Diagnostic and Prognostic Value of Immune/Inflammation Biomarkers for Venous Thromboembolism: Is It Reliable for Clinical Practice?

Figures & data

Figure 1 (A) The number of studies on immune/inflammation biomarkers in VTE increased dramatically from 2005 to 2021. (B) A number of researchers around the world have published numerous research findings in this area, among which American researchers have published papers with the highest impact factors. (C) Studies on immune/inflammation biomarkers are conducted in various countries, among which Turkish researchers have reported the most.

Table 1 Studies of NLR for VTE

Study	Year	Country	Study Design	Number of Individuals	Age (Years)	VTE Type	Follow Up	Outcomes	NLR Cut-Off	Sensitivity (%)	Specificity (%)	AUC	OR/HR and p value
Duman et al^Citation21	2021	Turkey	Retrospective	828	62 (51–73)^b	PE	12 months	30-day/6-month/12-month mortality	6.1/3.25/3.14	75/71.4/68.6	75.6/60.7/59.8	0.75/0.71/0.67	HR=13.8/2.77/2.0, p=0.001/0.001/0.003
Bi et al^Citation13	2021	China	Retrospective	72	60.10±0.99^a (High-risk) 59.23±0.87^a (Moderate-risk) 59.26±0.82^a (Low-risk)	APE	NA	Mortality	NA	77.9	89	0.861	NA
Go et al^Citation36	2021	Republic of Korea	Retrospective	114	69 (35–84)^b	DVT	NA	Mortality	NA	NA	NA	NA	HR=1.324, p=0.428
Peng et al^Citation31	2021	China	Retrospective	52	75.67±8.48^a	VTE	In hospital	Probability of VTE	NA	NA	NA	NA	OR=2.003, p=0.078
Köse et al^Citation9	2020	Turkey	Retrospective	103	67.6±13.1^a	PE	39 months	Probability of PE and long-term mortality	NA	NA	NA	NA	OR:1.52, p<0.001; HR:1.17, p=0.003 (Moderate-low and low risk PE); HR:0.99, p=0.859 (Moderate-high and high risk PE)
Liu et al^Citation17	2020	China	Retrospective	101	64.00 (57.50–71.00)^b	PAPE	30 days	30-day mortality	12	62.5	90.9	0.823	OR=1.171, p=0.000
Phan et al^Citation20	2020	USA	Retrospective	191	59.5±16.0^a (survived), 62.3 ±15.2^a (died)	APE	In hospital	All-cause and In-hospital mortality	5.46	75	66.9	0.692	NA, p<0.01
Ghaffari et al^Citation23	2020	USA	Retrospective	492	62.1± 17.2^a	APE	12 months	Mortality	NA	NA	NA	NA	NA, p=0.206
Kasapoğlu et al^Citation14	2019	Turkey	Retrospective	550	68 (19–86)^b	APE	30 days	30-day mortality	7.3	69	48	0.604	HR=1.27, p=0.669; HR=1.27, p=0.669 (subgroup without comorbidities)
Telo et al^Citation19	2019	Turkey	Retrospective	82	61.18±15.51^a	APE	30 days	In-hospital mortality and 30-day mortality	3.56	66	53	0.675	NA
Farah et al^Citation25	2019	Israel	Retrospective	272	62±18.9^a	Acute VTE	NA	Probability of acute VTE	5.3	69	57	0.67	OR=1.2, p=0.041
Seo et al^Citation29	2019	South Korea	Retrospective	102	69.8±7.9^a	VTE	In hospital	Probability of acute VTE	1.9	57.8	55.6	0.589	OR=1.95, p=0.013
Ertem et al^Citation24	2018	Turkey	Retrospective	294	67.21±14.74^a	APE	30 days	In-hospital mortality and 30-day mortality	NA	NA	NA	NA	HR:0.990, p=0.240
Grilz et al^Citation33	2018	Austria	Retrospective	128	62 (50–68)^b	VTE	24 months	Probability of VTE and 24-month mortality	5.7	NA	NA	NA	HR=1.2, p=0.049
Fuentes et al^Citation48	2018	USA	Retrospective	13	58 (51–64)^b	VTE	21.3 months	Probability of acute VTE	NA	46.2	47.5	0.47	HR=0.8, p=0.8
Artoni et al^Citation26	2018	Italy	Retrospective	486	47.9±16.1^a	VTE	NA	Probability of acute VTE	NA	NA	NA	NA	OR=0.69, p>0.05
Yao et al^Citation28	2018	China	Retrospective	120	64.1± 13.2^a	DVT	In hospital	Probability of acute DVT	NA	NA	NA	0.533, 0.613	OR=1.11, p<0.035 (preoperative NLR), OR=1.20, p<0.001 (postoperative NLR)
Jia et al^Citation18	2017	China	Retrospective	154	62.54±16.90^a (survived), 56.60±14.80^a (died)	APE	30 days	30-day mortality	7.03	83.3	75.6	0.803	NA
Ming et al^Citation34	2017	China	Retrospective	115	52.17±14.13^a	Acute DVT	NA	Probability of acute DVT	1.76	83.5	41	0.82	OR=1.889, p=0.024
Ateş et al^Citation8	2017	Turkey	Retrospective	34	64.1±15.8^a	APE	In hospital	Probability of PE	NA	NA	NA	0.893	OR:2.22, p<0.001 (massive APE)
Mehmet Karataş et al^Citation22	2016	Turkey	Retrospective	203	65.8±18.1^a	APE	20 months	30-day mortality and long-term mortality	NA	NA	NA	NA	HR=1.13, p=0.01
Ma et al^Citation16	2016	China	Retrospective	248	66 (52–74, survived)^b, 75 (65–83, died)^b	APE	30 days	30-day mortality	5.99	80	66.7	0.79	OR = 1.13, p=0.003
Grimnes et al^Citation32	2016	Norway	Retrospective	25,107	48.4±17.2^a	VTE	9.95 years	Probability of VTE and Mortality	NA	NA	NA	NA	HR=2.36, p=0.21; HR=2.13, p=0.02
Celik et al^Citation10	2015	Turkey	Retrospective	112	59±16^a	APE	In hospital	Probability of PE	NA	NA	NA	NA	OR=0.887, p=0.068
Barker et al^Citation30	2015	USA	Retrospective	10	65±5^a	VTE	In hospital	Probability of acute VTE	NA	NA	NA	NA	OR=1.38, p=0.02
Bakirci et al^Citation40	2015	Turkey	Retrospective	77	53.7±10.2^a	VTE	In hospital	Probability of acute VTE	1.84	88.2	67.6	0.849	NA
Soylu et al^Citation12	2014	Turkey	Retrospective	142	58.9±14.5^a	APE	In hospital	In-hospital mortality	5.7	81	71	0.697	OR = 10.8, p=0.019
Akgüllü et al^Citation11	2014	Turkey	Retrospective	206	61.8± 11.8^a	APE	3.0 (2.0–5.0) days	Early mortality	8.4	76.67	81.82	0.825	OR = 1.079, p=0.037
Ferroni et al^Citation35	2014	Italy	Retrospective	55	NA	DVT	9 months	Probability of acute DVT	3	59	57	0.55	HR=2.5, p=0.06
Kayrak et al^Citation15	2013	Turkey	Retrospective	359	62±16^a (survived), 73±10^a (died)	APE	30 days	30-day mortality	9.2	68.6	80.5	NA	HR=1.03, p=0.008

Notes: ^aMean±standard deviation; ^bInterquartile range.

Abbreviations: PE, pulmonary embolism; APE, acute pulmonary embolism; PAPE, postoperative acute pulmonary embolism; DVT, deep venous thrombosis; VTE, venous thromboembolism; NA, not available; HR, hazard ratio; OR, odds ratio.

Figure 2 (A) The AUC of NLR ranged from 0.47 to 0.893, the sensitivity from 46.2% to 88.2%, the specificity from 41% to 90.9%, and the cutoff value from 1.76 to 12, indicating that NLR provide promising predictive capability for VTE, but the results varied between studies. (B) The AUC of PLR ranged from 0.4 to 0.905, the sensitivity from 30% to 97.66%, the specificity from 47.9% to 82.8%, and the cutoff value from 12.8 to 325, indicating that PLR has certain predictive value for VTE, whereas the results also varied between studies.

Table 2 Studies of PLR for VTE

Study	Year	Country	Study Design	Number of Individuals	Age (Years)	VTE Type	Follow Up	Outcomes	PLR Cut-Off	Sensitivity (%)	Specificity (%)	AUC	OR/HR and p value
Duman et al^Citation21	2021	Turkey	Retrospective	828	62 (51–73)^b	PE	12 months	30-day/6-month/12-month mortality	158.38/156.38/152.38	62.5/65.3/64.3	47.9/54.8/52.2	0.62/0.65/0.64	NA
Peng et al^Citation31	2021	China	Retrospective	52	75.67±8.48^a	VTE	In hospital	Probability of VTE	NA	NA	NA	NA	NA, p=0.051
Yamagata et al^Citation46	2021	Japan	Retrospective	101	72 (29–93)^b	VTE	In hospital	Probability of acute VTE	187.4	75	74.2	0.772	OR=13.375, P=0.001
Köse et al^Citation9	2020	Turkey	Retrospective	103	67.6±13.1^a	PE	39 months	Probability of PE and long-term mortality	NA	NA	NA	NA	OR:1.0, p=0.453; HR:1.0, p=0.545 (Moderate-low and low risk PE); HR:1.01, p=0.046 (Moderate-high and high risk PE)
Liu et al^Citation17	2020	China	Retrospective	101	64.00 (57.50–71.00) ^b	PAPE	30 days	30-day mortality	NA	NA	NA	NA	NA, p=0.193
Phan et al^Citation20	2020	USA	Retrospective	191	59.5±16.0^a (survived), 62.3 ±15.2^a (died)	APE	In hospital	All-cause and In-hospital mortality	256.6	53.6	82.8	0.693	NA, p<0.01
Ghaffari et al^Citation23	2020	USA	Retrospective	492	62.1± 17.2^a	APE	12 months	Mortality	12.8	61	63.2	0.61	NA, p<0.01
Kasapoğlu et al^Citation14	2019	Turkey	Retrospective	550	68 (19–86)^b	APE	30 days	30-day mortality	170	63	53	0.582	HR=1.4, p=0.503
Telo et al^Citation19	2019	Turkey	Retrospective	82	61.18±15.51^a	APE	30 days	In-hospital mortality and 30-day mortality	156	74	64	0.717	OR=6.325, p<0.01
Farah et al^Citation25	2019	Israel	Retrospective	272	62±18.9^a	Acute VTE	NA	Probability of acute VTE	NA	NA	NA	NA	NA, p>0.05
Ertem et al^Citation24	2018	Turkey	Retrospective	294	67.21±14.74^a	APE	30 days	In-hospital mortality and 30-day mortality	NA	NA	NA	NA	NA, p=0.241
Grilz et al^Citation33	2018	Austria	Retrospective	128	62 (50–68)^b	VTE	24 months	Probability of VTE and 24-month mortality	264	NA	NA	NA	HR=1.5, p<0.001
Fuentes et al^Citation48	2018	USA	Retrospective	13	58 (51–64)^b	VTE	21.3 months	Probability of acute VTE	NA	NA	NA	0.4	HR=0.8, p=0.8
Artoni et al^Citation26	2018	Italy	Retrospective	486	47.9±16.1^a	VTE	NA	Probability of acute VTE	NA	NA	NA	NA	OR=0.89, p>0.05
Yao et al^Citation28	2018	China	Retrospective	120	64.1± 13.2^a	DVT	In hospital	Probability of acute DVT	NA	NA	NA	0.561	OR=0.99, p<0.001 (postoperative PLR)
Tham et al^Citation49	2018	USA	Retrospective	306	61.82± 14.44^a	VTE	30 days	Probability of VTE	320	97.66	71.43	0.905	OR=95.95, p<0.001
Jia et al^Citation18	2017	China	Retrospective	154	62.54±16.90^a (survived), 56.60±14.80^a (died)	APE	30 days	30-day mortality	NA	NA	NA	NA	NA, p=0.246
Ming et al^Citation34	2017	China	Retrospective	115	52.17±14.13^a	Acute DVT	NA	Probability of acute DVT	NA	NA	NA	0.61	NA, p>0.05
Ateş et al^Citation8	2017	Turkey	Retrospective	639	64.1±15.8^a	APE	In hospital	Probability of PE	NA	NA	NA	0.877	OR:1.59, p<0.001 (massive APE)
Karataş et al^Citation22	2016	Turkey	Retrospective	203	65.8±18.1^a	APE	20 months	30-day mortality and long-term mortality	NA	NA	NA	NA	HR=1.002, p=0.01
Ma et al^Citation16	2016	China	Retrospective	248	66 (52–74, survived)^b, 75 (65–83, died)^b	APE	30 days	30-day mortality	325	65	80.7	0.789	OR = 1.002, p=0.003
Celik et al^Citation10	2015	Turkey	Retrospective	112	59±16^a	APE	In hospital	Probability of PE	NA	NA	NA	NA	OR=0.998, p=0.340
Kundi et al^Citation45	2015	Turkey	Retrospective	646	60±16^a	APE	In hospital	In-hospital mortality	149	77.1	76.3	0.860	NA, p<0.001
Ferroni et al^Citation35	2014	Italy	Retrospective	55	NA	DVT	9 months	Probability of acute DVT	260	30	80	0.54	HR=2.4, p=0.027
Yang et al^Citation47	2014	China	Retrospective	76	62.0± 8.9^a	VTE	2 months	Probability of VTE	260	NA	NA	NA	OR=2.757, P=0.025

Notes: ^aMean±standard deviation; ^bInterquartile range.

Abbreviations: PE, pulmonary embolism; APE, acute pulmonary embolism; PAPE, postoperative acute pulmonary embolism; DVT, deep venous thrombosis; VTE, venous thromboembolism; NA, not available; HR, hazard ratio; OR, odds ratio.

Duman D, Sonkaya E, Yildirim E, et al. Association of inflammatory markers with mortality in patients hospitalized with non-massive pulmonary embolism. Turk Thorac J. 2021;22(1):24–30. doi:10.5152/TurkThoracJ.2021.190076

 PubMed Web of Science ®Google Scholar

Bi W, Liang S, He Z, et al. The Prognostic Value of the Serum Levels of Brain Natriuretic Peptide, Troponin I, and D-Dimer, in Addition to the Neutrophil-to-Lymphocyte Ratio, for the Disease Evaluation of Patients with Acute Pulmonary Embolism. Int J Gen Med. 2021;14:303–308. doi:10.2147/IJGM.S288975

 PubMed Web of Science ®Google Scholar

Go SI, Lee A, Lee US, et al. Clinical significance of the neutrophil-lymphocyte ratio in venous thromboembolism patients with lung cancer. Lung Cancer. 2014;84(1):79–85. doi:10.1016/j.lungcan.2014.01.014

 PubMed Web of Science ®Google Scholar

Peng J, Wang H, Zhang L, Lin Z. Construction and efficiency analysis of prediction model for venous thromboembolism risk in the elderly after hip fracture. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2021;46(2):142–148.

 PubMedGoogle Scholar

Kose N, Yildirim T, Akin F, Yildirim SE, Altun I. Prognostic role of NLR, PLR, and LMR in patients with pulmonary embolism. Bosn J Basic Med Sci. 2020;20(2):248–253.

 PubMed Web of Science ®Google Scholar

Liu C, Zhan HL, Huang ZH, et al. Prognostic role of the preoperative neutrophil-to-lymphocyte ratio and albumin for 30-day mortality in patients with postoperative acute pulmonary embolism. BMC Pulm Med. 2020;20(1):180. doi:10.1186/s12890-020-01216-5

 PubMed Web of Science ®Google Scholar

Phan T, Brailovsky Y, Fareed J, et al. Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios predict all-cause mortality in acute pulmonary embolism. Clin Appl Thromb Hemost. 2020;26:1076029619900549. doi:10.1177/1076029619900549

 Web of Science ®Google Scholar

Ghaffari S, Parvizian N, Pourafkari L, et al. Prognostic value of platelet indices in patients with acute pulmonary thromboembolism. J Cardiovasc Thorac Res. 2020;12(1):56–62. doi:10.34172/jcvtr.2020.09

 PubMed Web of Science ®Google Scholar

Kasapoglu US, Olgun YS, Arikan H, et al. Comparison of neutrophil to lymphocyte ratio with other prognostic markers affecting 30 day mortality in acute pulmonary embolism. Tuberk Toraks. 2019;67(3):179–189. doi:10.5578/tt.68519

 PubMed Web of Science ®Google Scholar

Telo S, Kuluozturk M, Deveci F, Kirkil G. The relationship between platelet-to-lymphocyte ratio and pulmonary embolism severity in acute pulmonary embolism. Int Angiol. 2019;38(1):4–9. doi:10.23736/S0392-9590.18.04028-2

 PubMed Web of Science ®Google Scholar

Farah R, Nseir W, Kagansky D, Khamisy-Farah R. The role of neutrophil-lymphocyte ratio, and mean platelet volume in detecting patients with acute venous thromboembolism. J Clin Lab Anal. 2020;34(1):e23010. doi:10.1002/jcla.23010

 PubMed Web of Science ®Google Scholar

Seo WW, Park MS, Kim SE, et al. Neutrophil-Lymphocyte Ratio as a Predictor of Venous Thromboembolism after Total Knee Replacement. J Knee Surg. 2021;34(2):171–177. doi:10.1055/s-0039-1694043

 PubMedGoogle Scholar

Ertem AG, Yayla C, Acar B, et al. Relation between lymphocyte to monocyte ratio and short-term mortality in patients with acute pulmonary embolism. Clin Respir J. 2018;12(2):580–586. doi:10.1111/crj.12565

 PubMed Web of Science ®Google Scholar

Grilz E, Posch F, Konigsbrugge O, et al. Association of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio with the risk of thromboembolism and mortality in patients with cancer. Thromb Haemost. 2018;118(11):1875–1884. doi:10.1055/s-0038-1673401

 PubMed Web of Science ®Google Scholar

Fuentes HE, Oramas DM, Paz LH, et al. Venous thromboembolism is an independent predictor of mortality among patients with gastric cancer. J Gastrointest Cancer. 2018;49(4):415–421. doi:10.1007/s12029-017-9981-2

 PubMed Web of Science ®Google Scholar

Artoni A, Abbattista M, Bucciarelli P, et al. Platelet to lymphocyte ratio and neutrophil to lymphocyte ratio as risk factors for venous thrombosis. Clin Appl Thromb Hemost. 2018;24(5):808–814. doi:10.1177/1076029617733039

 PubMed Web of Science ®Google Scholar

Yao C, Zhang Z, Yao Y, et al. Predictive value of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio for acute deep vein thrombosis after total joint arthroplasty: a retrospective study. J Orthop Surg Res. 2018;13(1):40. doi:10.1186/s13018-018-0745-x

 PubMedGoogle Scholar

Jia D, Liu F, Zhang Q, et al. Rapid on-site evaluation of routine biochemical parameters to predict right ventricular dysfunction in and the prognosis of patients with acute pulmonary embolism upon admission to the emergency room. J Clin Lab Anal. 2018;32(4):e22362. doi:10.1002/jcla.22362

 PubMed Web of Science ®Google Scholar

Ming L, Jiang Z, Ma J, et al. Platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, and platelet indices in patients with acute deep vein thrombosis. Vasa. 2018;47(2):143–147. doi:10.1024/0301-1526/a000683

 PubMed Web of Science ®Google Scholar

Ates H, Ates I, Bozkurt B, et al. What is the most reliable marker in the differential diagnosis of pulmonary embolism and community-acquired pneumonia? Blood Coagul Fibrinolysis. 2016;27(3):252–258. doi:10.1097/MBC.0000000000000391

 PubMed Web of Science ®Google Scholar

MB Karataş, İpek G, Onuk T, et al. Assessment of prognostic value of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in patients with pulmonary embolism. Acta Cardiol Sin. 2016;3(32):313–320.

 Google Scholar

Ma Y, Mao Y, He X, et al. The values of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in predicting 30 day mortality in patients with acute pulmonary embolism. BMC Cardiovasc Disord. 2016;16:123. doi:10.1186/s12872-016-0304-5

 PubMed Web of Science ®Google Scholar

Grimnes G, Horvei LD, Tichelaar V, Braekkan SK, Hansen JB. Neutrophil to lymphocyte ratio and future risk of venous thromboembolism and mortality: the Tromso Study. Haematologica. 2016;101(10):e401–e404. doi:10.3324/haematol.2016.145151

 PubMed Web of Science ®Google Scholar

Celik A, Ozcan IT, Gundes A, et al. Usefulness of admission hematologic parameters as diagnostic tools in acute pulmonary embolism. Kaohsiung J Med Sci. 2015;31(3):145–149. doi:10.1016/j.kjms.2014.12.004

 PubMed Web of Science ®Google Scholar

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(2):163–168. doi:10.1007/s10195-015-0378-3

 PubMedGoogle Scholar

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(2):181–185. doi:10.1177/1076029613494469

 PubMed Web of Science ®Google Scholar

Soylu K, Gedikli O, Eksi A, et al. Neutrophil-to-lymphocyte ratio for the assessment of hospital mortality in patients with acute pulmonary embolism. Arch Med Sci. 2016;12(1):95–100. doi:10.5114/aoms.2016.57585

 PubMed Web of Science ®Google Scholar

Akgullu C, Omurlu IK, Eryilmaz U, et al. Predictors of early death in patients with acute pulmonary embolism. Am J Emerg Med. 2015;33(2):214–221. doi:10.1016/j.ajem.2014.11.022

 PubMed Web of Science ®Google Scholar

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(5):1234–1240. doi:10.1002/ijc.29076

 PubMed Web of Science ®Google Scholar

Kayrak MB, Erdogan HI, Solak Y, et al. Prognostic value of neutrophil to lymphocyte ratio in patients with acute pulmonary embolism: a restrospective study. Heart Lung Circ. 2014;23(1):56–62. doi:10.1016/j.hlc.2013.06.004

 PubMed Web of Science ®Google Scholar

Yamagata K, Fukuzawa S, Uchida F, et al. Is Preoperative Plate-Lymphocyte Ratio a Predictor of Deep Vein Thrombosis in Patients With Oral Cancer During Surgery? J Oral Maxillofac Surg. 2021;79(4):914–924. doi:10.1016/j.joms.2020.10.024

 PubMed Web of Science ®Google Scholar

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(1):85–91. doi:10.1177/0194599818756851

 PubMed Web of Science ®Google Scholar

Kundi H, Balun A, Cicekcioglu H, et al. The relation between platelet-to-lymphocyte ratio and Pulmonary Embolism Severity Index in acute pulmonary embolism. Heart Lung. 2015;44(4):340–343. doi:10.1016/j.hrtlng.2015.04.007

 PubMed Web of Science ®Google Scholar

Yang W, Liu Y. Platelet-lymphocyte ratio is a predictor of venous thromboembolism in cancer patients. Thromb Res. 2015;136(2):212–215. doi:10.1016/j.thromres.2014.11.025

 PubMed Web of Science ®Google Scholar