Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 9  |  Issue : 3  |  Page : 236-242

Role of neutrophil-lymphocyte ratio and mean platelet volume in the outcome of atherosclerotic peripheral vascular disease interventions


Department of Vascular Surgery, Madurai Medical College, Madurai, Tamil Nadu, India

Date of Submission06-Jul-2022
Date of Acceptance28-Jul-2022
Date of Web Publication21-Aug-2022

Correspondence Address:
Sudharsan Reddy Yalamuru
Department of Vascular Surgery, Madurai Medical College, Madurai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijves.ijves_39_22

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  Abstract 


Purpose: Classically, neutrophils have been neglected in the pathophysiology of atherosclerosis. However, recent studies have highlighted their role. Similarly, the role of platelets in peripheral artery disease (PAD) has become evident now. The significance of neutrophil-lymphocyte ratio (NLR) and mean platelet volume (MPV) has been independently studied and found that elevated values are associated with poor outcomes of atherosclerotic peripheral vascular disease interventions. However, the measure of association of NLR and MPV to the outcomes of intervention has not been studied. Hence, this study was undertaken to examine the measure of association of NLR and MPV to the outcomes of atherosclerotic peripheral vascular disease interventions. Methodology: This is a prospective study conducted between January 1, 2020, and September 30, 2021, with 6 months of follow-up. Patients aged 21 years or more, diagnosed to have atherosclerotic peripheral vascular disease, and undergoing interventions (endovascular and open procedure) are included in the study. Patients <21 years, not willing for any intervention, and with acute presentations were excluded. The primary endpoint assessed is graft patency at 6 months, and the secondary endpoints assessed are clinical improvement (which is a combined measure of change in ankle–brachial index, Rutherford grade, and ulcer status) at 1 and 6 months, redo procedure, and amputations within the follow-up period. Results: From January 2020 to September 2021, a total of 156 patients with atherosclerotic peripheral vascular disease fulfilled the inclusion and exclusion criteria. We observed that in 109 (69.9%) patients who had completed 6-month follow-up, 91 (83.5%) patients had graft patency and 18 (16.5%) patients had occluded graft. Independent receiver operating characteristic curve analysis of MPV and NLR showed that lower mean NLR and MPV values (cutoff taken as 10.15 for MPV) are associated with increased graft patency at 6 months than higher mean NLR and MPV values (NLR, P < 0.001; MPV, P = 0.024). Discriminant analysis model developed with MPV and NLR as the set of predictors showed that NLR and MPV together are good predictors of graft patency at 6 months (Wilk's lambda: χ2 = 45.54, P < 0.001). However, logistic regression analysis has shown that, in comparison to NLR, MPV is not a strong predictor of graft patency. Lower mean NLR value was associated with lower amputation rate (P < 0.001), lower mortality rate (P < 0.001), and higher clinical improvement rate at 1st month (P < 0.001) and at 6 months (P < 0.001) than patients with higher mean NLR. However, there was no statistically significant difference between two groups in predicting chance of redo procedure (P = 0.424). There was no statistically significant difference between the mean MPV values among patients who underwent amputation (P = 0.864), died (P = 0.640), or had redo procedure (P = 0.883), except for clinical improvement outcome where lower mean MPV value was associated with higher rate of clinical improvement at 1st month (P < 0.001) and 6 months (P < 0.001) than higher mean MPV value. Conclusion: In patients with atherosclerotic peripheral vascular disease, NLR value is a better predictor of outcomes after intervention than MPV, and lower mean NLR values are associated with increased rate of graft patency, clinical improvement, fewer amputations, and deaths.

Keywords: Atherosclerotic peripheral vascular disease, mean platelet volume, neutrophil-lymphocyte ratio


How to cite this article:
Balaji S K, Robinson C S, Yalamuru SR, Kumar SG, Maruthupandian AK, Ahmed SM, Bharat Arun M V, Ray R. Role of neutrophil-lymphocyte ratio and mean platelet volume in the outcome of atherosclerotic peripheral vascular disease interventions. Indian J Vasc Endovasc Surg 2022;9:236-42

How to cite this URL:
Balaji S K, Robinson C S, Yalamuru SR, Kumar SG, Maruthupandian AK, Ahmed SM, Bharat Arun M V, Ray R. Role of neutrophil-lymphocyte ratio and mean platelet volume in the outcome of atherosclerotic peripheral vascular disease interventions. Indian J Vasc Endovasc Surg [serial online] 2022 [cited 2022 Sep 24];9:236-42. Available from: https://www.indjvascsurg.org/text.asp?2022/9/3/236/354075




  Introduction Top


Atherosclerosis is an inflammatory disease of the arterial wall, presenting with myriad systemic features.

Neutrophils in atherosclerosis

  1. The two major pillars in the pathophysiology of atherosclerosis are hyperlipidemia and inflammation which are interconnected.[1],[2] Even though neutrophils are the most abundant leukocyte in circulation, their role in the pathophysiology of atherosclerosis has been neglected. The reasons being their short life span marked ability to undergo phenotypic changes and lack of sensitive and specific detection methods. However, recent studies have provided convincing evidence for the presence of neutrophils in atherosclerotic plaques and their contribution during various stages of atherosclerosis. [Figure 1] depicts the role of neutrophils in the pathogenesis of atherosclerosis.
  2. Figure 1: Role of neutrophils in pathogenesis of atherosclerosis[3]

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    1. Neutrophils are recruited to the atherosclerotic lesion
    2. Activated neutrophils secrete granule proteins such as myeloperoxidase, azurocidin, and proteinase-3, which induce expression of adhesion molecules and permeability changes and limit the bioavailability of nitric oxide, altogether aggravating endothelial dysfunction
    3. Granule proteins induce adhesion and recruitment of inflammatory monocytes
    4. Granule proteins promote macrophage polarization toward a proinflammatory M1 phenotype
    5. Binding α-defensin to low-density lipoprotein (LDL) traps LDL in the vessel wall. Oxidation of LDL through myeloperoxidase-dependent mechanisms enhances foam cell formation which is the prototypical cell in the atherosclerotic plaque.[4]


Why neutrophil-lymphocyte ratio is chosen as an inflammatory marker?

Neutrophil-lymphocyte ratio (NLR) is chosen, in our study, as a marker for inflammation associated with atherosclerosis due to the following two reasons:

  1. Hypercholesterolemia increases the neutrophilic CXCR2 expression and the circulating levels of its ligand CXCL1, thus promoting release of neutrophils from the bone marrow. Hyperlipidemia disturbs the tightly regulated cytokine system controlling neutrophil homeostasis at various levels, ultimately increasing peripheral neutrophil counts[5]
  2. NLR was introduced as a new inflammation marker due to positive correlation between NLR, tumor necrosis factor-alpha (TNF-α), and other inflammatory markers, and the calculation of NLR is very simple and cheap method when compared with the other inflammatory cytokines including interleukin (IL)-6, IL-1β, and TNF-α.[6]


Hence, NLR has been chosen as a marker for inflammation associated with atherosclerosis.

NLR is the ratio of the number of neutrophils to the number of lymphocytes in the peripheral blood. Normal value is 0.78–3.53. Recent studies have shown that NLR is strongly associated with death and other adverse outcomes after intervention for peripheral artery disease (PAD).[7],[8],[9]

Platelets in atherosclerosis

Although traditionally not conceived as immune cells, platelets hold important functions in the immune response and are involved in the pathogenesis of atherosclerosis. Areas of high shear stress lead to platelet activation which then recruit leukocytes interact with antigen-presenting dendritic cells and contribute to inflammation and atherosclerosis progression. Mean platelet volume (MPV), a measure of platelet size, is an important marker of platelet activity. MPV is a machine-calculated measurement of the average size of platelets found in the blood. Normal range is 9.4–12.3 fL. According to recent studies, MPV is found to be independently associated with PAD.[10]

The significance of NLR and MPV has been independently studied and found that elevated values are associated with poor outcomes after intervention.[11],[12] However, the measure of association of NLR and MPV to the outcomes of intervention has not been studied. Hence, this study was undertaken to examine the measure of association of NLR and MPV to the outcomes of atherosclerotic peripheral vascular disease interventions.


  Methodology Top


This is a prospective study conducted from January 1, 2020, to September 30, 2021, with 6 months of follow-up thereafter. During this period, all the consenting patients satisfying the inclusion and exclusion criteria were selected for the study. Patients aged 21 years or more presenting with symptoms of PAD, with diagnosis confirmed on imaging, and who underwent interventions (endovascular or open procedure) were included in the study. Exclusion criteria are patients <21 years, not willing for any intervention, and with acute presentations. NLR and MPV values of all the patients enrolled in the study are obtained preoperatively and recorded. Reference values used in the study are – normal NLR range 0.78–3.53 and normal MPV range 9.4–12.3 fL.

After preoperative optimization, they were taken up for intervention. Choice of open/endovascular intervention was decided by the team of vascular surgeons, and the same team performed the interventions for all the patients. The primary endpoint assessed is graft patency at 6 months, and the secondary endpoints assessed are clinical improvement at 1 and 6 months and major amputation and redo procedure within the 6-month follow-up period.

Definitions of endpoints

  1. Graft patency: Demonstrated by duplex scanning. Grafts with less than 20% stenosis, peak systolic velocity <150 cm/s, velocity ratio (PSV at lesion/PSV proximal) <1.5, and absent or mild spectral broadening in systole were considered patent[13]
  2. Clinical improvement which is a combined measure of change in ankle–brachial index (ABI), Rutherford grade, and ulcer status is recorded as mentioned below.[14]


    • +3 – Markedly improved: No ischemic symptoms and any foot lesions completely healed; ABI essentially “normalized” (increased to more than 0.90)
    • +2 – Moderately improved: No open foot lesions; still symptomatic but only with exercise and improved by at least one category; ABI not normalized but increased by more than 0.10
    • +1 – Minimally improved: >0.10 increase in ABI but no categorical improvement or vice versa (i.e., upward categorical shift without an increase in ABI of more than 0.10)
    • 0 – No change: No categorical shift and <0.10 changes in ABI
    • −1 – Mildly worse: No categorical shift but ABI decreased more than 0.10, or downward categorical shift with ABI decrease <0.10
    • −2 – Moderately worse: One category worse or unexpected minor amputation
    • −3 – Markedly worse: More than one category worse or unexpected major amputations.


  3. Major amputation is defined as amputation proximal to tarsometatarsal joint
  4. Redo procedure - Redo surgery or endovascular intervention within 6 months.


Statistical analysis

All the statistical analysis was performed using IBM Corp. released 2010. IBM SPSS Statistics for Windows, Version 19.0. (Armonk, NY: IBM Corp). The categorical variables in the study were summarized as frequency and percentage. The continuous variables in the study were summarized as mean with standard deviation. To find the optimum cutoff for MPV in predicting the graft patency, receiver operating characteristic curve (ROC) was plottedfor the continuous variable MPV in predicting the graft patency, the area under this curve was estimated. Consequently, a cut-off point was chosen from the values of MPV, for which both the sensitivity and specificity was high in predicting the graft patency. This cut-off is termed as optimum. Logistic regression model and discriminant analysis function were modeled for estimating the predictive ability of MPV and NLR in graft patency. AUC values for ROC curves were estimated for comparison. The mean values of NLR and MPV were compared between secondary outcomes using independent Student's t-test. Spearman's rank correlation was estimated to assess the linear relationship between NLR and MPV with clinical improvement scores. All the analysis was performed at 5% level of significance, and a P < 0.05 was considered statistically significant.


  Results Top


Among 156 patients, 148 were male (94.87%) and 8 were female (5.12%). The mean age of the study population is 53.59 (10.14). Among the study population, 56 (35.89%) patients were diabetic, 24 (15.38%) had hypertension, coronary artery disease was seen in 12 (7.69%), history of chronic obstructive pulmonary diseases, bronchial asthma, and tuberculosis was present in 10 (6.41%), history of stroke was present in 4 (2.56%), and 2 (1.28%) patients had chronic kidney disease. Clinically, 16 (10.25%) patients belonged to Rutherford Grade 3, 16 (10.25%) belonged to Rutherford Grade 4, 84 (53.84%) patients were in Rutherford Grade 5, and 40 (25.64%) had with Rutherford Grade 6 disease. Aorto iliac lesions were seen in 46 (29.48%) patients, whereas 73 (46.79%) patients had femoropopliteal lesions and 29 (18.58%) had tibial lesions. Eight (5.12%) patients had aneurysms of the abdominal and thoracic aorta. Of the study population, 102 (65.38%) patients underwent open surgical repair, 42 (26.92%) patients underwent endovascular intervention, and 12 (7.69%) had hybrid procedure [Table 1]. Of 156 patients, 109 (69.9%) patients were able to complete 6-month follow-up, as 38 (24.35%) patients died and 9 (5.76%) were lost to follow-up.
Table 1: The study population

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Graft patency

In our study, out of the total 156 patients, the mean NLR value of the patients was 3.82 (2.81) units and the mean MPV value of the patients was 9.31 (1.46) units. We observed that in 109 (69.9%) patients who had completed the 6 months of follow-up, 91 (83.5%) patients had graft patency and 18 (16.5%) patients had occluded graft.

A ROC curve was plotted to assess the discriminative ability of MPV in predicting graft patency and to find the optimum cutoff for the same [Figure 2]. The AUC for MPV was estimated to be 0.669 (95% confidence interval [CI]: 0.509, 0.830) which came out to be statistically significant (P = 0.024) [Table 2]. Consequently, a cut-off point was chosen from the values of MPV, with a sensitivity and specificity of 66.7% and 76.9% respectively in predicting the graft patency. This cut-off (10.15) is termed as optimum.
Figure 2: ROC curve analysis to assess the discriminative ability of MPV in predicting graft patency, ROC: Receiver operating characteristic curve

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Table 2: Receiver operating characteristic curve analysis of neutrophil-lymphocyte ratio and mean platelet volume in predicting graft patency

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A ROC curve was plotted to assess the discriminative ability of NLR in predicting graft patency and to find the optimum cutoff for the same [Figure 3]. The area under the curve for NLR was estimated to be 0.828 (95% CI: 0.696, 0.961) which came out to be statistically significant (P value <0.001) and specificity of NLR was estimated to be 77.8% and 84.6% respectively [Table 2].
Figure 3: ROC curve analysis to assess the discriminative ability of NLR in predicting graft patency. ROC: Receiver operating characteristic curve, NLR: Neutrophil-lymphocyte ratio

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A logistic regression analysis was also performed with MPV and NLR as the independent variables in predicting the graft patency [Figure 4]. The odds ratio (OR) for NLR was estimated to be 0.43 (95% CI: 0.292, 0.619) which was statistically significant (P < 0.001) whereas the OR for MPV was estimated to be 1.02 (95% CI: 0.674, 1.551) which was not statistically significant (P = 0.918) [Table 3]. The ROC curve for the logistic regression model gave the AUC to be 0.826 (95% CI: 0.691, 0.961), which came out to be statistically significant (P < 0.001) [Table 4].
Figure 4: ROC curve for the logistic regression model. ROC: Receiver operating characteristic curve

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Table 3: Logistic regression analysis with mean platelet volume and neutrophil-lymphocyte ratio as the independent variables in predicting the graft patency

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Table 4: Receiver operating characteristic values for logistic regression analysis and discriminant analysis

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A discriminant analysis model was developed with MPV and NLR as the set of predictors to predict the graft patency. The Wilk's lambda, which determines the discriminatory ability of the function, was estimated to be 0.651 which came out to be statistically significant (χ2 = 45.54, P < 0.001). The Eigenvalue of the discriminant function was estimated to be 0.537 with 0.591 as the canonical correlation. The group centroid for occluded group was 1.63 and for patent group was −0.32 for the discriminant function. The discriminant function is given by:

Z = −1.527 + 0.576(NLR) + (−0.036)(MPV)

The ROC curve for the discriminant function [Figure 5] gave the AUC to be 0.827 (95% CI: 0.692, 0.962) which came out to be statistically significant (P < 0.001) [Table 4].
Figure 5: ROC curve for the discriminant function analysis. ROC: Receiver operating characteristic curve

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Secondary outcomes

The mean values of NLR and MPV were compared using independent Student's t-test between patients who had amputation and those who did not during the follow-up time [Table 5]. The mean NLR for those who had amputation was 6.32 (3.17) whereas for those who did not have amputation was 3.54 (2.64), which came out to be significantly different between the two groups (P < 0.001). The mean MPV for those who had amputation was estimated to be 9.37 (2.01) whereas for those who did not have amputation was 9.31 (1.39), which was not statistically different between the groups (P = 0.864).
Table 5: Comparison of secondary outcomes

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The mean values of NLR and MPV were compared using independent Student's t-test between patients who died and those who did not die during the follow-up period [Table 5]. The mean NLR for those who died was 5.68 (3.79) whereas for those who did not die was 3.22 (2.12), which came out to be significantly different between the two groups (P < 0.001). The mean MPV for those who died was estimated to be 9.21 (1.41) whereas for those who did not die was 9.34 (1.48), which was not statistically different between the groups (P = 0.640).

The mean values of NLR and MPV were compared using independent Student's t-test between patients who had undergone intervention again and those who did not in the follow-up period [Table 5]. The mean NLR for those who had intervention again was 4.56 (3.73) whereas for those who did not was 3.79 (2.76), which was not found to be significantly different between the two groups (P = 0.424). The mean MPV for those who underwent redo intervention was estimated to be 9.18 (2.72) whereas for those who did not undergo intervention again was 9.32 (1.36), which was not statistically different between the groups (P = 0.883).

Spearman's rank correlation was performed to assess the linear association between NLR and MPV with clinical improvement at 1st and 6th month [Table 6]. The correlation coefficient between NLR and clinical improvement at 1st month was estimated to be r = −0.552 (P < 0.001) and for clinical improvement at 6th month was estimated to be r = −0.444 (P < 0.001). The correlation coefficient between MPV and clinical improvement at 1st month was estimated to be r = −0.341 (P < 0.001) and for clinical improvement at 6th month was estimated to be r = −0.451 (P < 0.001).
Table 6: Comparison of correlation coefficient between neutrophil-lymphocyte ratio, mean platelet volume with clinical improvement at 1 and 6 months

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  Discussion Top


PAD of the lower extremities is a manifestation of a systemic atherosclerotic disease affecting 200 million people globally.[11] These patients can present with claudication or chronic limb-threatening ischemia (rest pain or tissue loss). Patients presenting with nonlifestyle-limiting claudication are managed with the best medical therapy which includes antiplatelet agents, statins, and supervised exercise program. Risk factor modifications, such as smoking cessation and control of comorbid conditions, are also of paramount importance in these patients. However, revascularization is indicated for patients with disabling claudication and individuals presenting with chronic limb-threatening ischemia. The revascularization options available include both endovascular and surgical therapies.

However, restenosis and graft occlusion after revascularization is a major concern that mandates identifying factors of long-term patency. The severity of lesion, type of lesion, type of conduit used, and length of outflow artery in operative procedures are among the predictors of patency rate after peripheral revascularization.[15],[16],[17] Increasing clinical evidence indicates that inflammatory burden also correlates with outcomes for peripheral vascular interventions[18],[19] as inflammation plays a major role in initiation and progression of PAD disease processes. Although revascularization procedures are increasingly being used for the treatment of patients with PAD, there is a paucity of studies that investigate the role of inflammatory markers in the long-term patency rate of intervention. NLR and MPV are two inflammatory markers associated with initiation and progression of atherosclerosis. Multiple studies have shown that elevated values of NLR and MPV values are associated with poor outcomes after intervention.

In our study of 156 patients who underwent interventions for PADs with 109 (69.9%) patients completing the 6-month follow-up, we observed that 91 (83.5%) patients had graft patency and 18 (16.5%) patients had occluded graft. Statistical analysis showed that lower mean NLR is associated with increased graft patency at 6 months than higher mean NLR (P < 0.001) and lower mean NLR value is also associated with lower amputation rate (P < 0.001), lower mortality rate (P < 0.001), and higher clinical improvement rate at 1st month (P < 0.001) and at 6 months (P < 0.001) than in patients with higher mean NLR. However, there was no statistically significant difference between two groups in predicting chance of redo procedure (P = 0.424). Bath et al. demonstrated that preoperative high NLR was strongly associated with in-hospital death (OR 5.4, 95% CI 1.68–17.07) and amputation (OR 2.5, 95% CI 1.65–3.87).[7] Similarly, GonzÁlez-Hernandez et al. in their study found that high NLR values were independent predictors of patency loss (hazard ratio [HR]: 1.77, 95% CI [1.01–3.10], P = 0.04) and worse amputation-free survival (HR: 2.10, 95% CI [1.06–4.14], P = 0.03) rates at 24 months.[20] Bhutta et al.; in their retrospective analysis of 1021 patients who underwent interventions for PAD, found that a preoperative high NLR was associated with increased risk of death.[21]

There was no statistically significant difference between the mean MPV values among patients who underwent amputation (P = 0.864), died (P = 0.640), or had redo procedure (P = 0.883), except for clinical improvement outcome where lower mean MPV value was associated with higher rate of clinical improvement at 1st month (P < 0.001) and 6 months (P < 0.001) than higher mean MPV value. Furthermore, lower mean MPV value (cutoff 10.15) was associated with increased graft patency at 6 months (P = 0.024).However, the logistic regression analysis performed with MPV and NLR as the independent variables in predicting the graft patency showed that the odds ratio for MPV was 1.02 (95% CI: 0.674, 1.551) which was not statistically significant (P = 0.918), whereas the odds ratio for NLR was 0.43 (95% CI: 0.292, 0.619) which was statistically significant (P < 0.001). This suggests that in the presence of NLR as a covariate, MPV was not a significant predictor of graft patency. Even though according to recent studies MPV is found to be independently associated with PAD,[10] in our study in comparison to NLR, MPV was not found to be a strong predictor of graft patency and was unable to predict outcomes such as higher amputation or mortality rate. Dettori et al. in a meta-analysis of 22 studies involving 8832 patients found that among all the indexes (NLR, lymphocyte-to-monocyte ratio, monocyte-to-lymphocyte ratio, MPV, platelet to lymphocyte ratio, red blood cell distribution width) examined, NLR showed the most promising results in predicting amputations and general outcomes of surgical treatments for PAD, as well as postamputation complications and prognosis.[22]

Based on these findings and those of the other similar studies previously mentioned, we propose that higher mean NLR values are associated with poorer outcomes with respect to clinical improvement, graft patency, and limb salvage and have high mortality rate among patients undergoing interventions for atherosclerotic peripheral vascular diseases. These observations stress the need to incorporate NLR into multimodal risk predictor tools for predicting postoperative outcomes and the necessity to formulate protocols for more frequent assessment of graft patency in patients with high preoperative NLR for achieving better limb salvage rates.

Furthermore, these observations open up another avenue for the use of NLR value in PAD, i.e., to study the role of NLR value in predicting the outcomes in intermittent claudicant patients treated with the best medical therapy.

Limitations

The main limitation of this study is the shorter follow-up period of 6 months; hence, the association of NLR and MPV to long-term outcomes could not be studied. NLR values in the postoperative period and the follow-up visits have not been obtained, which might have thrown more light on understanding the role of serial NLR values with respect to outcomes. Other limitations of our study are having fewer patients of PAD other than lower extremity disease and MPV being calculated from a single blood sample, which did not allow assessment of MPV over time. Hence, we plan to extend our study duration to 3 years with 2 years of follow-up postprocedure with serial measurements of NLR and MPV. With a longer study period, more sample size, and serial measurements of NLR and MPV, we aim to overcome these limitations.


  Conclusion Top


From the observations noted in our study, we conclude that preoperative NLR represents a valuable prognostic marker for clinical improvement, graft patency, amputation risk, and mortality in PAD patients undergoing interventions, whereas MPV was not found to be a reliable marker for predicting most immediate and intermediate results of interventions for PAD. We recommend incorporating NLR into a multimodal risk prediction tool for assessing outcomes in PAD patients.

Acknowledgment

We would like to acknowledge the support from VSI in the form of providing a research grant.

Financial support and sponsorship

VSI Research Grant (Arterial category – Young Achiever Award-2020) supported the study.

Conflicts of interest

There are no conflicts of interest.



 
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Dettori P, Mangoni AA, Zinellu A, Carru C, Paliogiannis P. Blood cell count biomarkers, risk, and outcomes of ischemia-related lower limb amputations: Systematic review. Int J Low Extrem Wounds 2020. Available from: https://pubmed.ncbi.nlm.nih.gov/33045850/. [Last accessed on 2022 Jul 06]. doi:10.1177/1534734620961785.  Back to cited text no. 22
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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