Elevated soluble thrombomodulin is associated with organ failure and mortality in children with acute respiratory distress syndrome (ARDS): a prospective observational cohort study

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Abstract

Introduction

The significance of endothelial injury in children with the acute respiratory distress syndrome (ARDS) has not been well studied. Plasma levels of soluble thrombomodulin (sTM), an endothelial surface protein involved in coagulation, have been associated with endothelial injury. We hypothesized that elevated plasma sTM would correlate with mortality and organ failure in children with ARDS.

Methods

We conducted a multicenter prospective observational study of pediatric patients with ARDS between 2008 and 2014. sTM was measured in plasma collected less than 24 hours from ARDS diagnosis. Outcomes were intensive care unit mortality and organ dysfunction by pediatric logistic organ dysfunction scores. Logistic regression was used to adjust for clinically relevant covariates.

Results

Plasma sTM was higher in patients with indirect lung injury compared to direct lung injury (100 ng/mL vs. 86 ng/mL, p = 0.02). Increased sTM levels were correlated with more organ dysfunction in the entire study population (Spearman’s rho = 0.37, p < 0.01). Overall mortality was 16 %. sTM levels were associated with increased mortality in patients with indirect lung injury (OR 2.7 per log(sTM), p = 0.02). These relationships were independent of age, oxygenation defect, or presence of acute kidney injury.

Conclusion

Elevated plasma sTM levels are associated with organ dysfunction in children with ARDS and with higher mortality in children with indirect lung injury. These findings highlight the importance of endothelial injury in children with ARDS and may guide the development of future therapies targeted toward endothelial stabilization, repair, or functional replacement in this population.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-1145-9) contains supplementary material, which is available to authorized users.

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Most cited references 29

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A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation.

James K. Tsuruta, Mark Crowther, Howard Levy … (2013)

To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation. Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial. Two hundred and thirty-three ICUs in 17 countries. All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score. Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity. A total of 750 patients were randomized, nine of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between the two groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran-Mantel-Haenszel two-sided p value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event-free and alive days between the two groups. d-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline. ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.

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Dysfunction of endothelial protein C activation in severe meningococcal sepsis.

Vadim Levin, C Esmon, S Kondaveeti … (2001)

Impairment of the protein C anticoagulation pathway is critical to the thrombosis associated with sepsis and to the development of purpura fulminans in meningococcemia. We studied the expression of thrombomodulin and the endothelial protein C receptor in the dermal microvasculature of children with severe meningococcemia and purpuric or petechial lesions. We assessed the integrity of the endothelium and the expression of thrombomodulin and the endothelial protein C receptor in biopsy specimens of purpuric lesions from 21 children with meningococcal sepsis (median age, 41 months), as compared with control skin-biopsy specimens. The expression of endothelial thrombomodulin and of the endothelial protein C receptor was lower in the patients with meningococcal sepsis than in the controls, both in vessels with thrombosis and in vessels without thrombosis. On electron microscopical examination, the endothelial cells were generally intact in both thrombosed and nonthrombosed vessels. Plasma thrombomodulin levels in the children with meningococcal sepsis (median, 6.4 ng per liter) were higher than those in the controls (median, 3.6 ng per liter; P=0.002). Plasma levels, protein C antigen, protein S antigen, and antithrombin antigen were lower than those in the controls. In two patients treated with unactivated protein C concentrate, activated protein C was undetectable at the time of admission, and plasma levels remained low. In severe meningococcal sepsis, protein C activation is impaired, a finding consistent with down-regulation of the endothelial thrombomodulin-endothelial protein C receptor pathway.

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Author and article information

Contributors

Benjamin E. Orwoll:

ORCID: http://orcid.org/0000-0002-5023-3385

(415) 476-3690 , orwoll@ucsf.edu

Aaron C. Spicer: aspicer@partners.org

Matt S. Zinter: Matt.Zinter@ucsf.edu

Mustafa F. Alkhouli: Mustafa.Alkhouli@ucsf.edu

Robinder G. Khemani: RKhemani@chla.usc.edu

Heidi R. Flori: hflori@mail.cho.org

John M. Neuhaus: John.Neuhaus@ucsf.edu

Carolyn S. Calfee: Carolyn.Calfee@ucsf.edu

Michael A. Matthay: MatthayM@anesthesia.ucsf.edu

Anil Sapru: Anil.Sapru@ucsf.edu

Journal

Journal ID (nlm-ta): Crit Care

Title: Critical Care

Publisher: BioMed Central (London )

ISSN (Print): 1364-8535

ISSN (Electronic): 1466-609X

Publication date (Electronic): 14 December 2015

Publication date PMC-release: 14 December 2015

Publication date (Print): 2015

Volume: 19

Electronic Location Identifier: 435

Affiliations

[ ]Department of Pediatrics, Division of Critical Care, University of California, San Francisco Benioff Children’s Hospital, 550 16th St, Box 0106, San Francisco, CA 94143 USA

[ ]Division of Pediatric Critical Care, University of California, San Francisco Benioff Children’s Hospital, 747 52nd St., Oakland, 94609 CA USA

[ ]Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, 55 Fruit St., Boston, 02114 MA USA

[ ]Department of Anesthesiology and Critical Care Medicine, Children’s Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, 90027 CA USA

[ ]Department of Epidemiology and Biostatistics, University of California, San Francisco School of Medicine, 550 16th St., San Francisco, 94158 CA USA

[ ]Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, 555 Mission Bay Blvd. South, San Francisco, 94158 CA USA

Author information

Benjamin E. Orwoll http://orcid.org/0000-0002-5023-3385

Article

Publisher ID: 1145

DOI: 10.1186/s13054-015-1145-9

PMC ID: 4699329

PubMed ID: 26652251

SO-VID: 0b8ffb68-6a4c-4a0d-b739-d47f8151414a

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. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 16 September 2015

Date accepted : 20 November 2015

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;

Award ID: HL085526

Award ID: HL114484

Award ID: R37HL51856

Award Recipient : Michael A. Matthay Anil Sapru

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ScienceOpen disciplines: Emergency medicine & Trauma

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ScienceOpen disciplines: Emergency medicine & Trauma

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Elevated soluble thrombomodulin is associated with organ failure and mortality in children with acute respiratory distress syndrome (ARDS): a prospective observational cohort study

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Abstract

Introduction

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Results

Conclusion

Electronic supplementary material

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Irish Journal of Paramedicine

Most cited references 29

A Wilcoxon-type test for trend.

A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation.

Dysfunction of endothelial protein C activation in severe meningococcal sepsis.

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Cited by 23

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