Increased levels of the inflammatory biomarker C-reactive protein at baseline are associated with childhood sickle cell vasocclusive crises

Suba Krishnan, Yamaja Setty, Suhita G Betal, Vaidyula Vijender, Koneti Rao, Carlton Dampier, Marie Stuart, Suba Krishnan, Yamaja Setty, Suhita G Betal, Vaidyula Vijender, Koneti Rao, Carlton Dampier, Marie Stuart

Abstract

Several lines of evidence suggest that sickle cell disease (SCD) is associated with a chronic inflammatory state. In this study of 70 children with SCD at steady state evaluated by a broad panel of biomarkers representing previously examined mechanisms of pathogenicity in SCD, high sensitivity C-reactive protein (hs-CRP), a marker of low-grade, systemic inflammation, emerged as the most significant laboratory correlate of hospitalizations for pain or vaso-occlusive (VOC) events. While markers of increased haemolytic status, endothelial activation and coagulation activation all correlated positively with VOC events by univariate analysis, baseline hs-CRP levels provided the most significant contribution to the association in multiple regression models (22%), and, hs-CRP, along with age, provided the best fit in negative binomial models. These data highlight the clinical relevance of the role of inflammation in paediatric VOC, providing both a rationale for future therapeutic strategies targeting inflammation in microvessel occlusive complications of SCD, and the potential clinical use of hs-CRP as a biomarker in childhood SCD.

References

    1. Akohoue SA, Shankar S, Milne GL, Morrow J, Chen KY, Ajayi WU, Buchowski MS. Energy expenditure, inflammation, and oxidative stress in steady-state adolescents with sickle cell anemia. Pediatric Research. 2007;61:233–238.
    1. Belcher JD, Bryant CJ, Nguyen J, Bowlin PR, Kielbik MC, Bischof JC, Hebbel RP, Vercellotti GM. Transgenic sickle mice have vascular inflammation. Blood. 2003;101:3953–3959.
    1. 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:H2715–H2725.
    1. Blann AD, Mohan JS, Bareford D, Lip GY. Soluble P-selectin and vascular endothelial growth factor in steady state sickle cell disease: relationship to genotype. Journal of Thrombosis and Thrombolysis. 2008;25:185–189.
    1. Bourantas KL, Dalekos GN, Makis A, Chaidos A, Tsiara S, Mavridis A. Acute phase proteins and interleukins in steady state sickle cell disease. European Journal of Haematology. 1998;61:49–54.
    1. Burger PC, Wagner DD. Platelet P-selectin facilitates atherosclerosis lesion development. Blood. 2003;101:2661–2666.
    1. Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. New England Journal of Medicine. 1995;332:1317–1322.
    1. Cook NR, Buring JE, Ridker PM. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Annals of Internal Medicine. 2006;145:21–29.
    1. Conover WJ. 2nd edn. New York: John Wiley and Sons; 1980. Practical Non-Parametric Statistics.
    1. Duits AJ, Schnog JB, Lard LR, Saleh AW, Rojer RA. Elevated IL-8 levels during sickle cell crisis. European Journal of Haematology. 1998;61:302–305.
    1. 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;104:3378–3385.
    1. Folsom AR, Chambless LE, Ballantyne CM, Coresh J, Heiss G, Wu KK, Boerwinkle E, Mosley TH, Jr, Sorlie P, Diao G, Sharrett AR. An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers: the atherosclerosis risk in communities study. Archives of Internal Medicine. 2006;166:1368–1373.
    1. Ford ES, Giles WH, Myers GL, Rifai N, Ridker PM, Mannino DM. C-reactive protein concentration distribution among US children and young adults: findings from the National Health and Nutrition Examination Survey, 1999–2000. Clinical Chemistry. 2003;49:1353–1357.
    1. Frenette PS, Atweh GF. Sickle cell disease: old discoveries, new concepts, and future promise. Journal of Clinical Investigation. 2007;117:850–858.
    1. Frenette PS, Moyna C, Hartwell DW, Lowe JB, Hynes RO, Wagner DD. Platelet-endothelial interactions in inflamed mesenteric venules. Blood. 1998;91:1318–1324.
    1. Hedo CC, Aken’ova YA, Okpala IE, Durojaiye AO, Salimonu LS. Acute phase reactants and severity of homozygous sickle cell disease. Journal of Internal Medicine. 1993;233:467–470.
    1. Hibbert JM, Hsu LL, Bhathena SJ, Irune I, Sarfo B, Creary MS, Gee BE, Mohamed AI, Buchanan ID, Al-Mahmoud A, Stiles JK. Proinflammatory cytokines and the hypermetabolism of children with sickle cell disease. Experimental Biology and Medicine. 2005;230:68–74.
    1. Hurlimann J, Thorbecke GJ, Hochwald GM. The liver as the site of C-reactive protein formation. Journal of Experimental Medicine. 1966;123:365–378.
    1. Kato GJ, Martyr S, Blackwelder WC, Nichols JS, Coles WA, Hunter LA, Brennan ML, Hazen SL, Gladwin MT. Levels of soluble endothelium-derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality. British Journal of Haematology. 2005;130:943–953.
    1. Kato GJ, McGowan V, Machado RF, Little JA, Taylor Jt, Morris CR, Nichols JS, Wang X, Poljakovic M, Morris SM, Jr, Gladwin MT. 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.
    1. Kaul DK, Hebbel RP. Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice. Journal of Clinical Investigation. 2000;106:411–420.
    1. Kimberly MM, Vesper HW, Caudill SP, Cooper GR, Rifai N, Dati F, Myers GL. Standardization of immunoassays for measurement of high-sensitivity C-reactive protein. Phase I: evaluation of secondary reference materials. Clinical Chemistry. 2003;49:611–616.
    1. Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, Hutchinson WL, Pepys MB. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999;99:237–242.
    1. Macy EM, Hayes TE, Tracy RP. Variability in the measurement of C-reactive protein in healthy subjects: implications for reference intervals and epidemiological applications. Clinical Chemistry. 1997;43:52–58.
    1. Makis AC, Hatzimichael EC, Stebbing J, Bourantas KL. C-reactive protein and vascular cell adhesion molecule-1 as markers of severity in sickle cell disease. Archives of Internal Medicine. 2006;166:366–368.
    1. Miller ST, Sleeper LA, Pegelow CH, Enos LE, Wang WC, Weiner SJ, Wethers DL, Smith J, Kinney TR. Prediction of adverse outcomes in children with sickle cell disease. New England Journal of Medicine. 2000;342:83–89.
    1. Mohan JS, Lip GY, Wright J, Bareford D, Blann AD. Plasma levels of tissue factor and soluble E-selectin in sickle cell disease: relationship to genotype and to inflammation. Blood Coagulation and Fibrinolysis. 2005;16:209–214.
    1. Moshage HJ, Roelofs HM, van Pelt JF, Hazenberg BP, van Leeuwen MA, Limburg PC, Aarden LA, Yap SH. The effect of interleukin-1, interleukin-6 and its interrelationship on the synthesis of serum amyloid A and C-reactive protein in primary cultures of adult human hepatocytes. Biochemical and Biophysical Research Communications. 1988;155:112–117.
    1. O’Driscoll S, Height SE, Dick MC, Rees DC. Serum lactate dehydrogenase activity as a biomarker in children with sickle cell disease. British Journal of Haematology. 2008;140:206–209.
    1. Pathare A, Kindi SA, Daar S, Dennison D. Cytokines in sickle cell disease. Hematology. 2003;8:329–337.
    1. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. Journal of Clinical Investigation. 2003;111:1805–1812.
    1. Platt OS. Sickle cell anemia as an inflammatory disease. Journal of Clinical Investigation. 2000;106:337–338.
    1. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease. Life expectancy and risk factors for early death. New England Journal of Medicine. 1994;330:1639–1644.
    1. Powars DR, Chan L, Schroeder WA. The influence of fetal hemoglobin on the clinical expression of sickle cell anemia. Annals of the New York Academy of Sciences. 1989;565:262–278.
    1. Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO, III, Schechter AN, Gladwin MT. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nature Medicine. 2002;8:1383–1389.
    1. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. New England Journal of Medicine. 2000;342:836–843.
    1. Roberts WL. CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: laboratory tests available to assess inflammation--performance and standardization: a background paper. Circulation. 2004;110:e572–e576.
    1. Setty BN, Rao AK, Stuart MJ. Thrombophilia in sickle cell disease: the red cell connection. Blood. 2001;98:3228–3233.
    1. 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.
    1. Singhal A, Doherty JF, Raynes JG, McAdam KP, Thomas PW, Serjeant BE, Serjeant GR. Is there an acute-phase response in steady-state sickle cell disease? Lancet. 1993;341:651–653.
    1. Stuart MJ, Nagel RL. Sickle-cell disease. Lancet. 2004;364:1343–1360.
    1. Vainas T, Stassen FR, de Graaf R, Twiss EL, Herngreen SB, Welten RJ, van den Akker LH, van Dieijen-Visser MP, Bruggeman CA, Kitslaar PJ. C-reactive protein in peripheral arterial disease: relation to severity of the disease and to future cardiovascular events. Journal of Vascular Surgery. 2005;42:243–251.
    1. Verma S, Szmitko PE, Ridker PM. C-reactive protein comes of age. Nature Clinical Practice. Cardiovascular Medicine. 2005;2:29–36.
    1. Vidula H, Tian L, Liu K, Criqui MH, Ferrucci L, Pearce WH, Greenland P, Green D, Tan J, Garside DB, Guralnik J, Ridker PM, Rifai N, McDermott MM. Biomarkers of inflammation and thrombosis as predictors of near-term mortality in patients with peripheral arterial disease: a cohort study. Annals of Internal Medicine. 2008;148:85–93.
    1. Vigushin DM, Pepys MB, Hawkins PN. Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease. Journal of Clinical Investigation. 1993;91:1351–1357.
    1. Westerman MP, Green D, Gilman-Sachs A, Beaman K, Freels S, Boggio L, Allen S, Zuckerman L, Schlegel R, Williamson P. Antiphospholipid antibodies, proteins C and S, and coagulation changes in sickle cell disease. Journal of Laboratory and Clinical Medicine. 1999;134:352–362.

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