Correlations between hematological indicators and other known markers in acute coronary syndromes
Introduction: Recently, many hematologic markers have identified as prognostic and diagnostic indicators in different acute coronary syndrome (ACS) patients. In particular, neutrophil / lymphocyte ratio (NLR) and platelet / lymphocyte ratio (PLR) are recognized as markers in the diagnosis and prognosis of ACS. In this study, our aim was to investigate the correlation between the diagnostic yield of PLR and NLR values and other markers such as troponin in all ACS patients.
Material and methods: 319 patients admitted to our hospital with ACS and 283 control patients were included in the study. Leukocyte, neutrophil, platelet, lymphocyte counts, PLR, NLR and high sensitive troponin I (HsTnI) measurements were taken.
Results: Leukocyte, neutrophil and platelet counts were significantly higher in the ACS group than the controls (p <0.001). Lymphocyte count was significantly lower in the ACS group than the controls (p <0.001). NLR and PLR were found to be significantly higher in the ACS group than the controls (4.0 ± 3.3 vs 2.1 ± 1.4 and 126.3 ± 68.9 vs 106.9 ± 49.4, p <0.001, respectively). NLR was showed significant correlation with HsTnI, PLR, angina time, presence of ST elevation and T wave negativity (p <0.05), and PLR revealed significant correlation with NLR, HsTnI, ST elevation and T wave negativity (p <0.05).
Conclusion: Hematologic markers were found to be significantly higher in the ACS group than the controls. The difference also continued in subgroup analyzes. NLR and PLR correlated with many other ACS indicators.
Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide.(1) One of the most important causes of CAD is atherosclerosis and atherosclerosis is considered to be an inflammatory disease.(2) Previous studies have shown serious evidence that atherosclerosis is systemic rather than focal disease.(2) Recently, many studies have been published, which demonstrate that hematological markers measured in peripheral blood count such as platelet, neutrophil, lymphocyte are predictors in the diagnosis and the determination of the prognosis of acute coronary syndromes (ACS).(3,4) Increased platelet activation has been reported to play a role in the onset and the progression of atherosclerosis.(5) It has been reported that increased platelet count is associated with platelet activation and may be associated with thrombotic tendency and major adverse cardiac events.(3,5)
On the other hand, there are reports that low lymphocyte counts are associated with lymphocyte apoptosis in prolonged inflammation, decreased immune-reactivity, and may also cause major adverse cardiac events.(5-7) As a result, proliferation and relative thrombocytosis are seen in the megakaryocytic series with inflammation.(7) Thus, in some studies, high platelet / lymphocyte ratio (PLR) and neutrophil / lymphocyte ratio (NLR) are predicted to better reflect inflammation and pro-thrombotic states and may be predictors of prognosis in acute ACS patients.(7,8) In our study, we aimed to investigate the diagnostic efficiency of PLR and NLR values and their correlation with other predictors such as high sensitivity troponin I in ACS patients admitted to our hospital.
Patients and Method
This single-center comparative study was conducted in a tertiary heart center. The study was approved by the local Ethics committee and informed consent of the patients and controls were obtained. 319 patients admitted to our hospital with the diagnosis ACS between 2015 and 2017 were included in the study. In the same time period, 283 healthy individuals who applied to our outpatient clinics were included in the study as a control group. Subsequently, the ACS group was divided into subgroups as unstable angina pectoris (USAP), non-ST elevation myocardial infarction (NSTEMI), and ST elevation myocardial infarction (STEMI). Patients with severe valve disease, decompensated heart failure, malignancy, hematological disease, systemic inflammatory disease, active infection, autoimmune disease, severe renal or hepatic insufficiency and those using steroids were excluded from the study.
The demographic and biochemical parameters of the patients and controls were obtained from the files. NLR and PLR were calculated from the neutrophil, platelet and lymphocyte counts obtained from the hemogram. PLR and NLR were calculated by dividing platelet count by lymphocyte count, respectively, by dividing the number of neutrophils by the number of lymphocytes. For the measurement of high sensitive troponin I (HsTnI) EDTA whole blood sample was used, HsTnI was measured by the method of the AQT90 FLEX cardiac Troponin I immunoassay (Radiometer Medical ApS, Copenhagen, Denmark), and the method is a one-step sandwich immunofluorometric assay based on the use of three monoclonal antibodies, two for the capture and one for the detection.(9)
Complete blood count (CBC) was measured from EDTA whole blood samples via BC 6800 auto analyzer (Mindray Medical International Limited, Shenzhen, China). Other biochemical measurements such as glucose, HDL, LDL, total cholesterol and triglycerides were made from serum samples via Cobas systems (Roche Diagnostic Basel, Switzerland) by using commercial kits (Roche Diagnostic Basel, Switzerland).(9) Two levels of internal quality controls were made for all devices.
Statistical analysis was performed using SPSS version 15.0 (SPSS Inc., Chicago, Illinois, USA). Continuous variables were described by mean and standard deviation. Categorical variables were described in percent. Mann-Whitney U-test and student t-test were used for continuous variables, while chi-square test was used for categorical variables. Kruskal-Wallis test and Mann-Whitney U-test were used for subgroup analysis. Spearman test was used for correlation analysis. The diagnostic accuracy of high sensitive troponin I, NLR and PLR for ACS was calculated by receiver operating characteristic (ROC) analysis.
319 ACS patients (219, 68.7%, male) and 283 controls (181, 64%, male) were included in the study. There were 114 (35.7%) patients with USAP, 101 (31.7%) patients with NSTEMI and 104 (32.6%) patients with STEMI in the ACS subgroups. The demographic, clinical, electrocardiographic and biochemical parameters of the patients are shown in Table 1. Neutrophil and platelet counts were significantly higher in the ACS groups than in the control group (p <0.001 respectively). Lymphocyte count was lower in the ACS group than in the control group (p <0.001). NLR and PLR were significantly higher in the ACS group than in the control group (p <0.001).
In the ACS subgroup analysis, NLR and PLR values were significantly higher in STEMI patients than in USAP and NSTEMI patients (p <0.001) (Table 2).
Correlation analyzes revealed that NLR correlated with HsTnI, PLR, ST elevation, ST depression, T wave negativity and angina duration (Table 3). PLR was correlated with NLR, HsTnI, ST elevation and T wave negativity (Table 3).
Receiver operating characteristic (ROC) analysis results are given in Table 4. When the cut-off value for NLR was taken as 2.5, the sensitivity of NLR for the diagnosis of ACS was found 63.6%, specificity 80.2%, negative predictive value 66.1% and positive predictive value 78.6% (95% confidence interval 0.66-0.75). When the cut off value for PLR was taken as 101.2, the sensitivity of PLR for the diagnosis of ACS was determined as 54.9%, specificity, 54.4%, negative predictive value 51.7% and positive predictive value 57.6% (95% confidence interval 0.54-0.63).
In recent years, NLR and PLR have become important markers easily measured from peripheral blood and have proven diagnostic and prognostic information in patients with ACS.(10) In our study, NLR and PLR values were found to be higher in all ACS patients than the control group in accordance with the literature. In subgroup analyzes, NLR and PLR values were significantly higher in STEMI patients than NSTEMI and USAP patients. NLR and PLR were correlated with each other and with other parameters which have proven prognostic information in ACS patients such as high sensitive troponin I (Table 3). Sezer et al. showed that the number of neutrophils and the mean platelet volume in patients with acute myocardial infarction were associated with reperfusion injury after infarct-related artery occlusion opened.(10) In many inflammatory conditions neutrophils are stimulated to release many cytokines and cytotoxic or proteolytic enzymes.(4)
These enzymes have adverse effects on the ischemic heart by damaging endothelial cells, stimulating the coagulation system, blocking the microvascular circulation, and increasing infarct expansion.(4) Lymphocytes, as parts of the adaptive immunity system, fight against inflammation and suppress inflammation.(2) Thus, low lymphocyte counts have been associated with atherosclerosis progression and poor clinical outcomes.(2) Zouridakis et al found that low lymphocyte counts in unstable angina pectoris patients are strongly associated with future cardiac events.(11)
Although the pathophysiological mechanism of this condition is not fully understood, lymphocyte count is thought to reflect the early response of myocardial ischemia to physiological stress and systemic immunodeficiency.(4) Conversely, high lymphocyte counts during ACS reflect a strong immune response and the prognosis of these patients is better.(4) Instead of examining neutrophils and lymphocytes separately, NLR has been shown to be more prognostic.(2) Wang et al. have shown that NLR is predictive of all-cause mortality and cardiovascular events in patients undergoing coronary angiography.(12) Likewise, Tamhane et al. found that NLR value in patients with percutaneous coronary intervention is related to in-hospital and 6-month mortality.(13) Ayca et al. have shown that NLR is associated with stent thrombosis.(14)
NLR has been studied by different investigators in relation to different scoring systems showing CAD severity and it has been shown to be related to NLR by SYNTAX, GRACE and TIMI scores.(15-17) In our study, similarly, the NLR values were higher in the ACS group than in the control group. Correlation analyzes showed that NLR correlated with high sensitive troponin I, PLR, ST elevation, ST depression, T wave negativity and angina duration. NLR was found to have a sensitivity of 63.6% and a specificity of 80.2% for ACS diagnosis. The role of platelets in ACS is versatile.(4) The platelet count is associated with the underlying inflammation because inflammatory mediators stimulate megakaryocytic proliferation and result in a prothrombotic state with relative thrombocytosis.(4,5)
As platelet levels increase, more platelet rich thrombosis is observed in atherosclerotic plaques, and antiplatelet therapy response is reduced.(4) It is known that platelets are associated with endothelial activation as well as inflammatory functions.(2) Active platelets release pro-angiogenic mediators and regulate the microvasculature of blood vessels.(18) As essential components of coronary thrombus formation, platelets play an important role in ACS.(2) In the CADILLAC study, increased platelet counts were also associated with restenosis and stent thrombosis.(19) PLR is thought to better reflect both inflammation and coagulation pathways.(4) In their study using optical coherence tomography, Wang et al showed that high PLR is associated with sensitive plaque properties such as thinner fibrous cap, wider lipid load in non-target vessels in ACS patients.(20)
The authors suggested that the relation between PLR and sensitive plaques is associated with immunologic and inflammatory pathways.(20) The relationship between PLR and CAD severity is also shown in other publications.(21) For example, Kurtul et al. have shown that high PLR is associated with moderate to high SYNTAX score in patients with ACS.(21) In another study, high platelet counts have been shown to be associated with microvascular plug formation, thrombus formation, and vasoconstriction and no-reflow development.(8) PLR has been shown to be associated with mortality in STEMI and NSTMI patients.(22) Oylumlu et al noted that high PLR values in ACS patients were associated with in-hospital mortality.(4)
In their meta-analysis, Li et al. showed that increased PLR is associated with in hospital and long-term mortality and cardiovascular events in ACS patients.(5) Yıldız et al. have also shown that high PLR values are associated with no-reflow development after percutaneous interventions.(23) Prajapati et al. showed a relationship between increased PLR and NLR and decreased HDL values in CAD patients.(18) The combined use of NLR and PLR suggests that more prognostic information will be obtained. In this context, Choi et al. found that combined NLR and PLR elevations were associated with long-term cardiovascular events.(22) Hematological markers have also been shown in other publications as indicators of inflammation. Similar to other studies, in our study, NLR and PLR in patients with ACS were higher than in the control group. The difference of present study from the other studies is that all the ACS subgroups were included and examined in the same study and that the NLR and PLR were high in all the subgroups.
Inflammatory and thrombotic processes play a crucial role in the development of atherosclerosis, atherosclerotic plaque destabilization and clot formation after plaque rupture. In the diagnosis and prognosis of ACS, there are still needs for reliable, easy, inexpensive and fast detectable markers. PLR and NLR are cheap and easy to use markers in the diagnosis and the prognosis of ACS patients but definite cut off values are needed to use these markers. Large scale and comprehensive studies are needed to reveal absolute cut off values for these markers.
- Bekler A, Gazi E, Yılmaz M, Temiz A, Altun B, Barutcu A, Peker T. Could elevated platelet-lymphocyte ratio predict left ventricular systolic dysfunction in patients with non-ST elevated acute coronary syndrome? Anatol J Cardiol 2015; 15: 385-390.
- Budzianowski J, Pieszko K, Burchardt P, Hickiewicz J. The role of hematological indices in patients with acute coronary syndrome. Hindawi Disease Markers 2017; 2017: 3041565. doi: 10.1155/2017/3041565.
- Thaulow E, Erikssen J, Sandvik L, Stormorken H, CohnPF. Blood platelet count and function are related to total and cardiovascular death in apparently healthy men. Circulation 1991; 84: 613-617.
- Oylumlu M, Yıldız A, Polat N, Bilik MZ, Akyuz A, Acet H, Soydinc S. Platelet-to-lymphocyte ratio is a predictor of in-hospital mortality patients with acute coronary syndrome. Anatol J Cardiol 2015; 15: 277-283.
- Li H, Zhou Y, Ma Y, Han S, Zhou L. The prognostic value of the platelet-to-lymphocyte ratio in acute coronary syndrome:a systematic review and meta-analysis. Kardiologia Polska 2017; 75: 666-673.
- Ommen SR, Hammill SC, Gibbons RJ. The relative lymphocyte count predicts death in patients receiving implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2002; 25: 1424-1428.
- Edem E, Türker MP, Erkan A, Taş S, Çil A, Vural MG, Akdeniz B. Platelet-to-lymphocyte ratio but not neutrophil-to-lymphocyte ratio predicts high on-treatment platelet reactivity in clopidogrel-treated patients with acute coronary syndrome. Indian J Pharmacol 2016; 48: 355-359.
- Azab B, Shah N, Akerman M, McGinn JT Jr. Value of platelet/lymphocyte ratio as a predictor of all-cause mortality after non-ST elevation myocardial infarction. J Thromb Thrombolysis 2012; 34: 326-334.
- Isiksacan N, Biyik I, Koser M, Ozalp B, Baycan OF, Yazan S, Aktürk IF. Comparison of high sensitive and conventional troponin assays in diagnosis of acute myocardial infarction. Turk J Biochem 2017; 42 : 77-85.
- Sezer M, Okcular I, Goren T, Oflaz H, F, Bilge A, Meric M, Umman S. Association of haematological indices with the degree of microvascular injury in patients with acute anterior wall myocardial infarction treated with primary percutaneous coronary intervention. Heart 2007; 93: 313-318.
- Zouridakis EG, Garcia-Moll X, Kaski JC. Usefulness of the blood lymphocyte count in predicting recurrent instability and death in patients with unstable angina pectoris. Am J Cardiol 2000; 86: 449-51.
- Wang X, Zhang G, Jiang X, Lu Z, Xu L. Neutrophil to lymphocyte ratio in relation to risk of all- cause mortality and cardiovascular events among patients undergoing angiography or cardiac revascularization: a meta-analysis of observational studies. Atherosclerosis 2014; 234: 206-213.
- Tamhane UU, Aneja S, Montgomery D, Eagle KA, Gurm HS. Association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute coronary syndrome. Am J Cardiol. 2008; 102: 653-7.
- Ayça B, Akın F, Celik O, Sahin I, Okuyan E, Dinckal MH. Neutrophil to lymphocyte ratio is related to stent thrombosis and high mortality in patients with acute myocardial infarction. Angiology 2015; 66: 545-552.
- Altun B, Turkon H, Tasolar, Gazi E, Barutcu A, Bekler A, Colkesen Y. The relationship between high-sensitive troponin T, neutrophil lymphocyte ratio and SYNTAX score. Scand J Clin Lab Invest. 2014; 74: 108-15.
- Ergelen M, Uyarel H, Altay S, Kul S, Ayhan E, Isık T, Erdogan E, Turfan M. Predictive value of elevated neutrophil to lymphocyte ratio in patients undergoing primary angioplasty for ST-segment elevation myocardial infarction. Clin Appl Thromb Hemost. 2014; 20: 427-32.
- Sawant AC, Adhikari P, Narra SR, Srivatsa SV, Mills PK, Srivatsa SS. Neutrophil to lymphocyte ratio pre- dicts short- and long-term mortality following revascularization therapy for ST elevation myocardial infarction. Cardiol J. 2014; 21: 500-8.
- Prajapati JH, Sahoo S, Nikam T, Shah KH, Maheriya B, Parmar M. Association of high density lipoprotein with platelet to lymphocyte and neutrophil tol lymphocyte ratios in coronary artery disease patients. J Lipids. 2014; 2014: 686791.
- Nikolsky E, Grines CL, Cox DA, Garcia E, Tcheng JE, Sadeghi M, Mehran R, Stone GW. Impact of baseline platelet count in patients undergoing primary percutaneous coronary intervention in acute myocardial infarction (from the CADILLAC trial). Am J Cardiol. 2007; 99: 1055-61.
- Wang X, Xie Z, Liu X, Huang X, Lin J, Yu B, Hou J. Association of platelet to lymphocyte ratio with non-culprit atherosclerotic plaque vulnerability in patients with acute coronary syndrome: an optical coherence tomography study. BMC Cardiovasc Disord. 2017; 17: 175.
- Kurtul A, Murat SN, Cetin M, Ornek E. Association of platelet-to-lymphocyte ratio with severity and complexity of coronary artery disease in patients with acute coronary syndromes. Am J Cardiol. 2014;114: 972-8.
- Choi SW, Choi DH, Ku YH, Ha SI, Park G. Clinical outcome prediction from mean platelet volume in patients undergoing percutaneous coronary intervention in Korean cohort: Implications of more simple and useful test than platelet function testing. Platelets. 2014; 25: 322-327.
- Yıldız A, Yuksel M, Oylumlu M, Polat N, Akyuz A, Acet H, Aydin M, Ulgen MS. The utility of the platelet–lymphocyte ratio for predicting no reflow in patients with ST-segment elevation myocardial infarction. Clin Appl Thromb Hemost. 2015; 21: 223-8.