The NLR, PLR, LMR Ratios in Venous Thromboembolism (VTE): A Study on Patients Affected by VTE with Active Cancer Compared to N0on-VTE

VTE is classified as the third most common vascular disease affecting as many as 10 million people per year [1,2]. Inflammation seems to play a role in initiating and progressing VTE, so a number of biomarkers have been evaluated which focus on flagging up the risk of VTE [3-5]. The close link between inflammation and exaggerated coagulation in VTE has been debated as well as the role played by blood stream cells such as activated leukocytes and platelets [6,7].

The Platelet-to-Lymphocyte Ratio (PLR), the Neutrophil-to Lymphocyte Ratio (NLR) and the monocyte-to-High-Density Lipoprotein (HDL) ratio (MHR) have been  considered in many studies focused on different diseases. Nevertheless, their significance and consistency are still debated therefore, this study aims to assess the levels and significance of NLR, PLR and MHR in patients affected by VTE (PE, DVT, PE+DVT) alone, by VTE with active cancer and VTE without cancer.

Two hundred and seventy-one patients have been admitted to the emergency room of the university hospital G. Rodolico (Catania, Italy) suffering from VTE. Two hundred and twenty-two patients were affected with VTE alone, and forty-seven were suffering from VTE with active cancer. Ninety-six patients out of the two hundred and seventy-one were affected with DVT of the lower limbs, eighty-eight were diagnosed with PE, and forty-nine patients were suffering from both thrombotic venous diseases PE+DVT. We also considered forty-nine hospitalized patients with neither VTE  or active cancer.  The NLR, PLR and MLR ratios were measured as follows: NLR was calculated by neutrophil counts (×103/L)/total Lymphocyte counts (×103/L), PLR was calculated by platelet counts (×103/L)/total lymphocyte counts (×103/L), and MHR was calculated by monocyte counts (×103/L)/HDL-C (mg/dl).

The NLR, PLR, LMR distributions were described as being in the median and inter-quartile range. Mann-Whitney’s U test was used to compare the values of the NLR, PLR, LMR found in VTE patients with or without cancer. Their correlations were analyzed with Spearman’s correlation test. The overall diagnostic accuracy of the biomarkers (NLR, PLR, LMR) underwent ROC analysis. The area under the ROC curve (AUC) was calculated. The cut-off value for diagnosis of VTE was identified by ROC analysis, and its sensitivity, specificity, positive and negative predictive values were calculated. A p-value < 0.05 was considered as significant. All statistical analyses were performed using the SPSS 29.0 software package (SPSS Inc., Cary, NC) [8,9].

The NLR, PLR and LMR values were higher in VTE patients compared to others. The differences were statistically significant (Table 1). The PLR and NLR values were higher in VTEs with active cancer (Table 2). All the ratios were measured in separate subgroups of VTEs: PE, DVTs or PE+DVTs. The NLR ratio was higher in the PE subgroup, while the LMR ratio was higher in the PE+DVT subgroup (Table 3). The ROC curve analysis shows 0.685 of the AUC value (CI 95% 0.606 and 0.765) in the PE subgroup (Figure 1). Based on 4.97 as the cut-off point of the NLR ratio, the sensitivity and specificity were 0.629 and 0.371 respectively. The positive and negative predictive value was 4.96% and 98.0%, respectively [10]. 

Table 1: Distribution of the biomarkers measured in the VTE and in no VTE patients. Mann-Whitney’s test. 

Table 2. Distribution of the biomarkers found in the VTE patients with  and without cancer Mann-Whitney’s test. 

Table 3. Distribution of the ratios found in VTE patients diagnosed as the pulmonary embolism (PE), deep vein thrombosis (DVT) and pulmonary embolism + deep vein thrombosis (PE+DVT). Kruskal-Wallis’s test.

Figure 1: ROC curve analysis showing the specificity and sensitivity capability of the NLR ratio for detecting (suspecting) the pulmonary thromboembolism.

It is known that the neutrophil count and Neutrophil/Lymphocyte Ratio (NLR), are considered indicators of inflammation [11]. Inflammation has been accepted as a mechanism of thrombus formation in the veins. Inflammation triggers the coagulation system particularly by inducing the release of tissue factor. It is significant that neutrophils activate neutrophil Extracellular Traps (NETs) which in turn activate coagulative factor XII and increase tissue factor production. Overall, they lead to activating coagulative and extrinsic pathways [12-16]. There is a higher risk of VTE. The NLR is a simple indicator related to inflammation and could be used to study thrombotic disease occluding both the venous (i.e. VTE) and arterial circulation (arterial thrombosis) [17,18]. Although some study results have determined a relationship between NLR and VTE, the significance of NLR is still being debated although results from clinical and experimental studies (i.e mouse model) have suggested that NLR is an independent prognostic factor for pulmonary embolism^, [19,20]. NLR was not associated with the risk of first time or recurrent VTE. Hu, et al. found that a high NLR can be considered a diagnostic marker for VTE [21] while Artoni et al suggested that a high NLR was not related to an increased risk of VTE [22]. 

Farah, et al. claimed that a high NLR could be a predictor of acute VTE [23]. Monocytes can contribute to the development of thrombosis because of the release of pro-inflammatory cytokines, and they can interact with platelets and endothelial cells. The role of monocytes in the pathogenesis of thrombosis (arterial and venous). In our opinion, there seem to be interesting conclusion from a systematic review and meta-analysis of inflammatory biomarkers and venous thromboembolism articles reporting that the neutrophil-lymphocyte ratio increases during the acute phase of VTE and authors have concluded that activated inflammatory biomarkers not only correlated with a higher risk of VTE but they may play a role in the occurrence of VTE in different patient settings [24]. Our study enrolled patients suffering from VTE as well as from VTE with active cancer. Hospitalized patients without VTE and cancer were also considered. Ratios, were higher in VTE patients compared to non-VTE patients. NLR was higher in patients suffering from PE compared to DVT and DVT+PE patients. Diversely, both PLR and MLR values measured in VTE patients including PE, DVT and DVT+PE showed no differences between them. When 4.97 was identified as an optimal cut-off point in the ROC curve analysis of NLR biomarkers we found reliable diagnostic accuracy. We hypothesized that NLR can be considered as having a negative predictive significance (98%) in not suspecting (or diagnosing) PE. We hypothesized that NLR could be a potential marker for excluding PE particularly for patients with a low or moderate Well’s score. It should be emphasized that a number of diseases can raise the levels of the D-dimer results of this study suggesting a potential role for NLR in diagnosing or suspecting both VTE and PE. This can be justified because the D-dimer levels is an intriguing marker for patients with VTE and can be higher in patients suffering from multiple diseases such as those admitted to emergency medical departments and/or to internal medicine units. It is widely known that older patients suffering from multiple chronic diseases are fragile and most frequently hospitalized in internal medicine and/or in emergency medical units and show thromboembolic risk. Based on our results when we take into account both the sensitivity and negative predictive capabilities of NLR, this marker could be helpful in screening for PE risk (or occurrence) in patients showing low or moderate Well’s scores. The negative screening for one of the clinical profiles of VTE (i.e. PE) should lower the number of CT scans with contrast dye. To date, CT scan with contrast dye represents the gold standard in diagnosing PE however, they also show side effects such as transient kidney or acute kidney damage. Thus, there are limits or contraindications particularly for patients suffering from altered renal clearance or with chronic renal insufficiency. In addition, we want to draw attention to two significant questions: a reduced number of CT scan has economic effects as do diagnostic techniques that are expensive and not easily repeatable. Based on our results, we hypothesize evaluating the ratio data in addition to the data from pre-test scores (i.e. Wells, Geneva) which aim to determine the probability of VTE occurrence.

The strength of this study consists in a non-selected population because the patients were referred to various hospital departments and then finally diagnosed as VTE patients based on CT scans. 

The limitation of this study consists in a reduced number of patients enrolled by a single medical center. We encourage more studies encompassing several clinical units to evaluate the role of straightforward cellular markers that are closely related to inflammation which in turn is crucial to the pathophysiological key in explaining the thrombotic phenomenon.

Authors declare non conflict of interest.

SSS: Planning, recruiting, writing, revising; DPM: Recruiting, revising; CG: Recruiting, revising; FM: Statistical analysis, revising; CD: Recruiting, revising.

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