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High Serum Soluble Fas Ligand Levels in Non-survivor Traumatic Brain Injury Patients

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Abstract

Purpose

Soluble Fas Ligand (sFasL) is one of the main ligands that activates the apoptosis extrinsic pathway. Higher expression of FasL in brain samples and higher cerebrospinal fluid FasL concentrations in traumatic brain injury (TBI) patients than in controls have been found. However, the potential association between blood sFasL concentrations and TBI mortality has not been reported. Therefore, the objective of this study was to determine whether that association exists.

Methods

We included patients with a severe isolated TBI, defined as < 9 points in Glasgow Coma Scale (GCS) and < 10 non-cranial aspects points in Injury Severity Score in this observational and prospective study performed in 5 Intensive Care Units. We measured serum sFasL concentrations on day 1 of TBI.

Results

We found that 30-day survivor (n = 59) in comparison to non-survivor patients (n = 24) had higher GCS (p = 0.001), lower age (p = 0.004), lower APACHE-II score (p < 0.001), lower intracranial pressure (ICP) (p = 0.01), lower computer tomography (CT) findings of high risk of death (p = 0.02) and lower serum sFasL concentrations (p < 0.001). The area under the curve for mortality prediction by serum sFasL levels was of 75% (95% CI = 63%–87%; p < 0.001). In Kaplan–Meier analysis was found that patients with serum sFasL levels > 29.2 pg/mL had a higher mortality rate (Hazard ratio = 6.2; 95% CI = 2.6–14.8; p < 0.001). Multiple logistic regression analysis found an association between serum sFasL levels and mortality after controlling for GCS, age and CT findings (OR = 1.055; 95% CI = 1.018–1.094; p = 0.004), and after controlling for APACHE-II, ICP and CT findings (OR = 1.048; 95% CI = 1.017–1.080; p = 0.002).

Conclusions

The association between serum sFasL levels and 30-day mortality in TBI patients was the major novel finding of our study; however, future validation could be interesting to confirm those results.

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Abbreviations

TBI:

Traumatic brain injury

GCS:

Glasgow Coma Scale

ISS:

Injury Severity Score

PaO2 :

Pressure of arterial oxygen/fraction inspired oxygen

FIO2 :

Pressure of arterial oxygen/fraction inspired oxygen

aPTT:

Activated partial thromboplastin time

APACHE II:

Acute Physiology and Chronic Health Evaluation

References

  1. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons. Guidelines for the management of severe traumatic brain injury. J Neurotrauma. 2007;24:S1-106.

    Article  Google Scholar 

  2. Zhang X, Chen Y, Jenkins LW, Kochanek PM, Clark RS. Bench-to-bedside review: apoptosis/programmed cell death triggered by traumatic brain injury. Crit Care. 2005;9:66–75.

    Article  CAS  Google Scholar 

  3. Kunz A, Dirnagl U, Mergenthaler P. Acute pathophysiological processes after ischaemic and traumatic brain injury. Best Pract Res Clin Anaesthesiol. 2010;24:495–509.

    Article  CAS  Google Scholar 

  4. Cavallucci V, D’Amelio M. Matter of life and death: the pharmacological approaches targeting apoptosis in brain diseases. Curr Pharm Des. 2011;17:215–29.

    Article  CAS  Google Scholar 

  5. Wang K, Liu B, Ma J. Research progress in traumatic brain penumbra. Chin Med J (Engl). 2014;127:1964–8.

    Google Scholar 

  6. Rovegno M, Soto PA, Sáez JC, von Bernhardi R. Biological mechanisms involved in the spread of traumatic brain damage. Med Intensiva. 2012;36:37–44.

    Article  CAS  Google Scholar 

  7. Glushakova OY, Glushakov AA, Wijesinghe DS, Valadka AB, Hayes RL, Glushakov AV. Prospective clinical biomarkers of caspase-mediated apoptosis associated with neuronal and neurovascular damage following stroke and other severe brain injuries: Implications for chronic neurodegeneration. Brain Circ. 2017;3:87–108.

    PubMed  PubMed Central  Google Scholar 

  8. Zhang X, Graham SH, Kochanek PM, Marion DW, Nathaniel PD, Watkins SC, Clark RSB. Caspase-8 expression and proteolysis in human brain after severe head injury. FASEB J. 2003;17:1367–9.

    Article  CAS  Google Scholar 

  9. Miñambres E, Ballesteros MA, Mayorga M, Marin MJ, Muñoz P, Figols J, López-Hoyos M. Cerebral apoptosis in severe traumatic brain injury patients: an in vitro, in vivo, and postmortem study. J Neurotrauma. 2008;25:581–91.

    Article  Google Scholar 

  10. Jiang W, Jin P, Wei W, Jiang W. Apoptosis in cerebrospinal fluid as outcome predictors in severe traumatic brain injury: an observational study. Med (Baltimore). 2020;99:e20922.

    Article  CAS  Google Scholar 

  11. Uzan M, Erman H, Tanriverdi T, Sanus GZ, Kafadar A, Uzun H. Evaluation of apoptosis in cerebrospinal fluid of patients with severe head injury. Acta Neurochir (Wien). 2006;148:157–64.

    Article  Google Scholar 

  12. Lenzlinger PM, Marx A, Trentz O, Kossmann T, Morganti-Kossmann MC. Prolonged intrathecal release of soluble Fas following severe traumatic brain injury in humans. J Neuroimmunol. 2002;122:167–74.

    Article  CAS  Google Scholar 

  13. Crespo AR, Da Rocha AB, Jotz GP, Schneider RF, Grivicich I, Pinheiro K, Zanoni C, Regner A. Increased serum sFas and TNFalpha following isolated severe head injury in males. Brain Inj. 2007;21:441–7.

    Article  Google Scholar 

  14. Qiu J, Whalen MJ, Lowenstein P, Fiskum G, Fahy B, Darwish R, Aarabi B, Yuan J, Moskowitz MA, MA, . Upregulation of the Fas receptor death-inducing signaling complex after traumatic brain injury in mice and humans. J Neurosci. 2002;22:3504–11.

    Article  CAS  Google Scholar 

  15. Ertel W, Keel M, Stocker R, Imhof HG, Leist M, Steckholzer U, Tanaka M, Trentz O, Nagata S. Detectable concentrations of Fas ligand in cerebrospinal fluid after severe head injury. J Neuroimmunol. 1997;80:93–6.

    Article  CAS  Google Scholar 

  16. Baker SP, O’Neill B, Haddon W Jr, Long WB. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. J Trauma. 1974;14:187–96.

    Article  CAS  Google Scholar 

  17. Teasdale G, Jennett B. Assessement of coma and impaired consciousness. A practical scale. Lancet. 1974;2:81–4.

    Article  CAS  Google Scholar 

  18. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818–29.

    Article  CAS  Google Scholar 

  19. Marshall LF, Marshall SB, Klauber MR, Van Berkum CM, Eisenberg H, Jane JA, Luerssen TG, Marmarou A, Foulkes MA. The diagnosis of head injury requires a classification based on computed axial tomography. J Neurotrauma. 1992;9(Suppl 1):S287-292.

    PubMed  Google Scholar 

  20. Kleinbaum DG, Kupper LL, Muller KE, Nizam A. Polynomial regression. In: Kleinbaum DG, Kupper LL, Muller KE, Nizam A, editors. Applied regression analysis and other multivarible methods. California: Duxbury Press; 1998. p. 281–316.

    Google Scholar 

  21. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3:32–5.

    Article  CAS  Google Scholar 

  22. Yin XH, Yan JZ, Yang G, Chen L, Xu XF, Hong XP, Wu SL, Hou XY, Zhang GY. PDZ1 inhibitor peptide protects neurons against ischemia via inhibiting GluK2-PSD-95-module-mediated Fas signaling pathway. Brain Res. 2016;1637:64–70.

    Article  CAS  Google Scholar 

  23. Yin XH, Han YL, Zhuang Y, Yan JZ, Li C. Geldanamycin inhibits Fas signaling pathway and protects neurons against ischemia. Neurosci Res. 2017;124:33–9.

    Article  CAS  Google Scholar 

  24. Ullah I, Chung K, Oh J, Beloor J, Bae S, Lee SC, Lee M, Kumar P, Lee SK. Intranasal delivery of a Fas-blocking peptide attenuates Fas-mediated apoptosis in brain ischemia. Sci Rep. 2018;8:15041.

    Article  Google Scholar 

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Acknowledgments

This study was supported by a grant from Instituto de Salud Carlos III (PI-18-00500) (Madrid, Spain) and co-financed with Fondo Europeo de Desarrollo Regional (FEDER). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Funding

This study was supported by a grant from Instituto de Salud Carlos III (PI-18–00500) (Madrid, Spain) and co-financed with Fondo Europeo de Desarrollo Regional (FEDER).

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Authors and Affiliations

  1. Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, 38320, Santa Cruz de Tenerife, Spain

    Leonardo Lorente, Judith Cabrera & Andrea Alvarez-Castillo

  2. Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Crta del Rosario s/n, 38010, Santa Cruz de Tenerife, Spain

    María M. Martín

  3. Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, 38320, Tenerife, Spain

    Antonia Pérez-Cejas, Agustín F. González-Rivero & Carmen Ferrer-Moure

  4. Intensive Care Unit, Hospital General de La Palma, Buenavista de Arriba, s/n, Breña Alta, 38713, La Palma, Spain

    Luis Ramos-Gómez

  5. Intensive Care Unit, Hospital Universitario Dr. Negrín, CIBERES, Barranco de La Ballena s/n, 35010, Las Palmas de Gran Canaria, Spain

    Jordi Solé-Violán

  6. Intensive Care Unit, Hospital Insular, Plaza Dr. Pasteur s/n, 35016, Las Palmas, Spain

    Juan J. Cáceres

  7. Research Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, 38320, Santa Cruz de Tenerife, Spain

    Alejandro Jiménez

Authors
  1. Leonardo Lorente
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  2. María M. Martín
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  3. Antonia Pérez-Cejas
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  4. Agustín F. González-Rivero
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  6. Jordi Solé-Violán
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  7. Juan J. Cáceres
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  8. Judith Cabrera
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  9. Andrea Alvarez-Castillo
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  10. Carmen Ferrer-Moure
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  11. Alejandro Jiménez
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Contributions

LL conceived, designed and coordinated the study, participated in acquisition of data, and drafted the manuscript; MMM, LRG, JSV, JJC, JC and AAC participated in acquisition of data and provided useful suggestions; APC, AFGR and CFM carried out serum sFasL levels determinations and provided useful suggestions; AJ interpreted the data and provided useful suggestions; all authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Leonardo Lorente.

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Conflict of interest

The authors declare that they have no competing interests.

Informed Consent

This study was carried after the approval of Institutional Review Board of all participating hospitals and with the written informed consent from legal guardians of patients.

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Lorente, L., Martín, M.M., Pérez-Cejas, A. et al. High Serum Soluble Fas Ligand Levels in Non-survivor Traumatic Brain Injury Patients. Neurocrit Care 35, 249–254 (2021). https://doi.org/10.1007/s12028-020-01158-0

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  • DOI: https://doi.org/10.1007/s12028-020-01158-0

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