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Table of Contents    
ORIGINAL ARTICLE
Year : 2014  |  Volume : 62  |  Issue : 5  |  Page : 498-502

Diagnostic and prognostic significance of suPAR in traumatic brain injury


Intensive Care Unit, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

Date of Submission28-May-2014
Date of Decision24-Aug-2014
Date of Acceptance03-Oct-2014
Date of Web Publication12-Nov-2014

Correspondence Address:
Li Yu
Intensive Care Unit, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430014
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.144439

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 » Abstract 

Background: Soluble urokinase plasminogen activator receptor (suPAR) is a highly sensitive marker that reflects increased inflammation and is positively correlated with pro-inflammatory biomarkers. The aim of this prospective observational study was to explore the relationship between the plasma concentration of suPAR and traumatic brain injury (TBI). Materials and Methods: In all 112 patients with TBI were included. Patients coming within 12 h whose highest abbreviated injury score (AIS) was 3 or less (other than head injury) were considered to be isolated TBI. Blood samples were obtained on admission. In all ninety healthy volunteers were enrolled as control group. Levels of plasma suPAR were determined using an enzyme-linked immunosorbent assay (ELISA) kit according to the manufacturer's instructions. Plasma D-dimer was measured and Glasgow Coma Scale (GCS) score was assessed at the same time. Results: Plasma suPAR values were statistically significantly higher in TBI patients than in controls (patients; 14.89 ± 6.94, controls; 2.79 ± 0.69, P < 0.01). The suPAR levels were strongly associated with the severity of TBI patients. The suPAR levels increased in association with the severity of brain injury, significance being found among all three groups: severe, moderate and mild TBI. The suPAR levels in non-survivals were significantly increased compared to the survivals (P < 0.05). Plasma levels of suPAR were strongly correlated to the GCS score (r = −0.854) and the levels of D-dimer (r = 0.753, both P < 0.01). Receiver operating characteristic curve (ROC) analysis of suPAR levels indicated that suPAR values had a high diagnostic specificity and sensitivity to differentiate survivals from non-survivals, the area underneath the ROC curve (AUROC) was 0.801 (95% CI: 0.698-0.903). The optimal suPAR cut-off value in predicting mortality was 15.70 ng/ml (sensitivity: 70.4%; specificity: 65.9%). Conclusions: Plasma levels of suPAR are elevated in TBI patients. Prognosis was worse in the patient group with elevated suPAR. High suPAR levels indicate a poorer prognosis in TBI patients.


Keywords: Prognosis, soluble urokinase plasminogen activator receptor, traumatic brain injury, urokinase plasminogen activator receptor


How to cite this article:
Yu L, Wu X, Wang H, Long D, Yang J, Zhang Y. Diagnostic and prognostic significance of suPAR in traumatic brain injury. Neurol India 2014;62:498-502

How to cite this URL:
Yu L, Wu X, Wang H, Long D, Yang J, Zhang Y. Diagnostic and prognostic significance of suPAR in traumatic brain injury. Neurol India [serial online] 2014 [cited 2019 Sep 21];62:498-502. Available from: http://www.neurologyindia.com/text.asp?2014/62/5/498/144439

These two authors contributed equally to this work and should be considered co-first authors



 » Introduction Top


Traumatic brain injury (TBI) is common in individuals of all ages with high morbidity and mortality, resulting in tremendous human and financial cost. [1],[2] The TBI refers to any external force inflicted to the head region disrupting the brain functions. [3] The commonest causes of TBI in adults are road traffic accidents (40%) and falls (37%). The incidence of TBI range between 150 and 450 cases/100000/year across the globe. [4],[5],[6] To make a quick, accurate and objective diagnosis in the early stage of TBI, biomarkers have attracted the researchers' attention.

Several biomarkers have been shown to serve as indicators of the severity of TBI. The serum levels of neuron specific enolase (NSE), [7] ubquitin c-terminal hydrolase-L1 (UCH-L1), [8] and Tau protein, [9] all elements of the neuronal damage, as well as of glial cell injury marker, glial fibrillary acidic protein (GFAP) predicts the outcome of TBI. [10] So does the serum levels of S100B protein. [11] On the contrary, although plasma myelin basic protein (MBP) is elevated in almost all the patients with TBI, high MBP level does not indicate a more severe disease. [12]

The urokinase plasminogen activator receptor (uPAR/CD87) is expressed on a number of different cells including monocytes, macrophages and neutrophils. [13] This membrane protein may be released from the cell surface, thus forming a free soluble receptor, soluble urokinase plasminogen activator receptor (suPAR). Plasma levels of suPAR have been shown to be a risk marker in patients with various diseases, like cancer, autoimmune diseases, malaria, tuberculosis, sepsis, and human immunodeficiency virus (HIV) infection. [14],[15],[16],[17],[18],[19],[20],[21],[22] High levels of suPAR are associated with increased risk of mortality and reflect disease severity. [23]

In this study we aimed to characterize plasma suPAR levels in TBI patients compared to healthy individuals in order to reveal if suPAR could be used as a clinical marker in TBI.


 » Materials and Methods Top


Study participants

This study was approved by the research ethical committee of Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology. From January 2011 to January 2014, 112 TBI patients with various stages of disease duration and activity and 90 healthy individuals were enrolled in this study. Patients delivered within 12 h whose highest abbreviated injury score (AIS) was 3 or less (other than head injury) were considered to be isolated TBI cases and were included. Healthy controls were volunteer blood donors and had a negative history of coagulation symptoms and negative status upon detailed physical and routine laboratory examination. Patients with known coagulation disorders, such as deep venous thrombosis or pulmonary embolism, and those on anticoagulant therapies that could result in coagulopathies were excluded. All the patients with TBI were treated in accordance with the principles of treatment. [24] Patients who abandoned treatment due to financial problems or did not coordinate the treatment were excluded.

Laboratory procedures

Blood samples for suPAR and routine laboratory rests (including D-dimer) were drawn on admission and Glasgow Coma Scale (GCS) score was assessed at the same time. Plasma from Ethylene diamine tetraacetic acid (EDTA) anticoagulated fasting blood samples was stored at −80° C until further analysis. Plasma suPAR levels concentrations were measured by the suPARnostic enzyme-linked immunosorbent assay (ELISA) (ViroGates A/S, Birkerψd, Denmark) as per the manufacturer's instructions. The plasma D-dimer level was measured with NycoCard® Reader II (Axis-Shield PoC, Oslo, Norway).

Statistical analysis

Patient data are reported as means ± SD for continuous variables or number/fraction for discrete data. Statistical analysis involving χ2 square tests, Student's t-test, Mann-Whitney U test and Tukey's test. Pearson's correlation coefficient analysis was used to examine the relationship between the GCS score and suPAR levels. We used a receiver operating characteristic (ROC) curve to assess the discriminative power of suPAR in the diagnosis or exclusion of TBI. P < 0.05 were considered significant. All statistical analysis was performed using statistical software Statistical Package for the Social Sciences (SPSS 17.0, SSPS Inc., Chicago, IL, USA). The figures were drawn using GraphPad Prism (GraphPad Software, Version 5.0, San Diego, CA).


 » Results Top


Baseline data

During the study, 112 patients (75 males and 37 females) with TBI met the inclusion criteria. The demographic data is summarized in [Table 1]. The suPAR values were higher in TBI patients than in controls [Table 1]. The mechanisms of injury were categorized into four classes: Traffic accidents, violent assaults, falls and others [Table 1]. The plasma suPAR levels were significantly higher in the patients than healthy individuals. When considering the exact injury sustained by the patients, there was no significant difference in plasma suPAR level (not listed).
Table 1: Clinical characteristics of healthy individuals and traumatic brain injury patients

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Plasma levels of suPAR in patients with TBI

Analysis of the patient group revealed that suPAR levels increased in a linear relation to the severity of brain injury [Table 2] and [Table 3], significance being found among all three groups: Severe, moderate and mild (Tukey's test). The suPAR levels were over two times higher in patients with severe TBI than the patients with non-severe TBI [Table 2] and [Figure 1]. Tukey's test indicated that the suPAR levels of the severe injury group were also significantly different from either the moderate or mild injury group (P < 0.05, [Table 3]). In addition, we assessed the suPAR levels in surviving patients and non-surviving patients. The suPAR levels in non-survivals were significantly increased compared to the survivals (P < 0.05) [Table 4] and [Figure 1].
Figure 1: Plasma suPAR levels in association with injury severity (a) and prognosis (b)

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Table 2: Plasma suPAR levels in association with injury severity

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Table 3: Plasma suPAR levels in association with injury severity (Tukey test)

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Table 4: Plasma suPAR levels in association with prognosis

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Positive correlations were determined between the parameters [suPAR-GCS score in all patients (r=−0.854, P < 0.01), suPAR D-dimer in all patients (r = 0.753, P < 0.01)] [Figure 2].
Figure 2: Correlations between levels of suPAR and GCS score, (a) D-dimer (b) during clinical course

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When the suPAR results were analyzed using the ROC curve method, the area underneath the ROC curve (AUROC) was 0.801 (95% CI: 0.698-0.903), [Figure 3]. The optimal suPAR cut-off value in predicting mortality was 15.70 ng/ml (sensitivity: 70.4%; specificity: 65.9%).
Figure 3: ROC analysis of suPAR values

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 » Discussion Top


This study compared circulating levels of suPAR in patients with TBI. Patients with TBI had higher circulating levels of suPAR compared to healthy volunteers. In addition, suPAR values were higher in non-survivors as compared to survivors and the specific suPAR forms in plasma had independent prognostic value in patients with TBI; high levels were related to poor prognosis. The concentrations of the individual suPAR forms were independently associated with D-dimer and GCS score. In the ROC analysis, suPAR emerged as the best marker for case fatality.

Previous studies showed significantly higher systemic levels of suPAR in critically ill patients as compared with those in healthy controls. [20],[23],[25] The present study also shows that plasma levels of suPAR in TBI patients were higher than in healthy controls as well. Several studies investigated the prognostic value of suPAR in critically ill patients and found systemic levels of suPAR to be predictive of mortality. [19],[20],[21],[22],[23],[26],[27] Our study shows suPAR as a prognostic marker in patients with TBI as well, that is, high levels were related to poor prognosis and low levels to good prognosis.

Although suPAR has proven to have value as a biologic marker in a variety of pathologic conditions, little is known about the biochemical and molecular background of these observations. [14] Morales et al. [28] evaluated the association between traumatic intravascular hemorrhage and post-traumatic outcome using uPA knockout (uPA -/-) transgenic mice or wild-type littermates. They demonstrated that uPA plays a neuroprotective role of the fibrinolytic process following TBI. Although uPA plays a key role in the fibrinolytic pathway, its receptor (uPAR) appears to have little impact on fibrin turnover. [29] Beschorner et al. [30] examined necrotic brain lesions resulting from TBI and focal cerebral infarctions (FCI) by immunohistochemistry in order to investigate the pathophysiological role of uPAR following human brain injury. Following brain damage, uPAR + cells increased significantly and remained elevated until later stages. The uPAR participates in the formation of brain edema and thus contributes to secondary brain damage. The suPAR derives from proteolytic cleavage and release from cell membrane-bound uPAR. [31] In our study, plasma levels of suPAR were significantly higher in TBI patients compared to the controls. And we observed correlation between D-dimer levels and suPAR levels in TBI patients. This finding indirectly indicates that suPAR indeed has a correlation with coagulation.

The limitations of this study are the small sample size and the retrospective nature of the study. This might have introduced a significant bias in patient selection and data collection. There could still be some limitations which we may not have taken into account. The severity of TBI was assessed according to AIS score. The soft tissue injuries could have also possibly triggered the coagulation cascade. Sepsis, which is commonly present in traumatic injury patients, is associated with increased suPAR levels.

In conclusion, our results indicate that suPAR can be used as biochemical marker in predicting the course of TBI. Further studies are needed in this field considering that it can be used in the treatment and predicting response.


 » Acknowledgments Top


We are grateful to the staff of the Department of intensive care unit(ICU), Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology for providing samples and clinical information. We wish to thank all the patients and volunteers who participated in this study.

 
 » References Top

1.
Rezaei S, Asgari K, Yousefzadeh S, Moosavi HA, Kazemnejad E. Effects of neurosurgical treatment and severity of head injury on cognitive functioning, general health and incidence of mental disorders in patients with traumatic brain injury. Arch Trauma Res 2012;1:93-100.  Back to cited text no. 1
    
2.
Algattas H, Huang JH. Traumatic brain injury pathophysiology and treatments: Early, intermediate, and late phases post-injury. Int J Mol Sci 2013;15:309-41.  Back to cited text no. 2
    
3.
Yokobori S, Mazzeo AT, Hosein K, Gajavelli S, Dietrich WD, Bullock MR. Preconditioning for traumatic brain injury. Transl Stroke Res 2013;4:25-39.  Back to cited text no. 3
    
4.
Tsang KK, Whitfield PC. Traumatic brain injury: Review of current management strategies. Br J Oral Maxillofac Surg 2012;50:298-308.  Back to cited text no. 4
    
5.
Tennant A. Admission to hospital following head injury in England: Incidence and socio-economic associations. BMC Public Health 2005;5:21.  Back to cited text no. 5
    
6.
Tagliaferri F, Compagnone C, Korsic M, Servadei F, Kraus J. A systematic review of brain injury epidemiology in Europe. Acta Neurochir (Wien) 2006;148:255-68.  Back to cited text no. 6
    
7.
Kovesdi E, Luckl J, Bukovics P, Farkas O, Pál J, Czeiter E, et al. Update on protein biomarkers in traumatic brain injury with emphasis on clinical use in adults and pediatrics. Acta Neurochir (Wien) 2010;152:1-17.  Back to cited text no. 7
    
8.
Mondello S, Papa L, Buki A, Bullock MR, Czeiter E, Tortella FC, et al. Neuronal and glial markers are differently associated with computed tomography findings and outcome in patients with severe traumatic brain injury: A case control study. Crit Care 201l; 15:R156.  Back to cited text no. 8
    
9.
de Bont JM, Vanderstichele H, Reddingius RE, Pieters R, van Gool SW. Increased total-Tau levels in cerebrospinal fluid of pediatric hydrocephalus and brain tumor patients. Eur J Paediatr Neurol 2008;12:334-41.  Back to cited text no. 9
    
10.
Fraser DD, Close TE, Rose KL, Ward R, Mehl M, Farrell C, et al. Severe traumatic brain injury in children elevates glial fibrillary acidic protein in cerebrospinal fluid and serum. Pediatr Crit Care Med 2011;12:319-24.  Back to cited text no. 10
    
11.
Vos PE, Jacobs B, Andriessen TM, Lamers KJ, Borm GF, Beems T, et al. 1GFAP and Sl00B are biomarkers of traumatic brain injury: An observational cohort study. Neurology 2010;75:1786-93.  Back to cited text no. 11
    
12.
Machado-Vieira R, Yuan P, Brutsche N, DiazGranados N, Luckenbaugh D, Manji HK, et al. Brain-derived neurotrophic factor and initial antidepressant response to an N-methyl-D-aspartate antagonist. J Clin Psychiatry 2009;70:1662-6.  Back to cited text no. 12
    
13.
Blasi F, Carmeliet P. uPAR: A versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002;3:932-43.  Back to cited text no. 13
    
14.
Kjellman A, Akre O, Gustafsson O, Høyer-Hansen G, Lilja H, Norming U, et al. Soluble urokinase plasminogen activator receptor as a prognostic marker in men participating in prostate cancer screening. J Intern Med 2011;269:299-305.  Back to cited text no. 14
    
15.
Ostrowski SR, Ullum H, Goka BQ, Hoyer-Hansen G, Obeng-Adjei G, Pedersen BK, et al. Plasma concentrations of soluble urokinase-type plasminogen activator receptor are increased in patients with malaria and are associated with a poor clinical or a fatal outcome. J Infect Dis 2005;191:1331-41.  Back to cited text no. 15
    
16.
Eugen-Olsen J, Gustafson P, Sidenius N, Fischer TK, Parner J, Aaby P, et al. The serum level of soluble urokinase receptor is elevated in tuberculosis patients and predicts mortality during treatment: A community study from Guinea-Bissau. Int J Tuberc Lung Dis 2002;6:686-92.  Back to cited text no. 16
    
17.
Rabna P, Andersen A, Wejse C, Oliveira I, Gomes VF, Haaland MB, et al. High mortality risk among individuals assumed to be TB negative can be predicted using a simple test. Trop Med Int Health 2009;14:986-94.  Back to cited text no. 17
    
18.
Eugen-Olsen J. suPAR - a future risk marker in bacteremia. J Intern Med 2011;270:29-31.  Back to cited text no. 18
    
19.
Huttunen R, Syrjanen J, Vuento R, Hurme M, Huhtala H, Laine J, et al. Plasma level of soluble urokinase-type plasminogen activator receptor as a predictor of disease severity and case fatality in patients with bacteraemia: A prospective cohort study. J Intern Med 2011;270:32-40.  Back to cited text no. 19
    
20.
Molkanen T, Ruotsalainen E, Thorball CW, Jarvinen A. Elevated soluble urokinase plasminogen activator receptor (suPAR) predicts mortality in Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis 2011;30:1417-24.  Back to cited text no. 20
    
21.
Sidenius N, Sier CF, Ullum H, Pedersen BK, Lepri AC, Blasi F, et al. Serum level of soluble urokinase-type plasminogen activator receptor is a strong and independent predictor of survival in human immunodeficiency virus infection. Blood 2000;96:4091-5.  Back to cited text no. 21
    
22.
Uusitalo-Seppala R, Huttunen R, Tarkka M, Aittoniemi J, Koskinen P, Leino A, et al. Soluble urokinase-type plasminogen activator receptor in patients with suspected infection in the emergency room: A prospective cohort study. J Intern Med 2012;272:247-56.  Back to cited text no. 22
    
23.
Koch A, Voigt S, Kruschinski C, Sanson E, Duckers H, Horn A, et al. Circulating soluble urokinase plasminogen activator receptor is stably elevated during the first week of treatment in the intensive care unit and predicts mortality in critically ill patients. Crit Care 2011;15:R63.  Back to cited text no. 23
    
24.
Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS, Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al. Guidelines for the management of severe traumatic brain injury. I. Blood pressure and oxygenation. J Neurotrauma 2007;24 Suppl: S7-13.  Back to cited text no. 24
    
25.
Kofoed K, Schneider UV, Scheel T, Andersen O, Eugen-Olsen J. Development and validation of a multiplex add-on assay for sepsis biomarkers using xMAP technology. Clin Chem 2006;52:1284-93.  Back to cited text no. 25
    
26.
Kofoed K, Eugen-Olsen J, Petersen J, Larsen K, Andersen O. Predicting mortality in patients with systemic inflammatory response syndrome: An evaluation of two prognostic models, two soluble receptors, and a macrophage migration inhibitory factor. Eur J Clin Microbiol Infect Dis 2008;27:375-83.  Back to cited text no. 26
    
27.
Moller HJ, Moestrup SK, Weis N, Wejse C, Nielsen H, Pedersen SS, et al. Macrophage serum markers in pneumococcal bacteremia: Prediction of survival by soluble CD163. Crit Care Med 2006;34:2561-6.  Back to cited text no. 27
    
28.
Morales D, McIntosh T, Conte V, Fujimoto S, Graham D, Grady MS, et al. Impaired fibrinolysis and traumatic brain injury in mice. J Neurotrauma 2006;23:976-84.  Back to cited text no. 28
    
29.
Mondino A, Blasi F. uPA and uPAR in fibrinolysis, immunity and pathology. Trends Immunol 2004;25:450-5.  Back to cited text no. 29
    
30.
Beschorner R, Schluesener HJ, Nguyen TD, Magdolen V, Luther T, Pedal I, et al. Lesion-associated accumulation of uPAR/CD87- expressing infiltrating granulocytes, activated microglial cells/macrophages and upregulation by endothelial cells following TBI and FCI in humans. Neuropathol Appl Neurobiol 2000;6:522-7.  Back to cited text no. 30
    
31.
Thuno M, Macho B, Eugen-Olsen J. suPAR: The molecular crystal ball. Dis Markers 2009;27:157-72.  Back to cited text no. 31
    


    Figures

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

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

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