Comparison of the source and prognostic utility of cfDNA in trauma and sepsis

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Abstract

Background

Circulating cell-free DNA (cfDNA) may contribute to the pathophysiology of post-injury inflammation and coagulation in trauma. However, the source and mechanism of release of cfDNA in trauma is not well understood. One potential source of cfDNA is from Neutrophil Extracellular Traps (NETs), released by activated neutrophils during the process of NETosis. The primary objective of our study was to determine if cfDNA has prognostic utility in trauma. The secondary objective of this study was to determine the source of cfDNA in trauma compared to sepsis.

Methods

We studied trauma patients from two prospective observational cohort studies: the DNA as a Prognostic Marker in ICU Patients (DYNAMICS) study and the Endotoxin in Polytrauma (ENPOLY) study. We also studied septic patients from the DYNAMICS study. Citrated plasma samples were collected longitudinally from the patients (days 1 to 7). The following molecules were measured in the plasma samples: cfDNA, protein C (PC), myeloperoxidase (MPO) (a marker of neutrophil activation), citrullinated Histone H3 (H3Cit, a marker of NETosis), cyclophilin A (a marker of necrosis), and caspase-cleaved K18 (a marker of apoptosis).

Results

A total of 77 trauma patients were included ( n = 38 from DYNAMICS and n = 39 from ENPOLY). The median age was 49 years; 27.3% were female, and mortality was 16.9% at 28 days. Levels of cfDNA were elevated compared to healthy values but not significantly different between survivors and non-survivors. There was a positive correlation between MPO and cfDNA in septic patients ( r = 0.424, p < 0.001). In contrast, there was no correlation between MPO and cfDNA in trauma patients ( r = – 0.192, p = 0.115). Levels of H3Cit, a marker of NETosis, were significantly elevated in septic patients compared to trauma patients ( p < 0.01) while apoptosis and necrosis markers did not differ between the two groups.

Conclusion

Our studies suggest that the source and mechanism of release of cfDNA differ between trauma and sepsis patients. In sepsis, cfDNA is likely primarily released by activated neutrophils via the process of NETosis. In contrast, cfDNA in trauma appears to originate mainly from injured or necrotic cells. Although cfDNA is elevated in trauma and sepsis patients compared to healthy controls, cfDNA does not appear to have prognostic utility in trauma patients.

Trial registration

ClinicalTrials.gov Identifier: NCT01355042. Registered May 17, 2011

Electronic supplementary material

The online version of this article (10.1186/s40635-019-0251-4) contains supplementary material, which is available to authorized users.

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Most cited references 23

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Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases.

Steffen Massberg, Lenka Grahl, Marie-Luise von Bruehl … (2010)

Blood neutrophils provide the first line of defense against pathogens but have also been implicated in thrombotic processes. This dual function of neutrophils could reflect an evolutionarily conserved association between blood coagulation and antimicrobial defense, although the molecular determinants and in vivo significance of this association remain unclear. Here we show that major microbicidal effectors of neutrophils, the serine proteases neutrophil elastase and cathepsin G, together with externalized nucleosomes, promote coagulation and intravascular thrombus growth in vivo. The serine proteases and extracellular nucleosomes enhance tissue factor- and factor XII-dependent coagulation in a process involving local proteolysis of the coagulation suppressor tissue factor pathway inhibitor. During systemic infection, activation of coagulation fosters compartmentalization of bacteria in liver microvessels and reduces bacterial invasion into tissue. In the absence of a pathogen challenge, neutrophil-derived serine proteases and nucleosomes can contribute to large-vessel thrombosis, the main trigger of myocardial infarction and stroke. The ability of coagulation to suppress pathogen dissemination indicates that microvessel thrombosis represents a physiological tool of host defense.

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Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome.

J C Marshall, D J Cook, N V Christou … (1995)

To develop an objective scale to measure the severity of the multiple organ dysfunction syndrome as an outcome in critical illness. Systematic literature review; prospective cohort study. Surgical intensive care unit (ICU) of a tertiary-level teaching hospital. All patients (n = 692) admitted for > 24 hrs between May 1988 and March 1990. None. Computerized database review of MEDLINE identified clinical studies of multiple organ failure that were published between 1969 and 1993. Variables from these studies were evaluated for construct and content validity to identify optimal descriptors of organ dysfunction. Clinical and laboratory data were collected daily to evaluate the performance of these variables individually and in aggregate as an organ dysfunction score. Seven systems defined the multiple organ dysfunction syndrome in more than half of the 30 published reports reviewed. Descriptors meeting criteria for construct and content validity could be identified for five of these seven systems: a) the respiratory system (Po2/FIO2 ratio); b) the renal system (serum creatinine concentration); c) the hepatic system (serum bilirubin concentration); d) the hematologic system (platelet count); and e) the central nervous system (Glasgow Coma Scale). In the absence of an adequate descriptor of cardiovascular dysfunction, we developed a new variable, the pressure-adjusted heart rate, which is calculated as the product of the heart rate and the ratio of central venous pressure to mean arterial pressure. These candidate descriptors of organ dysfunction were then evaluated for criterion validity (ICU mortality rate) using the clinical database. From the first half of the database (the development set), intervals for the most abnormal value of each variable were constructed on a scale from 0 to 4 so that a value of 0 represented essentially normal function and was associated with an ICU mortality rate of or = 50%. These intervals were then tested on the second half of the data set (the validation set). Maximal scores for each variable were summed to yield a Multiple Organ Dysfunction Score (maximum of 24). This score correlated in a graded fashion with the ICU mortality rate, both when applied on the first day of ICU admission as a prognostic indicator and when calculated over the ICU stay as an outcome measure. For the latter, ICU mortality was approximately 25% at 9 to 12 points, 50% at 13 to 16 points, 75% at 17 to 20 points, and 100% at levels of > 20 points. The score showed excellent discrimination, as reflected in areas under the receiver operating characteristic curve of 0.936 in the development set and 0.928 in the validation set. The incremental increase in scores over the course of the ICU stay (calculated as the difference between maximal scores and those scores obtained on the first day [i.e., the delta Multiple Organ Dysfunction Score]) also demonstrated a strong correlation with the ICU mortality rate. In a logistic regression model, this incremental increase in scores accounted for more of the explanatory power than admission severity indices. This multiple organ dysfunction score, constructed using simple physiologic measures of dysfunction in six organ systems, mirrors organ dysfunction as the intensivist sees it and correlates strongly with the ultimate risk of ICU mortality and hospital mortality. The variable, delta Multiple Organ Dysfunction Score, reflects organ dysfunction developing during the ICU stay, which therefore is potentially amenable to therapeutic manipulation. (ABSTRACT TRUNCATED)

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The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition

Rolf Rossaint, Bertil Bouillon, Vladimir Cerny … (2016)

Background Severe trauma continues to represent a global public health issue and mortality and morbidity in trauma patients remains substantial. A number of initiatives have aimed to provide guidance on the management of trauma patients. This document focuses on the management of major bleeding and coagulopathy following trauma and encourages adaptation of the guiding principles to each local situation and implementation within each institution. Methods The pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma was founded in 2004 and included representatives of six relevant European professional societies. The group used a structured, evidence-based consensus approach to address scientific queries that served as the basis for each recommendation and supporting rationale. Expert opinion and current clinical practice were also considered, particularly in areas in which randomised clinical trials have not or cannot be performed. Existing recommendations were reconsidered and revised based on new scientific evidence and observed shifts in clinical practice; new recommendations were formulated to reflect current clinical concerns and areas in which new research data have been generated. This guideline represents the fourth edition of a document first published in 2007 and updated in 2010 and 2013. Results The guideline now recommends that patients be transferred directly to an appropriate trauma treatment centre and encourages use of a restricted volume replacement strategy during initial resuscitation. Best-practice use of blood products during further resuscitation continues to evolve and should be guided by a goal-directed strategy. The identification and management of patients pre-treated with anticoagulant agents continues to pose a real challenge, despite accumulating experience and awareness. The present guideline should be viewed as an educational aid to improve and standardise the care of the bleeding trauma patients across Europe and beyond. This document may also serve as a basis for local implementation. Furthermore, local quality and safety management systems need to be established to specifically assess key measures of bleeding control and outcome. Conclusions A multidisciplinary approach and adherence to evidence-based guidance are key to improving patient outcomes. The implementation of locally adapted treatment algorithms should strive to achieve measureable improvements in patient outcome. Electronic supplementary material The online version of this article (doi:10.1186/s13054-016-1265-x) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Nicholas L. Jackson Chornenki: Nicholas.jacksonchornenki@medportal.ca

Robert Coke: robert.coke@mail.mcgill.ca

Andrew C. Kwong: andrew.ch.kwong@gmail.com

Dhruva J. Dwivedi: Dhruva.Dwivedi@taari.ca

Michael K. Xu: xum5@mcmaster.ca

Ellen McDonald: emcdonal@mcmaster.ca

John C. Marshall: marshallj@smh.ca

Alison E. Fox-Robichaud: afoxrob@mcmaster.ca

Emmanuel Charbonney: emmanuel.charbonney@umontreal.ca

Patricia C. Liaw: Patricia.Liaw@taari.ca

Journal

Journal ID (nlm-ta): Intensive Care Med Exp

Journal ID (iso-abbrev): Intensive Care Med Exp

Title: Intensive Care Medicine Experimental

Publisher: Springer International Publishing (Cham )

ISSN (Electronic): 2197-425X

Publication date (Electronic): 22 May 2019

Publication date PMC-release: 22 May 2019

Publication date Collection: December 2019

Volume: 7

Electronic Location Identifier: 29

Affiliations

[1 ]ISNI 0000 0004 1936 8227, GRID grid.25073.33, Department of Medicine, , McMaster University, ; Hamilton, ON Canada

[2 ]GRID grid.418562.c, Thrombosis and Atherosclerosis Research Institute, ; Hamilton, ON L8L 2X2 Canada

[3 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Departments of Surgery and Critical Care Medicine, St. Michael’s Hospital, , University of Toronto, ; Toronto, ON Canada

[4 ]ISNI 0000 0001 2292 3357, GRID grid.14848.31, Department of Critical Care Medicine, Hôpital du Sacré-Coeur de Montreal and Hôpital de Trois-Rivières, , University of Montreal, ; Montreal, QC Canada

Article

Publisher ID: 251

DOI: 10.1186/s40635-019-0251-4

PMC ID: 6531595

PubMed ID: 31119471

SO-VID: 8ab195f5-03db-4741-bc36-c34bbf2b2706

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 19 November 2018

Date accepted : 30 April 2019

Funding

Funded by: CIHR

Award ID: MOP-106503

Award ID: MOP-136878

Award Recipient : Patricia C. Liaw

Funded by: FundRef http://dx.doi.org/10.13039/100001422, American Society of Hematology;

Award ID: Physician Scientist Career Development Award

Award Recipient : Nicholas L. Jackson Chornenki

Custom metadata

Keywords: cell-free dna,protein c,traumatic injury,netosis

Data availability:

Keywords: cell-free dna, protein c, traumatic injury, netosis

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Comparison of the source and prognostic utility of cfDNA in trauma and sepsis

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Abstract

Background

Methods

Results

Conclusion

Trial registration

Electronic supplementary material

Related collections

Open source discrete and agent-based modeling frameworks for biology

Most cited references 23

Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases.

Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome.

The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition

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Cited by 30

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