Serum Concentration of Growth Differentiation Factor-15 Is Independently Associated with Global Platelet Function and Higher Fibrinogen Values in Adult Healthy Subjects

Giuseppe Lippi; Gian Luca Salvagno; Elisa Danese; Giorgio Brocco; Matteo Gelati; Martina Montagnana; Fabian Sanchis-Gomar; Emmanuel J. Favaloro

doi:10.1055/s-0037-1603358

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2017; 43(06): 621-628
DOI: 10.1055/s-0037-1603358

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Serum Concentration of Growth Differentiation Factor-15 Is Independently Associated with Global Platelet Function and Higher Fibrinogen Values in Adult Healthy Subjects

Giuseppe Lippi

¹Section of Clinical Biochemistry, University of Verona, Verona, Italy

,

Gian Luca Salvagno

¹Section of Clinical Biochemistry, University of Verona, Verona, Italy

,

Elisa Danese

¹Section of Clinical Biochemistry, University of Verona, Verona, Italy

,

Giorgio Brocco

¹Section of Clinical Biochemistry, University of Verona, Verona, Italy

,

Matteo Gelati

¹Section of Clinical Biochemistry, University of Verona, Verona, Italy

,

Martina Montagnana

¹Section of Clinical Biochemistry, University of Verona, Verona, Italy

,

Fabian Sanchis-Gomar

²Department of Physiology, Instituto de Investigación INCLIVA, University of Valencia and Fundación Investigación Hospital Clínico Universitario de Valencia, Valencia, Spain

³Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York

,

Emmanuel J. Favaloro

⁴Department of Haematology, Sydney Centres for Thrombosis and Haemostasis, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, Australia

› Author Affiliations

Abstract

Growth differentiation factor-15 (GDF-15) has recently emerged as a strong and independent predictor of cardiovascular events and mortality. However, the pathophysiological mechanisms underlying this important association remain speculative. This study was aimed to investigate the potential associations between the serum concentration of GDF-15 and clinical or laboratory parameters in a population of ostensibly healthy subjects. The study population consisted of 44 healthy volunteers enrolled from the laboratory staff (14 males and 30 females; mean age, 47 ± 11 years), who had their blood collected for assessing complete blood cell count, GDF-15, serum creatinine, albumin, cardiac troponin T, galectin-3, routine coagulation tests, D-dimer, von Willebrand factor, and platelet function testing using platelet function analyzer-100. In univariate analysis, serum GDF-15 was found to be positively associated with age and plasma fibrinogen, and negatively associated with renal function and collagen-epinephrine (CEPI). In multiple linear regression analysis, serum GDF-15 remained significantly associated with renal function, CEPI, and plasma fibrinogen. Healthy subjects with GDF-15 above the median value had a twofold probability of displaying shorter CEPI closure times. Taken together, these results suggest that higher serum values of GDF-15 may be associated with overall global platelet hyperactivity and increased plasma fibrinogen, so providing another plausible explanation for the association between GDF-15, cardiovascular events, and mortality.

Keywords

growth differentiation factor-15 - GDF-15 - cardiovascular disease - platelets - PFA-100

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References

References
1 Benjamin EJ, Blaha MJ, Chiuve SE. , et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation 2017; 135 (10) e146-e603
2 Sanchis-Gomar F, Perez-Quilis C, Leischik R, Lucia A. Epidemiology of coronary heart disease and acute coronary syndrome. Ann Transl Med 2016; 4 (13) 256
3 GeneCards. GDF15 gene. Available at: http://www.genecards.org/cgi-bin/carddisp.pl?gene=GDF15 . Accessed March 15, 2017
4 Sanchis-Gomar F, Bonaguri C, Aloe R. , et al. Effects of acute exercise and xanthine oxidase inhibition on novel cardiovascular biomarkers. Transl Res 2013; 162 (02) 102-109
5 Fairlie WD, Zhang H, Brown PK, Russell PK, Bauskin AR, Breit SN. Expression of a TGF-beta superfamily protein, macrophage inhibitory cytokine-1, in the yeast Pichia pastoris. Gene 2000; 254 (1-2): 67-76
6 Corre J, Hébraud B, Bourin P. Concise review: growth differentiation factor 15 in pathology: a clinical role?. Stem Cells Transl Med 2013; 2 (12) 946-952
7 Wollert KC, Kempf T, Wallentin L. Growth differentiation factor 15 as a biomarker in cardiovascular disease. Clin Chem 2017; 63 (01) 140-151
8 Gerstein HC, Pare G, Hess S. , et al; ORIGIN Investigators. Growth differentiation factor 15 as a novel biomarker for metformin. Diabetes Care 2017; 40 (02) 280-283
9 Yang MH, Kim J, Khan IA, Walker LA, Khan SI. Nonsteroidal anti-inflammatory drug activated gene-1 (NAG-1) modulators from natural products as anti-cancer agents. Life Sci 2014; 100 (02) 75-84
10 Schlittenhardt D, Schober A, Strelau J. , et al. Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions. Cell Tissue Res 2004; 318 (02) 325-333
11 Daniels LB, Clopton P, Laughlin GA, Maisel AS, Barrett-Connor E. Growth-differentiation factor-15 is a robust, independent predictor of 11-year mortality risk in community-dwelling older adults: the Rancho Bernardo Study. Circulation 2011; 123 (19) 2101-2110
12 Wallentin L, Zethelius B, Berglund L. , et al. GDF-15 for prognostication of cardiovascular and cancer morbidity and mortality in men. PLoS One 2013; 8 (12) e78797
13 Meune C, Balmelli C, Twerenbold R. , et al. Utility of 14 novel biomarkers in patients with acute chest pain and undetectable levels of conventional cardiac troponin. Int J Cardiol 2013; 167 (04) 1164-1169
14 Zhang S, Dai D, Wang X. , et al. Growth differentiation factor-15 predicts the prognoses of patients with acute coronary syndrome: a meta-analysis. BMC Cardiovasc Disord 2016; 16: 82
15 George M, Jena A, Srivatsan V, Muthukumar R, Dhandapani VE. GDF 15--A novel biomarker in the offing for heart failure. Curr Cardiol Rev 2016; 12 (01) 37-46
16 Zeng X, Li L, Wen H, Bi Q. Growth-differentiation factor 15 as a predictor of mortality in patients with heart failure: a meta-analysis. J Cardiovasc Med (Hagerstown) 2017; 18 (02) 53-59
17 Lankeit M, Kempf T, Dellas C. , et al. Growth differentiation factor-15 for prognostic assessment of patients with acute pulmonary embolism. Am J Respir Crit Care Med 2008; 177 (09) 1018-1025
18 Duran L, Kayhan S, Guzel A. , et al. The prognostic values of GDF-15 in comparison with NT-proBNP in patients with normotensive acute pulmonary embolism. Clin Lab 2014; 60 (08) 1365-1371
19 Hijazi Z, Oldgren J, Lindbäck J. , et al; ARISTOTLE and RE-LY Investigators. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016; 387 (10035): 2302-2311
20 Hagström E, James SK, Bertilsson M. , et al; PLATO Investigators. Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study. Eur Heart J 2016; 37 (16) 1325-1333
21 Pasalic L, Wang SS, Chen VM. Platelets as biomarkers of coronary artery disease. Semin Thromb Hemost 2016; 42 (03) 223-233
22 Montoro-García S, Schindewolf M, Stanford S, Larsen OH, Thiele T. The role of platelets in venous thromboembolism. Semin Thromb Hemost 2016; 42 (03) 242-251
23 Lippi G. Genetic and nongenetic determinants of mean platelet volume. Blood 2016; 127 (02) 179-180
24 Rossaint J, Vestweber D, Zarbock A. GDF-15 prevents platelet integrin activation and thrombus formation. J Thromb Haemost 2013; 11 (02) 335-344
25 Lippi G, Mattiuzzi C. The biomarker paradigm: between diagnostic efficiency and clinical efficacy. Pol Arch Med Wewn 2015; 125 (04) 282-288
26 Lassila R. Platelet function tests in bleeding disorders. Semin Thromb Hemost 2016; 42 (03) 185-190
27 Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem 2010; 56 (02) 254-261
28 Wollert KC, Kempf T, Giannitsis E. , et al. An automated assay for growth differentiation factor 15. J Appl Lab Med 2017;
29 Levey AS, Stevens LA, Schmid CH. , et al; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150 (09) 604-612
30 Rohatgi A, Patel P, Das SR. , et al. Association of growth differentiation factor-15 with coronary atherosclerosis and mortality in a young, multiethnic population: observations from the Dallas Heart Study. Clin Chem 2012; 58 (01) 172-182
31 Hagström E, Held C, Stewart RA. , et al; STABILITY Investigators. Growth differentiation factor 15 predicts all-cause morbidity and mortality in stable coronary heart disease. Clin Chem 2017; 63 (01) 325-333
32 de Jager SC, Bermúdez B, Bot I. , et al. Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J Exp Med 2011; 208 (02) 217-225
33 Bonaterra GA, Zügel S, Thogersen J. , et al. Growth differentiation factor-15 deficiency inhibits atherosclerosis progression by regulating interleukin-6-dependent inflammatory response to vascular injury. J Am Heart Assoc 2012; 1 (06) e002550
34 Fuchs I, Frossard M, Spiel A, Riedmüller E, Laggner AN, Jilma B. Platelet function in patients with acute coronary syndrome (ACS) predicts recurrent ACS. J Thromb Haemost 2006; 4 (12) 2547-2552
35 Małek ŁA, Spiewak M, Filipiak KJ. , et al. Persistent platelet activation is related to very early cardiovascular events in patients with acute coronary syndromes. Kardiol Pol 2007; 65 (01) 40-45 , discussion 46
36 Hayes C, Kitahara S, Tcherniantchouk O. Decreased threshold of aggregation to low-dose epinephrine is evidence of platelet hyperaggregability in patients with thrombosis. Hematol Rep 2014; 6 (03) 5326
37 Stec JJ, Silbershatz H, Tofler GH. , et al. Association of fibrinogen with cardiovascular risk factors and cardiovascular disease in the Framingham Offspring Population. Circulation 2000; 102 (14) 1634-1638
38 Kaptoge S, Di Angelantonio E, Pennells L. , et al; Emerging Risk Factors Collaboration. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med 2012; 367 (14) 1310-1320
39 de Moerloose P, Boehlen F, Neerman-Arbez M. Fibrinogen and the risk of thrombosis. Semin Thromb Hemost 2010; 36 (01) 7-17
40 Favaloro EJ. Clinical utility of the PFA-100. Semin Thromb Hemost 2008; 34 (08) 709-733
41 Ho JE, Mahajan A, Chen MH. , et al. Clinical and genetic correlates of growth differentiation factor 15 in the community. Clin Chem 2012; 58 (11) 1582-1591
42 Lukaszyk E, Lukaszyk M, Koc-Zorawska E, Bodzenta-Lukaszyk A, Malyszko J. GDF-15, iron, and inflammation in early chronic kidney disease among elderly patients. Int Urol Nephrol 2016; 48 (06) 839-844
43 Nair V, Robinson-Cohen C, Smith MR. , et al. Growth differentiation factor-15 and risk of CKD progression. J Am Soc Nephrol 2017; ASN.2016080919
44 Sarnak MJ, Levey AS, Schoolwerth AC. , et al; American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003; 108 (17) 2154-2169
45 Salvagno GL, Pavan C. Prognostic biomarkers in acute coronary syndrome. Ann Transl Med 2016; 4 (13) 258
46 Jansen H, Koenig W, Jaensch A. , et al. Prognostic utility of galectin-3 for recurrent cardiovascular events during long-term follow-up in patients with stable coronary heart disease: results of the KAROLA study. Clin Chem 2016; 62 (10) 1372-1379
47 O'Donoghue ML, Morrow DA, Cannon CP. , et al. Multimarker risk stratification in patients with acute myocardial infarction. J Am Heart Assoc 2016; 5 (05) e002586
48 Montoro-García S, Hernández-Romero D, Jover E. , et al. Growth differentiation factor-15, a novel biomarker related with disease severity in patients with hypertrophic cardiomyopathy. Eur J Intern Med 2012; 23 (02) 169-174
49 Favaloro EJ. Clinical utility of closure times using the platelet function analyzer-100/200. Am J Hematol 2017; 92 (04) 398-404
50 Favaloro EJ. Utility of the von Willebrand factor collagen binding assay in the diagnosis of von Willebrand disease. Am J Hematol 2017; 92 (01) 114-118
51 Harrison P, Keeling D. Platelet hyperactivity and risk of recurrent thrombosis. J Thromb Haemost 2006; 4 (12) 2544-2546