Association of Platelet-to-Lymphocyte Ratio and Neutrophil-to-Lymphocyte Ratio with the Risk of Thromboembolism and Mortality in Patients with Cancer

Abstract

Patients with cancer are at risk of developing venous and arterial thromboembolism (VTE and ATE). Elevated platelet-to-lymphocyte (PLR) and neutrophil-to-lymphocyte ratios (NLR) have been suggested as potential biomarkers for cancer-associated chronic inflammation, VTE and mortality. We investigated the association between PLR and NLR with VTE, ATE and mortality in patients with cancer. Within a prospective cohort study, we followed-up patients with newly diagnosed or progressing cancer for objectively confirmed, symptomatic VTE, ATE and death. Fine and Gray competing-risk regression was used to model the risk of VTE and ATE. Overall survival was analysed with Kaplan–Meier estimators. From 2003 to 2013, 1,469 patients with solid cancer (median age: 61 years; 47.3% female) were recruited and followed for 2 years. Overall, 128 (8.7%) patients developed VTE, 41 (2.8%) ATE and 643 (43.8%) patients died. The sub-distribution hazard ratios (SHRs) for VTE per doubling of PLR and NLR were 1.0 (95% confidence interval [CI]: 0.8–1.3, p = 0.899) and 1.2 (1.0–1.4, p = 0.059), respectively. For ATE, the SHR per doubling of PLR and NLR were 1.0 (0.7–1.5, p = 0.940) and 1.2 (0.9–1.6, p = 0.191), respectively. A higher PLR (hazard ratio [HR] per doubling = 1.5, 1.4–1.7, p < 0.001) and a higher NLR (HR per doubling = 1.5, 1.4–1.7, p < 0.001) were associated with an increased risk of mortality after adjusting for age, sex and cancer stage. There was no statistically significant association between NLR and VTE occurrence in patients with cancer. Neither PLR nor NLR were associated with the risk of ATE. Both elevated PLR and NLR were independently associated with a twofold increased risk of mortality.

Keywords

thrombosis - cancer - platelet-to-lymphocyte ratio - neutrophil-to- lymphocyte ratio

Note

Cihan Ay and Ella Grilz had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Authors' Contributions

E.G. acquired, analysed and interpreted data, performed statistical analyses, co-ordinated the study and drafted the manuscript. O.K. acquired and interpreted data, and recruited patients. F.P. performed statistical analyses and critically revised the manuscript. I.S. critically revised the manuscript for important intellectual content and contributed to the study design. I.M.L. critically revised the manuscript for important intellectual content, was member of the adjudication committee and contributed to the study design. C.M. critically revised the manuscript for important intellectual content and contributed to the study design. I.P. designed and conceived the study, obtained funding, critically revised the manuscript for important intellectual content and provided administrative support. C.A. acquired the data, designed and supervised the study, obtained funding, critically revised the manuscript for important intellectual content and provided administrative support. All authors reviewed and edited the manuscript and finally approved the article.

• References

• 1 Ay C, Pabinger I, Cohen AT. Cancer-associated venous thromboembolism: burden, mechanisms, and management. Thromb Haemost 2017; 117 (02) 219-230
• 2 Grilz E, Königsbrügge O, Posch F, Lang IM, Pabinger I, Ay C. Frequency, risk factors, and impact on mortality of arterial thromboembolism in patients with cancer. Haematologica 2018; 103 (09) 1549-1556
• 3 Navi BB, Reiner AS, Kamel H. , et al. Risk of arterial thromboembolism in patients with cancer. J Am Coll Cardiol 2017; 70 (08) 926-938
• 4 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105 (09) 1135-1143
• 5 Riva N, Donadini MP, Ageno W. Epidemiology and pathophysiology of venous thromboembolism: similarities with atherothrombosis and the role of inflammation. Thromb Haemost 2015; 113 (06) 1176-1183
• 6 Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation 2005; 111 (25) 3481-3488
• 7 Pfeiler S, Stark K, Massberg S, Engelmann B. Propagation of thrombosis by neutrophils and extracellular nucleosome networks. Haematologica 2017; 102 (02) 206-213
• 8 Hisada Y, Mackman N. Cancer-associated pathways and biomarkers of venous thrombosis. Blood 2017; 130 (13) 1499-1506
• 9 Ferroni P, Riondino S, Formica V. , et al. Venous thromboembolism risk prediction in ambulatory cancer patients: clinical significance of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio. Int J Cancer 2015; 136 (05) 1234-1240
• 10 Yüksel M, Yıldız A, Oylumlu M. , et al. The association between platelet/lymphocyte ratio and coronary artery disease severity. Anatol J Cardiol 2015; 15 (08) 640-647
• 11 Sönmez O, Ertaş G, Bacaksız A. , et al. Relation of neutrophil-to-lymphocyte ratio with the presence and complexity of coronary artery disease: an observational study. Anadolu Kardiyol Derg 2013; 13 (07) 662-667
• 12 Teperman J, Carruthers D, Guo Y. , et al. Relationship between neutrophil-lymphocyte ratio and severity of lower extremity peripheral artery disease. Int J Cardiol 2017; 228: 201-204
• 13 Barker T, Rogers VE, Henriksen VT. , et al. Is there a link between the neutrophil-to-lymphocyte ratio and venous thromboembolic events after knee arthroplasty? A pilot study. J Orthop Traumatol 2016; 17 (02) 163-168
• 14 Bakirci EM, Topcu S, Kalkan K. , et al. The role of the nonspecific inflammatory markers in determining the anatomic extent of venous thromboembolism. Clin Appl Thromb Hemost 2015; 21 (02) 181-185
• 15 Belaj K, Pichler M, Hackl G. , et al. Association of the derived neutrophil-lymphocyte ratio with critical limb ischemia. Angiology 2016; 67 (04) 350-354
• 16 Tham T, Rahman L, Persaud C, Olson C, Costantino P. Venous thromboembolism risk in head and neck cancer: significance of the preoperative platelet-to-lymphocyte ratio. Otolaryngol Head Neck Surg 2018; 159 (01) 85-91
• 17 Szkandera J, Absenger G, Liegl-Atzwanger B. , et al. Elevated preoperative neutrophil/lymphocyte ratio is associated with poor prognosis in soft-tissue sarcoma patients. Br J Cancer 2013; 108 (08) 1677-1683
• 18 Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ. Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 2005; 91 (03) 181-184
• 19 Yang J-J, Hu Z-G, Shi W-X, Deng T, He S-Q, Yuan S-G. Prognostic significance of neutrophil to lymphocyte ratio in pancreatic cancer: a meta-analysis. World J Gastroenterol 2015; 21 (09) 2807-2815
• 20 Yu Y, Qian L, Cui J. Value of neutrophil-to-lymphocyte ratio for predicting lung cancer prognosis: a meta-analysis of 7,219 patients. Mol Clin Oncol 2017; 7 (03) 498-506
• 21 Ay C, Simanek R, Vormittag R. , et al. High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). Blood 2008; 112 (07) 2703-2708
• 22 Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials 1996; 17 (04) 343-346
• 23 Coviello V, Boggess M. Cumulative incidence estimation in the presence of competing risks. Stata J 2004; 4 (02) 103-112
• 24 Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16 (03) 1141-1154
• 25 Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94 (446) 496
• 26 Terbuch A, Posch F, Annerer LM. , et al. Long-term cardiovascular complications in stage I seminoma patients. Clin Transl Oncol 2017; 19 (11) 1400-1408
• 27 Ay C, Posch F, Kaider A, Zielinski C, Pabinger I. Estimating risk of venous thromboembolism in patients with cancer in the presence of competing mortality. J Thromb Haemost 2015; 13 (03) 390-397
• 28 Posch F, Thaler J, Zlabinger G-J. , et al. Soluble vascular endothelial growth factor (sVEGF) and the risk of venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study (CATS). Clin Cancer Res 2016; 22 (01) 200-206
• 29 Ay C, Dunkler D, Marosi C. , et al. Prediction of venous thromboembolism in cancer patients. Blood 2010; 116 (24) 5377-5382
• 30 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
• 31 Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood 2014; 123 (18) 2768-2776
• 32 Martinod K, Demers M, Fuchs TA. , et al. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc Natl Acad Sci U S A 2013; 110 (21) 8674-8679
• 33 Mauracher L-M, Posch F, Martinod K. , et al. Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients. J Thromb Haemost 2018; 16 (03) 508-518
• 34 Yang W, Liu Y. Platelet-lymphocyte ratio is a predictor of venous thromboembolism in cancer patients. Thromb Res 2015; 136 (02) 212-215
• 35 Thaler J, Ay C, Kaider A. , et al. Biomarkers predictive of venous thromboembolism in patients with newly diagnosed high-grade gliomas. Neuro-oncol 2014; 16 (12) 1645-1651
• 36 Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111 (10) 4902-4907
• 37 Riedl J, Preusser M, Nazari PMS. , et al. Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism. Blood 2017; 129 (13) 1831-1839
• 38 Yilmaz M, Tenekecioglu E, Arslan B. , et al. White blood cell subtypes and neutrophil-lymphocyte ratio in prediction of coronary thrombus formation in non-ST-segment elevated acute coronary syndrome. Clin Appl Thromb Hemost 2015; 21 (05) 446-452
• 39 Li DB, Hua Q, Liu Z. , et al. Association between inflammatory mediators and angiographic morphologic features indicating thrombus formation in patients with acute myocardial infarction. Chin Med J (Engl) 2009; 122 (15) 1738-1742
• 40 Suh B, Shin DW, Kwon H-M. , et al. Elevated neutrophil to lymphocyte ratio and ischemic stroke risk in generally healthy adults. PLoS One 2017; 12 (08) e0183706
• 41 Krenn-Pilko S, Langsenlehner U, Thurner E-M. , et al. The elevated preoperative platelet-to-lymphocyte ratio predicts poor prognosis in breast cancer patients. Br J Cancer 2014; 110 (10) 2524-2530
• 42 Szkandera J, Stotz M, Eisner F. , et al. External validation of the derived neutrophil to lymphocyte ratio as a prognostic marker on a large cohort of pancreatic cancer patients. PLoS One 2013; 8 (11) e78225
• 43 Absenger G, Szkandera J, Stotz M. , et al. Preoperative neutrophil-to-lymphocyte ratio predicts clinical outcome in patients with stage II and III colon cancer. Anticancer Res 2013; 33 (10) 4591-4594
• 44 Stotz M, Gerger A, Eisner F. , et al. Increased neutrophil-lymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer. Br J Cancer 2013; 109 (02) 416-421
• 45 Dalpiaz O, Luef T, Seles M. , et al. Critical evaluation of the potential prognostic value of the pretreatment-derived neutrophil-lymphocyte ratio under consideration of C-reactive protein levels in clear cell renal cell carcinoma. Br J Cancer 2017; 116 (01) 85-90
• 46 Wu Y, Chen Y, Yang X, Chen L, Yang Y. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were associated with disease activity in patients with systemic lupus erythematosus. Int Immunopharmacol 2016; 36: 94-99