Thrombosis Research 136 (2015) 212–215
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Platelet-lymphocyte ratio is a predictor of venous thromboembolism in cancer patients Wenjuan Yang, Ying Liu ⁎ Department of Emergency, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China
a r t i c l e
i n f o
Article history: Received 3 September 2014 Received in revised form 23 October 2014 Accepted 30 November 2014 Available online 3 December 2014 Keywords: Platelet-lymphocyte ratio Venous thromboembolism Cancer patients Predictor
a b s t r a c t Venous thromboembolism (VTE) is a common complication and a major cause of morbidity and mortality in patients with cancer. In cancer patients, laboratory parameters that predict venous thromboembolism (VTE) are scarce. Platelet/lymphocyte ratio (PLR), which can be easily calculated from the differential blood count, have been proposed as novel markers predictive of thrombotic events. The aim of this study was to determine whether PLR levels might represent significant prognostic indices in cancer patients with VTE. We retrospectively analyzed the clinical characteristics and laboratory parameters in 76 cancer patients with VTE, among 173 patients pathologically confirmed for cancer between June 2008 and December 2013.Receiving surgical procedure (51.3 VS 33.0%, p = 0.015), chemotherapy (51.3 VS 40.2%, p = 0.013) and the PLR N 260 (32.9 VS 14.4%, p = 0.004) were significantly different between the cancer patients with VTE and without VTE. Multiple logistic regression analysis showed that receiving surgical procedure (OR = 1.537, 95%CI = 1.241-1.984, p = 0.021), chemotherapy (OR = 1.969, 95%CI = 1.321-2.225, p = 0.013) and the PLR N 260 (OR = 2.757, 95%CI = 1.655-3.862, p = 0.025) were independent predictors of a VTE episode in patients with cancer. The results demonstrate that the PLR at the time of cancer diagnosis could be a useful clinically important, independent risk predictor for VTE in cancer patients. © 2014 Elsevier Ltd. All rights reserved.
Introduction Venous thromboembolism (VTE) which includes deep venous thrombosis (DVT) and pulmonary embolism (PE) is a common complication and a major cause of morbidity and mortality in patients with cancer [1,2]. An increasing number of studies have showed that patients with cancer were at an increased risk of venous thromboembolism (VTE) [3]. Moreover, recent researches showed that VTE was the second leading cause of death in cancer patients [4] and the most common cause of death in the postoperative period [5]. Thus, there is an urgent need for us to identify better biomarkers, especially serum biomarkers to predict VTE, which would help clinicians to adopt preventive and therapeutic strategies for risk patients. There are published literatures suggesting that the inflammation has a significant role in the pathogenesis of venous thrombosis. Inflammation may interfere with various stages of hemostasis, either through the activation of coagulation or through the inhibition of fibrinolysis and anticoagulant pathways [6]. In addition, it is believed that the cancer related inflammatory condition may change the
patient’s pro-coagulant system, and eventually result in thrombotic events [7]. In this context, the presence of VTE is likely to represent a nonspecific response to cancer-related inflammation. Therefore, markers of inflammation may provide useful information to predict VTE. At present, accumulating evidence demonstrated that increased systemic inflammation is associated with poor cancer-specific survival in a variety of cancers. Recently, an increasing number of studies have focused on the prognostic value of an elevated platelet-to-lymphocyte ratio (PLR) in patients with cancer [8,9]. Although PLR had been widely investigated in terms of their prognostic value on cancer survival outcomes [10,11], there are few literature reporting whether PLR is a predictor of venous thromboembolism in cancer patients. To our knowledge, only one literature reported the clinical value of the PLR at the time of VTE diagnosis, in which Ferroni et al found that PLR can be a predictor for response to anticoagulation and survival [12]. Therefore, we preformed this study aim to investigate the predictive value of PLR for venous thromboembolism in cancer patients. Methods
⁎ Corresponding author at: Department of Emergency, Shanghai Tenth People's Hospital of Tongji University, No.301,YanChang Rd(M), Shanghai, 200072, China. Tel./fax: + 86 21 60271196. E-mail address: [email protected] (Y. Liu).
http://dx.doi.org/10.1016/j.thromres.2014.11.025 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
Patients We enrolled 173 patients with primary or relapsing/recurrent solid cancers who were older than 18 years, receiving clinical care in the
W. Yang, Y. Liu / Thrombosis Research 136 (2015) 212–215
outpatient department setting of the Department of Medical Oncology in Shanghai Tenth People's Hospital of Tongji University, between June 2008 and December 2013. Cases and controls were patients of 18 years or older affected by histology confirmed cancer (metastatic or locally advanced) of the lung, stomach, colon, pancreas, kidney, ovary, breast, prostate, and other genitourinary organs. Cases were cancer patients who had a symptomatic or an asymptomatic VTE diagnosed b 2 months before the inclusion in the study. VTE were diagnosed based on radiological evaluation (computed tomography or Doppler ultrasound) among those patients. Controls were cancer patients without VTE enrolled in the same oncology units of the cases. Controls underwent imaging studies to exclude a VTE. The controls were selected to match the cases by sex, age, and cancer site. Clinical Data Baseline patient demographics and clinical characteristics were collected by medical chart review. Cancer stages were obtained at the time of initial diagnosis and anticancer treatment at the time of VTE diagnosis was also reviewed. Peripheral venous blood samples were obtained in all patients at the first day of cancer diagnosis. We used an automatic blood cell analyzer (Bayer Advia 2120) to evaluate the complete and differential blood cell counts. Routine hematology, chemistry and coagulation studies were also tested in all patients. The other biochemical parameters were determined by standard laboratory tests. The PLR was obtained by dividing the total count of platelets by lymphocytes count. The cut-off value for “high versus low” PLR has not been unified currently. Thus, in the present study, the cut-off value for “high versus low” PLR value was defined as previously reported. A PLR N 260 was considered elevated according to the published literature [12]. Statistical Analysis All statistical analyses were conducted by using SPSS 21.0 software. Continuous variables normally distributed were expressed as the means ± standard deviations and compared between the case and control groups using the t test. Continuous variables deviated from the normal distribution were expressed as median and range and compared using non-parametric statistical test. The categorical variables were presented as the number of patients and percentages and compared using the chi-square tests. The multiple logistic regression analysis was conducted to explore the risk factors of VTE. A p-value less than 0.05 was considered significant for all statistical analyses. Results We retrospectively analyzed the clinical characteristics, laboratory parameters, and PLR in 76(43.9%) cancer patients with VTE and 97(56.1%) cancer patients without VTE between July 2008 and August 2013.The average age of all the cancer patients was 62.0 ± 8.9 years. The majority of patients were female (54.9%). One hundred and seventy-three patients with solid tumors including gastrointestinal cancer (n = 52) breast cancer (n = 20), lung cancer (n = 58), genitourinary cancer (n = 15), prostate cancer (n = 9) and head-neck cancer (n = 19) were studied. Adenocarcinoma was the most frequent histology (49.7%). The proportion of metastatic cancers was 79.8%. 83 (48.0%) patients received corticosteroids treatment, 71(41.0%) patients underwent a surgical procedure and 84(48.6%) patients received chemotherapy. Baseline clinical characteristics and laboratory parameters between two groups are summarized in Table 1. According to the analysis made by chi-square test, the distributions of receiving surgical procedure (51.3 VS 33.0%, p = 0.015), chemotherapy (51.3 VS 40.2%, p = 0.013) and the PLR N260 (32.9 VS 14.4%, p = 0.004) were significantly different between the cancer patients with VTE and without VTE.
213
Table 1 Distribution of cancer patients with VTE (cases) and patients without VTE (controls). Variables Age (year, n, %) b60 60-69 ≥70 Gender (n, %) Male Female Cancer site (n, %) Gastrointestinal Breast Lung Genitourinary Prostate Head-neck Cancer stage (n, %) Locally advanced Metastatic Cancer histology (n, %) Adenocarcinoma Squamous cell carcinoma Carcinoma NOS Undifferentiated carcinoma Corticosteroids (n, %) Surgery (n, %) Chemotherapy (n, %) Hemoglobin(g/dL) MCV( fL) MCHC( g/dL) MCH(pg) MPV(fL) WBC(x109/L) lymphocyte(x109/L) Platelet(x109/L) PLR N 260(n, %)
Total(N = 173) Cases(n = 76) Controls(n = 97) P 50(28.9) 58(33.5) 65(37.6)
18(23.7) 27(35.5) 31(40.8)
32(33.0) 31(32.0) 34(35.1)
0.404
78(45.1) 95(54.9)
34(44.7) 42(55.3)
44(45.4) 53(54.6)
0.935
52(30.1) 20(11.6) 58(33.5) 15(8.7) 9(5.2 ) 19(11.0)
24(31.6) 9(11.8) 27(35.5) 7(9.2) 3(4.0) 6(7.9)
28(28.9) 11(11.3) 31(32.0) 8(8.3) 6(6.2) 13(13.4)
0.862
35(20.2) 138(79.8)
12(15.8) 64(84.2 )
23(23.7) 74(76.3)
0.198
86(49.7) 11(6.4)
41(54.0) 4(5.3)
45(46.4) 7(7.2)
0.445
58(33.5) 18(10.4)
26(34.2) 5(6.6)
32(33.0) 13(31.4)
83(48.0)
42(55.3)
41(42.3)
0.091
71(41.0) 84(48.6)
39(51.3) 45(59.2)
32(33.0) 39(40.2)
0.015⁎ 0.013⁎
14.89 ± 1.80 92.12 ± 8.20 34.93 ± 1.54 31.05 ± 3.20 8.46 ± 1.10 7.63 ± 0.71 1.70 ± 0.65 280 ± 82 39(22.5)
15.01 ± 1.76 90.67 ± 8.14 34.57 ± 1.55 30.72 ± 3.13 8.53 ± 1.11 7.99 ± 0.26 1.62 ± 0.67 289 ± 75 25(32.9)
14.76 ± 1.92 94.02 ± 8.44 35.29 ± 1.52 31.99 ± 3.10 8.42 ± 1.09 7.52 ± 0.95 1.75 ± 0.65 271 ± 86 14(14.4)
0.482 0.063 0.098 0.533 0.864 0.402 0.181 0.261 0.004⁎
The continuous variables are presented as mean (SD), ⁎ : p b 0.05.
The final logistic regression model for cancer patients with VTE was presented in Table 2. The result showed an increase of VTE for receiving surgical procedure (OR = 1.537, 95%CI = 1.241-1.984, p = 0.021), chemotherapy (OR = 1.969, 95%CI = 1.321-2.225, p = 0.013) and the PLR N260 (OR = 2.757, 95%CI = 1.655-3.862, p = 0.025). These variables were independent predictors of a VTE episode in patients with cancer. In particular, patients with PLR N260 had an approximately threefold increased risk of developing VTE than PLR ≤ 260. Discussion In this study, we retrospectively analyzed the clinical characteristics and laboratory parameters in cancer patients with and without VTE. The results demonstrated that PLR significantly higher in the case of cancer patients with VTE. PLR N260 was strongly associated with the occurrence of VTE, exceeding an approximately threefold increased risk. In addition, surgical procedure and chemotherapy also turned out to be independent risk factor for VTE in cancer patients.
Table 2 The multiple Logistic Regression of cancer patients with VTE. Variables
B
Wads
OR
95%CI
p
Surgery (Yes VS. No) Chemotherapy (Yes VS. No) PLR (N260 VS. ≤260)
2.673 1.526 2.506
1.543 6.571 4.965
1.537 1.969 2.757
1.241-1.984 1.321-2.225 1.655-3.862
0.021⁎ 0.013⁎ 0.025⁎
⁎ : p b 0.05
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W. Yang, Y. Liu / Thrombosis Research 136 (2015) 212–215
Although the results of the analysis are positive, the exact explanation for the observation that an elevated PLR among cancer patients indicates higher risk for VTE is not clearly defined. Inflammatory cells and mediators are fundamental components of the tumor microenvironment [13] and may interfere with various stages of hemostasis, either through the activation of coagulation or through the inhibition of fibrinolysis and anticoagulant pathways [14]. The pro-thrombotic state of cancer is driven by specific oncogenic events. Activation of the coagulation cascade appears integrally connected to the processes of tumor growth, metastasis, and angiogenesis [13,14]. Some studies have shown, for instance, that both fibrinogen defect and platelet activation defect can reduce metastatic potential. Thus, PLR as a marker of inflammation may provide useful information to predict VTE. In the current study, platelet counts were higher in VTE group, though a statistical significance was not observed. Studies showed that platelets played an important role in cancer related inflammation and can release various active mediators to promote tumor growth and progression [13,14]. Increased evidence exists that platelets play an important role in tumor angiogenesis [15] and a pre-chemotherapy high platelet count was associated with a significantly elevated risk of VTE [16,17]. Furthermore, lymphocyte counts were lower in VTE group in present study, though a statistical significance was not observed. Gibson et al found that the patients with low lymphocyte counts tend to be in poorer general health and more depressed than those with normal lymphocyte counts [18]. Lymphopenia may not only be a parameter correlated to survival but also a biological mechanism stimulating tumor progression [19]. Accordingly, PLR has been regarded as a prognostic factor in cancer patients due to integrating negative effects of both thrombocytosis and lymphopenia. PLR is better than platelet counts alone and lymphocyte alone as it encompassed the inflammatory value of these two separate blood counts [12]. Furthermore thrombocytosis and lymphocytopenia both correlate with the degree of host systemic inflammation, and the PLR was shown to be an independent risk factor for high inflammatory process and reflects a novel marker incorporating both hematologic indices [11]. Consist with other studies, our study also showed that that surgery and chemotherapy are risk factors for the occurrence of cancerassociated VTE. In this study, approximately 51% in cancer patients with VTE versus 33% in cancer patients without VTE undergoing surgery. Patients receiving chemotherapy are two approximately two fold more likely to develop VTE, likely due to a combination of endothelial injury, induction of activated protein C resistance [20], and cell destruction leading to increased exposure of procoagulant surfaces [21–23]. However, our results should be interpreted cautiously since some limitations exist in the study. First, there may be potential bias and inaccuracy in data collection, as the present study was evaluated retrospectively. Thus, a prospective study is needed to validate our results. Second, it is difficult to recruit the enough number of cases and matched controls at a single center. The reduction in the study sample size may affect the statistical power to identify the risk factors for VTE in patients with cancer included in the study. Therefore, it is possible that the role of some VTE risk factors was underestimated. Third, the cut-off value for “high versus low” PLR has not been unified currently. Thus, in the present study, the cut-off value for “high versus low” PLR value was defined as previously reported. Despite the limitations and the need for more data from additional studies, the results of this study point that PLR may predict VTE of cancer patients, provided that a uniform value for assessing PLR increase is set. We advocate that future large sample study to give a definitive cutoff value of PLR is recommended. Despite some limitations in this study, our results indicated that PLR increased approximately threefold risk of VTE in cancer patients after adjusting confounding factors. What is more, our results provide coherent evidence that elevated PLR was of a strong predictor of thrombosis in patients with cancers [12]. In previous studies, the platelet counts alone have been reported as an independent risk factor for cancer related VTE [24,25]. Compared to the platelet alone, our study indicated that
baseline evaluation of PLR might provide important information to predict higher risk of cancer related VET. In conclusion, our study demonstrated that PLR is significantly associated VTE and might be a potential prognostic biomarker for VTE in cancer patients. The parameter PLR can easily and routinely be measured in cancer patients and might be a valuable parameter for risk stratification of VTE in cancer patients. However, further large prospective studies are warranted to validate our findings. Conflict of Interest Statement None. Disclosure The authors declare that there is no source of financial support or commercial sponsorship of this study. References [1] Khorana AA. Cancer-associated thrombosis: updates and controversies. Hematology Am Soc Hematol Educ Program 2012;2012:626–30. http://dx.doi.org/10.1182/ asheducation-2012.1.626. [2] Connolly GC, Menapace L, Safadjou S, Francis CW, Khorana AA. Prevalence and Clinical Significance of Incidental and Clinically Suspected Venous Thromboembolism in Lung Cancer Patients. Clin Lung Cancer 2013;14(6):713–8. http://dx.doi.org/10. 1016/j.cllc.2013.06.003. [3] Falanga A, Zacharski L. Deep vein thrombosis in cancer: the scale of the problem and approaches to management. Ann Oncol 2005;16(5):696–701. http://dx.doi.org/10. 1093/annonc/mdi165. [4] Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007;5(3):632–4. http://dx.doi.org/10.1111/j.1538-7836.2007. 02374.x. [5] Agnelli G, Bolis G, Capussotti L, Scarpa RM, Tonelli F, Bonizzoni E, et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project. Ann Surg 2006;243(1):89–95. [6] Bakirci EM, Topcu S, Kalkan K, Tanboga IH, Borekci A, Sevimli S, et al. The Role of the Nonspecific Inflammatory Markers in Determining the Anatomic Extent of Venous Thromboembolism. Clin Appl Thromb Hemost 2013. http://dx.doi.org/10.1177/ 1076029613494469. [7] Rak J, Yu JL, Luyendyk J, Mackman N. Oncogenes, trousseau syndrome, and cancerrelated changes in the coagulome of mice and humans. Cancer Res 2006;66(22): 10643–6. http://dx.doi.org/10.1158/0008-5472.CAN-06-2350. [8] Kwon HC, Kim SH, Oh SY, Lee S, Lee JH, Choi HJ, et al. Clinical significance of preoperative neutrophil-lymphocyte versus platelet-lymphocyte ratio in patients with operable colorectal cancer. Biomarkers 2012;17(3):216–22. http://dx.doi.org/10.3109/ 1354750X.2012.656705. [9] Asher V, Lee J, Innamaa A, Bali A. Preoperative platelet lymphocyte ratio as an independent prognostic marker in ovarian cancer. Clin Transl Oncol 2011;13(7): 499–503. http://dx.doi.org/10.1007/s12094-011-0687-9. [10] Baranyai Z, Krzystanek M, Josa V, Dede K, Agoston E, Szasz AM, et al. The comparison of thrombocytosis and platelet-lymphocyte ratio as potential prognostic markers in colorectal cancer. Thromb Haemost 2014;111(3):483–90. http://dx.doi.org/10.1160/ TH13-08-0632. [11] Krenn-Pilko S, Langsenlehner U, Thurner EM, Stojakovic T, Pichler M, Gerger A, et al. The elevated preoperative platelet-to-lymphocyte ratio predicts poor prognosis in breast cancer patients. Br J Cancer 2014;110(10):2524–30. http://dx.doi.org/10. 1038/bjc.2014.163. [12] Ferroni P, Riondino S, Formica V, Cereda V, Tosetto L, La Farina F, et al. Venous thromboembolism risk prediction in ambulatory cancer patients: Clinical significance of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio. Int J Cancer 2014. http://dx.doi.org/10.1002/ijc.29076 [n/a-n/a]. [13] Balkwill FR, Mantovani A. Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol 2012;22(1):33–40. http://dx.doi.org/10. 1016/j.semcancer.2011.12.005. [14] Candido J, Hagemann T. Cancer-related inflammation. J Clin Immunol 2013; 33(Suppl. 1):S79–84. http://dx.doi.org/10.1007/s10875-012-9847-0. [15] Sierko E, Wojtukiewicz MZ. Platelets and angiogenesis in malignancy. Semin Thromb Hemost 2004;30(1):95–108. http://dx.doi.org/10.1055/s-2004-822974. [16] Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapyassociated venous thromboembolism in a prospective observational study. Cancer 2005;104(12):2822–9. http://dx.doi.org/10.1002/cncr.21496. [17] Simanek R, Vormittag R, Ay C, Alguel G, Dunkler D, Schwarzinger I, et al. High platelet count associated with venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). J Thromb Haemost 2010;8(1): 114–20. http://dx.doi.org/10.1111/j.1538-7836.2009.03680.x. [18] Gibson PH, Cuthbertson BH, Croal BL, Rae D, El-Shafei H, Gibson G, et al. Usefulness of neutrophil/lymphocyte ratio as predictor of new-onset atrial fibrillation after
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[23] Connolly GC, Khorana AA. Risk stratification for cancer-associated venous thromboembolism. Best Pract Res Clin Haematol 2009;22(1):35–47. http://dx.doi.org/10. 1016/j.beha.2008.12.006. [24] Swystun LL, Shin LY, Beaudin S, Liaw PC. Chemotherapeutic agents doxorubicin and epirubicin induce a procoagulant phenotype on endothelial cells and blood monocytes. J Thromb Haemost 2009;7(4):619–26. http://dx.doi.org/10.1111/j.15387836.2009.03300.x. [25] Jensvoll H, Blix K, Braekkan SK, Hansen JB. Platelet count measured prior to cancer development is a risk factor for future symptomatic venous thromboembolism: the Tromso Study. PLoS One 2014;9(3):e92011. http://dx.doi.org/10.1371/journal. pone.0092011.
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Platelet-lymphocyte ratio is a predictor of venous thromboembolism in cancer patients Wenjuan Yang, Ying Liu ⁎ Department of Emergency, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China
a r t i c l e
i n f o
Article history: Received 3 September 2014 Received in revised form 23 October 2014 Accepted 30 November 2014 Available online 3 December 2014 Keywords: Platelet-lymphocyte ratio Venous thromboembolism Cancer patients Predictor
a b s t r a c t Venous thromboembolism (VTE) is a common complication and a major cause of morbidity and mortality in patients with cancer. In cancer patients, laboratory parameters that predict venous thromboembolism (VTE) are scarce. Platelet/lymphocyte ratio (PLR), which can be easily calculated from the differential blood count, have been proposed as novel markers predictive of thrombotic events. The aim of this study was to determine whether PLR levels might represent significant prognostic indices in cancer patients with VTE. We retrospectively analyzed the clinical characteristics and laboratory parameters in 76 cancer patients with VTE, among 173 patients pathologically confirmed for cancer between June 2008 and December 2013.Receiving surgical procedure (51.3 VS 33.0%, p = 0.015), chemotherapy (51.3 VS 40.2%, p = 0.013) and the PLR N 260 (32.9 VS 14.4%, p = 0.004) were significantly different between the cancer patients with VTE and without VTE. Multiple logistic regression analysis showed that receiving surgical procedure (OR = 1.537, 95%CI = 1.241-1.984, p = 0.021), chemotherapy (OR = 1.969, 95%CI = 1.321-2.225, p = 0.013) and the PLR N 260 (OR = 2.757, 95%CI = 1.655-3.862, p = 0.025) were independent predictors of a VTE episode in patients with cancer. The results demonstrate that the PLR at the time of cancer diagnosis could be a useful clinically important, independent risk predictor for VTE in cancer patients. © 2014 Elsevier Ltd. All rights reserved.
Introduction Venous thromboembolism (VTE) which includes deep venous thrombosis (DVT) and pulmonary embolism (PE) is a common complication and a major cause of morbidity and mortality in patients with cancer [1,2]. An increasing number of studies have showed that patients with cancer were at an increased risk of venous thromboembolism (VTE) [3]. Moreover, recent researches showed that VTE was the second leading cause of death in cancer patients [4] and the most common cause of death in the postoperative period [5]. Thus, there is an urgent need for us to identify better biomarkers, especially serum biomarkers to predict VTE, which would help clinicians to adopt preventive and therapeutic strategies for risk patients. There are published literatures suggesting that the inflammation has a significant role in the pathogenesis of venous thrombosis. Inflammation may interfere with various stages of hemostasis, either through the activation of coagulation or through the inhibition of fibrinolysis and anticoagulant pathways [6]. In addition, it is believed that the cancer related inflammatory condition may change the
patient’s pro-coagulant system, and eventually result in thrombotic events [7]. In this context, the presence of VTE is likely to represent a nonspecific response to cancer-related inflammation. Therefore, markers of inflammation may provide useful information to predict VTE. At present, accumulating evidence demonstrated that increased systemic inflammation is associated with poor cancer-specific survival in a variety of cancers. Recently, an increasing number of studies have focused on the prognostic value of an elevated platelet-to-lymphocyte ratio (PLR) in patients with cancer [8,9]. Although PLR had been widely investigated in terms of their prognostic value on cancer survival outcomes [10,11], there are few literature reporting whether PLR is a predictor of venous thromboembolism in cancer patients. To our knowledge, only one literature reported the clinical value of the PLR at the time of VTE diagnosis, in which Ferroni et al found that PLR can be a predictor for response to anticoagulation and survival [12]. Therefore, we preformed this study aim to investigate the predictive value of PLR for venous thromboembolism in cancer patients. Methods
⁎ Corresponding author at: Department of Emergency, Shanghai Tenth People's Hospital of Tongji University, No.301,YanChang Rd(M), Shanghai, 200072, China. Tel./fax: + 86 21 60271196. E-mail address: [email protected] (Y. Liu).
http://dx.doi.org/10.1016/j.thromres.2014.11.025 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
Patients We enrolled 173 patients with primary or relapsing/recurrent solid cancers who were older than 18 years, receiving clinical care in the
W. Yang, Y. Liu / Thrombosis Research 136 (2015) 212–215
outpatient department setting of the Department of Medical Oncology in Shanghai Tenth People's Hospital of Tongji University, between June 2008 and December 2013. Cases and controls were patients of 18 years or older affected by histology confirmed cancer (metastatic or locally advanced) of the lung, stomach, colon, pancreas, kidney, ovary, breast, prostate, and other genitourinary organs. Cases were cancer patients who had a symptomatic or an asymptomatic VTE diagnosed b 2 months before the inclusion in the study. VTE were diagnosed based on radiological evaluation (computed tomography or Doppler ultrasound) among those patients. Controls were cancer patients without VTE enrolled in the same oncology units of the cases. Controls underwent imaging studies to exclude a VTE. The controls were selected to match the cases by sex, age, and cancer site. Clinical Data Baseline patient demographics and clinical characteristics were collected by medical chart review. Cancer stages were obtained at the time of initial diagnosis and anticancer treatment at the time of VTE diagnosis was also reviewed. Peripheral venous blood samples were obtained in all patients at the first day of cancer diagnosis. We used an automatic blood cell analyzer (Bayer Advia 2120) to evaluate the complete and differential blood cell counts. Routine hematology, chemistry and coagulation studies were also tested in all patients. The other biochemical parameters were determined by standard laboratory tests. The PLR was obtained by dividing the total count of platelets by lymphocytes count. The cut-off value for “high versus low” PLR has not been unified currently. Thus, in the present study, the cut-off value for “high versus low” PLR value was defined as previously reported. A PLR N 260 was considered elevated according to the published literature [12]. Statistical Analysis All statistical analyses were conducted by using SPSS 21.0 software. Continuous variables normally distributed were expressed as the means ± standard deviations and compared between the case and control groups using the t test. Continuous variables deviated from the normal distribution were expressed as median and range and compared using non-parametric statistical test. The categorical variables were presented as the number of patients and percentages and compared using the chi-square tests. The multiple logistic regression analysis was conducted to explore the risk factors of VTE. A p-value less than 0.05 was considered significant for all statistical analyses. Results We retrospectively analyzed the clinical characteristics, laboratory parameters, and PLR in 76(43.9%) cancer patients with VTE and 97(56.1%) cancer patients without VTE between July 2008 and August 2013.The average age of all the cancer patients was 62.0 ± 8.9 years. The majority of patients were female (54.9%). One hundred and seventy-three patients with solid tumors including gastrointestinal cancer (n = 52) breast cancer (n = 20), lung cancer (n = 58), genitourinary cancer (n = 15), prostate cancer (n = 9) and head-neck cancer (n = 19) were studied. Adenocarcinoma was the most frequent histology (49.7%). The proportion of metastatic cancers was 79.8%. 83 (48.0%) patients received corticosteroids treatment, 71(41.0%) patients underwent a surgical procedure and 84(48.6%) patients received chemotherapy. Baseline clinical characteristics and laboratory parameters between two groups are summarized in Table 1. According to the analysis made by chi-square test, the distributions of receiving surgical procedure (51.3 VS 33.0%, p = 0.015), chemotherapy (51.3 VS 40.2%, p = 0.013) and the PLR N260 (32.9 VS 14.4%, p = 0.004) were significantly different between the cancer patients with VTE and without VTE.
213
Table 1 Distribution of cancer patients with VTE (cases) and patients without VTE (controls). Variables Age (year, n, %) b60 60-69 ≥70 Gender (n, %) Male Female Cancer site (n, %) Gastrointestinal Breast Lung Genitourinary Prostate Head-neck Cancer stage (n, %) Locally advanced Metastatic Cancer histology (n, %) Adenocarcinoma Squamous cell carcinoma Carcinoma NOS Undifferentiated carcinoma Corticosteroids (n, %) Surgery (n, %) Chemotherapy (n, %) Hemoglobin(g/dL) MCV( fL) MCHC( g/dL) MCH(pg) MPV(fL) WBC(x109/L) lymphocyte(x109/L) Platelet(x109/L) PLR N 260(n, %)
Total(N = 173) Cases(n = 76) Controls(n = 97) P 50(28.9) 58(33.5) 65(37.6)
18(23.7) 27(35.5) 31(40.8)
32(33.0) 31(32.0) 34(35.1)
0.404
78(45.1) 95(54.9)
34(44.7) 42(55.3)
44(45.4) 53(54.6)
0.935
52(30.1) 20(11.6) 58(33.5) 15(8.7) 9(5.2 ) 19(11.0)
24(31.6) 9(11.8) 27(35.5) 7(9.2) 3(4.0) 6(7.9)
28(28.9) 11(11.3) 31(32.0) 8(8.3) 6(6.2) 13(13.4)
0.862
35(20.2) 138(79.8)
12(15.8) 64(84.2 )
23(23.7) 74(76.3)
0.198
86(49.7) 11(6.4)
41(54.0) 4(5.3)
45(46.4) 7(7.2)
0.445
58(33.5) 18(10.4)
26(34.2) 5(6.6)
32(33.0) 13(31.4)
83(48.0)
42(55.3)
41(42.3)
0.091
71(41.0) 84(48.6)
39(51.3) 45(59.2)
32(33.0) 39(40.2)
0.015⁎ 0.013⁎
14.89 ± 1.80 92.12 ± 8.20 34.93 ± 1.54 31.05 ± 3.20 8.46 ± 1.10 7.63 ± 0.71 1.70 ± 0.65 280 ± 82 39(22.5)
15.01 ± 1.76 90.67 ± 8.14 34.57 ± 1.55 30.72 ± 3.13 8.53 ± 1.11 7.99 ± 0.26 1.62 ± 0.67 289 ± 75 25(32.9)
14.76 ± 1.92 94.02 ± 8.44 35.29 ± 1.52 31.99 ± 3.10 8.42 ± 1.09 7.52 ± 0.95 1.75 ± 0.65 271 ± 86 14(14.4)
0.482 0.063 0.098 0.533 0.864 0.402 0.181 0.261 0.004⁎
The continuous variables are presented as mean (SD), ⁎ : p b 0.05.
The final logistic regression model for cancer patients with VTE was presented in Table 2. The result showed an increase of VTE for receiving surgical procedure (OR = 1.537, 95%CI = 1.241-1.984, p = 0.021), chemotherapy (OR = 1.969, 95%CI = 1.321-2.225, p = 0.013) and the PLR N260 (OR = 2.757, 95%CI = 1.655-3.862, p = 0.025). These variables were independent predictors of a VTE episode in patients with cancer. In particular, patients with PLR N260 had an approximately threefold increased risk of developing VTE than PLR ≤ 260. Discussion In this study, we retrospectively analyzed the clinical characteristics and laboratory parameters in cancer patients with and without VTE. The results demonstrated that PLR significantly higher in the case of cancer patients with VTE. PLR N260 was strongly associated with the occurrence of VTE, exceeding an approximately threefold increased risk. In addition, surgical procedure and chemotherapy also turned out to be independent risk factor for VTE in cancer patients.
Table 2 The multiple Logistic Regression of cancer patients with VTE. Variables
B
Wads
OR
95%CI
p
Surgery (Yes VS. No) Chemotherapy (Yes VS. No) PLR (N260 VS. ≤260)
2.673 1.526 2.506
1.543 6.571 4.965
1.537 1.969 2.757
1.241-1.984 1.321-2.225 1.655-3.862
0.021⁎ 0.013⁎ 0.025⁎
⁎ : p b 0.05
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Although the results of the analysis are positive, the exact explanation for the observation that an elevated PLR among cancer patients indicates higher risk for VTE is not clearly defined. Inflammatory cells and mediators are fundamental components of the tumor microenvironment [13] and may interfere with various stages of hemostasis, either through the activation of coagulation or through the inhibition of fibrinolysis and anticoagulant pathways [14]. The pro-thrombotic state of cancer is driven by specific oncogenic events. Activation of the coagulation cascade appears integrally connected to the processes of tumor growth, metastasis, and angiogenesis [13,14]. Some studies have shown, for instance, that both fibrinogen defect and platelet activation defect can reduce metastatic potential. Thus, PLR as a marker of inflammation may provide useful information to predict VTE. In the current study, platelet counts were higher in VTE group, though a statistical significance was not observed. Studies showed that platelets played an important role in cancer related inflammation and can release various active mediators to promote tumor growth and progression [13,14]. Increased evidence exists that platelets play an important role in tumor angiogenesis [15] and a pre-chemotherapy high platelet count was associated with a significantly elevated risk of VTE [16,17]. Furthermore, lymphocyte counts were lower in VTE group in present study, though a statistical significance was not observed. Gibson et al found that the patients with low lymphocyte counts tend to be in poorer general health and more depressed than those with normal lymphocyte counts [18]. Lymphopenia may not only be a parameter correlated to survival but also a biological mechanism stimulating tumor progression [19]. Accordingly, PLR has been regarded as a prognostic factor in cancer patients due to integrating negative effects of both thrombocytosis and lymphopenia. PLR is better than platelet counts alone and lymphocyte alone as it encompassed the inflammatory value of these two separate blood counts [12]. Furthermore thrombocytosis and lymphocytopenia both correlate with the degree of host systemic inflammation, and the PLR was shown to be an independent risk factor for high inflammatory process and reflects a novel marker incorporating both hematologic indices [11]. Consist with other studies, our study also showed that that surgery and chemotherapy are risk factors for the occurrence of cancerassociated VTE. In this study, approximately 51% in cancer patients with VTE versus 33% in cancer patients without VTE undergoing surgery. Patients receiving chemotherapy are two approximately two fold more likely to develop VTE, likely due to a combination of endothelial injury, induction of activated protein C resistance [20], and cell destruction leading to increased exposure of procoagulant surfaces [21–23]. However, our results should be interpreted cautiously since some limitations exist in the study. First, there may be potential bias and inaccuracy in data collection, as the present study was evaluated retrospectively. Thus, a prospective study is needed to validate our results. Second, it is difficult to recruit the enough number of cases and matched controls at a single center. The reduction in the study sample size may affect the statistical power to identify the risk factors for VTE in patients with cancer included in the study. Therefore, it is possible that the role of some VTE risk factors was underestimated. Third, the cut-off value for “high versus low” PLR has not been unified currently. Thus, in the present study, the cut-off value for “high versus low” PLR value was defined as previously reported. Despite the limitations and the need for more data from additional studies, the results of this study point that PLR may predict VTE of cancer patients, provided that a uniform value for assessing PLR increase is set. We advocate that future large sample study to give a definitive cutoff value of PLR is recommended. Despite some limitations in this study, our results indicated that PLR increased approximately threefold risk of VTE in cancer patients after adjusting confounding factors. What is more, our results provide coherent evidence that elevated PLR was of a strong predictor of thrombosis in patients with cancers [12]. In previous studies, the platelet counts alone have been reported as an independent risk factor for cancer related VTE [24,25]. Compared to the platelet alone, our study indicated that
baseline evaluation of PLR might provide important information to predict higher risk of cancer related VET. In conclusion, our study demonstrated that PLR is significantly associated VTE and might be a potential prognostic biomarker for VTE in cancer patients. The parameter PLR can easily and routinely be measured in cancer patients and might be a valuable parameter for risk stratification of VTE in cancer patients. However, further large prospective studies are warranted to validate our findings. Conflict of Interest Statement None. Disclosure The authors declare that there is no source of financial support or commercial sponsorship of this study. References [1] Khorana AA. Cancer-associated thrombosis: updates and controversies. Hematology Am Soc Hematol Educ Program 2012;2012:626–30. http://dx.doi.org/10.1182/ asheducation-2012.1.626. [2] Connolly GC, Menapace L, Safadjou S, Francis CW, Khorana AA. Prevalence and Clinical Significance of Incidental and Clinically Suspected Venous Thromboembolism in Lung Cancer Patients. Clin Lung Cancer 2013;14(6):713–8. http://dx.doi.org/10. 1016/j.cllc.2013.06.003. [3] Falanga A, Zacharski L. Deep vein thrombosis in cancer: the scale of the problem and approaches to management. Ann Oncol 2005;16(5):696–701. http://dx.doi.org/10. 1093/annonc/mdi165. [4] Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007;5(3):632–4. http://dx.doi.org/10.1111/j.1538-7836.2007. 02374.x. [5] Agnelli G, Bolis G, Capussotti L, Scarpa RM, Tonelli F, Bonizzoni E, et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project. Ann Surg 2006;243(1):89–95. [6] Bakirci EM, Topcu S, Kalkan K, Tanboga IH, Borekci A, Sevimli S, et al. The Role of the Nonspecific Inflammatory Markers in Determining the Anatomic Extent of Venous Thromboembolism. Clin Appl Thromb Hemost 2013. http://dx.doi.org/10.1177/ 1076029613494469. [7] Rak J, Yu JL, Luyendyk J, Mackman N. Oncogenes, trousseau syndrome, and cancerrelated changes in the coagulome of mice and humans. Cancer Res 2006;66(22): 10643–6. http://dx.doi.org/10.1158/0008-5472.CAN-06-2350. [8] Kwon HC, Kim SH, Oh SY, Lee S, Lee JH, Choi HJ, et al. Clinical significance of preoperative neutrophil-lymphocyte versus platelet-lymphocyte ratio in patients with operable colorectal cancer. Biomarkers 2012;17(3):216–22. http://dx.doi.org/10.3109/ 1354750X.2012.656705. [9] Asher V, Lee J, Innamaa A, Bali A. Preoperative platelet lymphocyte ratio as an independent prognostic marker in ovarian cancer. Clin Transl Oncol 2011;13(7): 499–503. http://dx.doi.org/10.1007/s12094-011-0687-9. [10] Baranyai Z, Krzystanek M, Josa V, Dede K, Agoston E, Szasz AM, et al. The comparison of thrombocytosis and platelet-lymphocyte ratio as potential prognostic markers in colorectal cancer. Thromb Haemost 2014;111(3):483–90. http://dx.doi.org/10.1160/ TH13-08-0632. [11] Krenn-Pilko S, Langsenlehner U, Thurner EM, Stojakovic T, Pichler M, Gerger A, et al. The elevated preoperative platelet-to-lymphocyte ratio predicts poor prognosis in breast cancer patients. Br J Cancer 2014;110(10):2524–30. http://dx.doi.org/10. 1038/bjc.2014.163. [12] Ferroni P, Riondino S, Formica V, Cereda V, Tosetto L, La Farina F, et al. Venous thromboembolism risk prediction in ambulatory cancer patients: Clinical significance of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio. Int J Cancer 2014. http://dx.doi.org/10.1002/ijc.29076 [n/a-n/a]. [13] Balkwill FR, Mantovani A. Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol 2012;22(1):33–40. http://dx.doi.org/10. 1016/j.semcancer.2011.12.005. [14] Candido J, Hagemann T. Cancer-related inflammation. J Clin Immunol 2013; 33(Suppl. 1):S79–84. http://dx.doi.org/10.1007/s10875-012-9847-0. [15] Sierko E, Wojtukiewicz MZ. Platelets and angiogenesis in malignancy. Semin Thromb Hemost 2004;30(1):95–108. http://dx.doi.org/10.1055/s-2004-822974. [16] Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapyassociated venous thromboembolism in a prospective observational study. Cancer 2005;104(12):2822–9. http://dx.doi.org/10.1002/cncr.21496. [17] Simanek R, Vormittag R, Ay C, Alguel G, Dunkler D, Schwarzinger I, et al. High platelet count associated with venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). J Thromb Haemost 2010;8(1): 114–20. http://dx.doi.org/10.1111/j.1538-7836.2009.03680.x. [18] Gibson PH, Cuthbertson BH, Croal BL, Rae D, El-Shafei H, Gibson G, et al. Usefulness of neutrophil/lymphocyte ratio as predictor of new-onset atrial fibrillation after
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