Platelet-to-lymphocyte ratio predicts short-term mortality in patients with moderate to severe traumatic brain injury

More than 50 million people worldwide suffer from TBI each year, and half of the whole population on earth will experience at least one TBI in their lifetime. However, the treatment and prediction of traumatic brain injury are still big challenges.

The Rotterdam CT score is a method created in 2005 to assess structural brain injury. Compared to the Marshall CT score, Rotterdam CT score added traumatic subarachnoid hemorrhage and intraventricular hemorrhage, simplified the score calculation system, and reduces the assessment difference between emergency department and NICU21. Studies have shown that the Rotterdam CT score can predict the mortality of adults and children TBI patients22,23,24, which is consistent with the results in our study.

At present, the biomarker research related to the prognosis of TBI mostly focuses on the combined detection of cerebrospinal fluid and/or blood. Markers such as S-100β, NSE, GFAP, UCH-L1, NF, Tau, and MBP are increased to different degrees in blood and cerebrospinal fluid after TBI, suggesting neuronal and astrocyte damage11. The detection of high S-100β in blood and cerebrospinal fluid contribute to identify progressive intracranial hemorrhage after TBI, which is associated with mortality and poor prognosis15.

Neuroinflammation is one of the important mechanisms of secondary injury in traumatic brain injury. Studies have shown that a large number of cytokines (TNFα, IL-1β, IL-6, -10, -18 etc.) and chemotaxis (CCL2, 5 and 20, CXCL1, 9 and 10 etc.) can be detected in the cerebrospinal fluid after TBI, which exacerbate oxidative stress and cause persistent neurological damage. For example, IL-18 is associated with disability and cognitive impairment in post-injury patients25. However, the detection of these markers has a high requirement for technology and equipment. Furthermore, the samples of cerebrospinal fluid are obtained through lumbar puncture or ventricular drainage. These repeated operations are invasive and not widely accepted by patients and their family members, resulting in limited clinical application and universalness. The aim of this study was to find a convenient and easy-to-follow biomarker for predicting short-term mortality in TBI.

PLR is the ratio of platelet to lymphocyte count, which can be obtained by routine laboratory calculation, and is easy to monitor. Studies have shown that PLR is associated with systemic non-specific inflammation and can predict poor prognosis of variety diseases, especially tumors, heart failure, etc.19,20,26. Different cut-off levels of PLR have been reported in patients with NSCLC, colorectal cancer and gastric cancer, varying from 150, 160 to 235 27,28,29. Despite the actual value, high pretreatment PLR suggests poor overall survival and progression-free survival in cancer patients, which is a reverse trend for TBI patients in our study. High PLR is also related to all-cause mortality in peritoneal dialysis patients, which has been reported recently30.

To our knowledge, this is the first research studying the relationship of PLR level with short-term mortality in TBI patients with moderate to severe TBI. Low PLR is mainly achieved by decreasing platelet count and increasing lymphocyte count. The primary injury mechanism of TBI leads to the rupture of capillaries and vessels and the destruction of the blood–brain barrier (BBB), triggering the interaction between platelets and endothelial cells or subendothelial matrix. This results in platelet adhesion-activation, and the formation of platelet embolism at the injury site for hemostasis. The balance between coagulation and anticoagulation is broken in moderate to severe TBI patients, leading to platelet overactivation and the number decreases at the early stage of injury. The spontaneous aggregation and subsequent excessive consumption induce secondary platelet depletion and increase bleeding risk. Studies had shown the increasing risk of intracranial hemorrhage progression when the platelet was less than 175 × 109/L31, and nine-fold higher mortality when the number is below 100 × 109/L32.

Huang et al. reported the effect of different gender on PLR ratio to predict cardiovascular mortality of peritoneal dialysis (PD) patients. For female PD patients, high PLR ratio was related to worse prognosis due to higher level of estrogen and low levels of serum iron33. Our study did not find the same effect of gender in our TBI patients. Other confounding variables about PLR incudes alcohol level, smoking and so on. More importantly, in our study, we used both adjusted and non-adjusted Cox regression model as well as ROC curve to test the predicting power of PLR. All results showed that PLR is independent and powerful, which means PLR may not be significantly affected by these confounding variables at least in the case of predicting short-term mortality in patients with moderate to severe TBI.

Lymphocytes are classified into T lymphocytes, B lymphocytes and NK cells according to their origin, morphological structure, surface markers and immune function. They are important cellular components of the body’s immune response. Animal experiments have shown that focal cortical contusion and subcortical neuronal damage occur within minutes after trauma, accompanied by a rapid local neuroinflammatory response34,35. This contributes to immune cells (macrophages, granulocytes, dendritic cells, NK cells etc.) accumulation in the injured area and surrounding tissues. The immune cell-derived cytokines (IL-1β, IL-18, TNFα, etc.) and chemokines (CCL2, CCL22, CCL17, etc.) further recruit immune cells (neutrophils, lymphocytes, lymphocytes, etc.) to the site of injury and coordinate subsequent activities36,37. This kind of immune response generates a self-perpetuating pro-inflammatory environment that damages the brain parenchyma. Peripheral inflammation also affects the outcome of TBI38. Peripheral immune cells rapidly expand and are activated after TBI with remarkable extravasation from spleen. These immune cells contribute to both innate and adaptive immune responses after TBI, with some infiltrating the central nervous system38,39. Once in the damaged brain area, T cells are activated by antigens on macrophages, dendritic cells, and microglia. The steady increase in T cell number and composition suggests a shift from innate non-specific immune to adaptive immune40,41. Decreased PLR level suggests early coagulation imbalance and neuroinflammation hyperactivity, which is independently associated with short-term mortality.

The limitations of our study are: firstly, this study is a single-center study. Secondly, this study is a retrospective cohort study. Although we use the multivariate regression model to reduce the interference, it is still unable to fully guarantee the complete balance and comparability of each group. Finally, further randomized controlled trials are needed to determine the underlying mechanism of the association between PLR and short-term mortality.

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