocytes to fibronectin. Blood. 1996;87(2):771-80.
39. Okpala I. The intriguing contribution of white blood cells to sickle cell disease - a red cell disorder. Blood Rev. 2004;18(1):65-73.
40. Mohandas N, Evans E. Adherence of sickle erythrocytes to vascular endothelial cells: requirement for both cell membrane changes and plasma factors. Blood. 1984;64(1):282-7.
41. Francis RB, Jr. Elevated Fibrin D-Dimer Fragment in Sickle Cell Anemia: Evidence for Activation of Coagulation during the Steady State as well as in Painful Crisis. Pathophysiology of Haemostasis and Thrombosis. 1989;19(2):105-11.
42. Brett Heimlich J, Speed JS, O'Connor PM, Pollock JS, Townes TM, Meiler SE, et al. Endothelin-1 contributes to the progression of renal injury in sickle cell disease via reactive oxygen species. British Journal of Pharmacology. 2016;173(2):386-95.
43. Shavit Y, Fridel K, Beilin B. Postoperative pain management and proinflammatory cytokines: animal and human studies. Journal of Neuroimmune Pharmacology. 2006;1(4):443-51.
44. Abbadie C, Bhangoo S, De Koninck Y, Malcangio M, Melik-Parsadaniantz S, White FA. Chemokines and pain mechanisms. Brain research reviews. 2009;60(1):125-34.