As per the results of this study, Neutrophil-to-lymphocyte ratio was found to be a strong predictor of the need for amputation. In the study conducted by Tasoglu et al, a preoperative NLR value of more than 5.2 was detected to be a stand alone predictive factor of amputation in patients with acute limb ischemia [26]. In the study by Demirtas et al, NLR was found to correlate well with severity in peripheral arterial disease [33]. Yepici et al evaluated the need for amputation in patients with diabetic foot infection and found NLR to be a strong predictor [34]. Dinc et al showed that a higher NLR translated to higher mortality in patients who had to undergo amputation [35]. Spark et al also found that higher NLR level is associated with greater mortality in patients presenting with chronic critical limb ischemia [36].
Neutrophilic infiltrate can cause endothelial damage by releasing various inflammatory mediators and proteolytic enzymes. On the contrary lymphocytes can modify the effect of neutrophils and they also have an anti-atherosclerotic role. Endothelial damage is reported to cause worse outcomes in diabetic wounds. [37]. Lymphocyte activity can augment the collateral circulation and thus could be associated with increased possibility of limb salvage. Lymphocytes also have a modulatory effect on the inflammatory response and augment rate of tissue repair by stimulating production of interleukin-10 [38]. The protective activity of lymphocytes might explain the lower NLR and PLR in those patients with limb ischemia who improve.
The current study also demonstrated the usefulness of PLR and SII as diagnostic markers. In the study by Erdogan et al, NLR and PLR were found to reduce in patients with acute limb ischemia who improve with medical treatment [39]. Saskin et al in their study reported that increased NLR and PLR are found to be associated with extremity amputation in acute arterial occlusions [27]. Gary et al demonstrated that elevated NLR (with a cut off 3.95) and elevated PLR (with a cut off 150) were associated with very high risk for critical limb ischemia in patients with peripheral arterial disease [31, 32]. In the research by Chen et al, it was found that although PLR is an independent risk factor for higher mortality, NLR was considerably more sensitive and also a better marker on the ROC curve [40].
Naturally, higher platelet counts are associated with increased platelet activity [41]. Literature shows that increased platelet activity potentially reflects exaggerated release of inflammatory mediators which in turn promotes destructive inflammatory processes [42]. Higher levels of platelets represent increased thrombosis and also accelerated release of mediators which enhance atherosclerosis and inflammation. It is proven that platelet hyperactivity along with thrombosis plays the major role in the patho-physiology of atherogenesis and thus indirectly contributes to illness and death [43]. Moreover, inflammatory mediators can induce thrombocytosis by stimulating megakaryocytes and therefore, increased levels of platelet may be indicative of pro-thrombotic activity and ongoing inflammatory processes [44].
However, literature search revealed some studies which found a limited role for NLR and PLR also. In a study on hand osteomyelitis, Wyman et al found C-reactive protein(CRP) to be the most sensitive marker and a CRP value greater than 100 mg/L was found strongly associated with sepsis. Total leucocyte count, NLR and also PLR were found to be of limited usefulness in this series [45].
To summarise, when compared with other laboratory parameters used to predict as prognostic markers in inflammation like erythrocyte sedimentation rate, interleukin-6, C-reactive protein and D-dimer levels, NLR is a useful and more practical marker for clinical application. Due to its very low cost and being easily obtained in routine blood tests without any need for special assay equipment, NLR has the potential to be a simple, near real-time, accessible, as well as cost-effective biomarker, especially in the setting of healthcare facilities with limited medical resources.
This study has some limitations. First, being a single centre study with a relatively limited number of subjects, potential presence of selection bias is there. However, we did attempt to reduce such a bias by applying strict inclusion as well as exclusion criteria. Also, because of the retrospective study design, it was impossible to standardise the process or timing of blood collection and hence, there was a potential for disparity between patients. Also, it is worth mentioning that a comparison between the prognostic significance of NLR, PLR and SII and other markers of inflammation or ischaemia- injury like interleukin 6, C-reactive protein, myoglobin or creatinine kinase, would have added additional value.