Skip to main content

Individualized recombinant human thrombomodulin (ART-123) administration in sepsis patients based on predicted phenotypes

The Original Article was published on 18 December 2018

Letter to the editor

Disseminated intravascular coagulation (DIC) is a relatively common complication of sepsis. The pathophysiology of septic DIC is associated with neutrophil extracellular trap (NET) formation [1] which results in subsequent thrombi formation known as immunothrombosis, especially in the liver. There are at least two known types of NETs; one type known as vital NETs is produced directly by activation of neutrophils on invasion by pathogens. The other type known as suicidal NETs is produced indirectly through the subsequent over-production of cytokines [2]. Vital NETs, which develop as an initial response to the pathogen, are shown to be suppressed by recombinant human thrombomodulin (ART-123), while suicidal NETs are not [1]. Therefore, ART-123 is potentially more effective when it is administered during the early phase of sepsis. In a phase 3 randomized controlled trial, ART-123 failed to show any differences in 28-day mortality compared to placebo [3]. In this trial, only patients with pre-existing coagulopathy were included based on the post hoc analysis of a phase 2 trial which had shown survival difference in this specific subgroup population. It is possible that the administration of ART-123 was too delayed to work effectively, since only patients with pre-existing coagulopathy were included and suicidal NETs were likely already activated in this population. Therefore, it is crucial to determine the cases that will benefit most from ART-123 treatment during the early phase.

There is increasing interest in the classification of sepsis [4] for personalized treatment options. More recently, a large, retrospective analysis based on machine learning method classified phenotypes of patients with sepsis into four clinical types (α, β, γ, and δ) that correlated with host response patterns using demographic data, physical examination findings, and laboratory data on arrival [5]. Of these, patients with the δ phenotype—characterized by liver dysfunction and shock—were more inclined to develop coagulopathy and had a higher mortality rate than those of patients with other phenotypes. Based on the findings of both studies, we hypothesize that patients with this phenotype are potentially most likely to benefit from ART-123. Since the phenotypes can be obtained before the patients develop coagulopathy, ART-123 can be administered during the early phase for those who are expected to develop coagulopathy. Further clinical trials with earlier intervention based on the clinical phenotyping for precision medicine are warranted to demonstrate mortality benefit of this theoretically effective medication for septic DIC.

Availability of data and materials

Not applicable.



Disseminated intravascular coagulation


Neutrophil extracellular traps


  1. Shimomura Y, Suga M, Kuriyama N, Nakamura T, Sakai T, Kato Y, et al. Recombinant human thrombomodulin inhibits neutrophil extracellular trap formation in vitro. J Intensive Care. 2016;4:48.

    Article  Google Scholar 

  2. Yipp BG, Kubes P. NETosis: how vital is it? Blood. 2013;122:2784–94.

    Article  CAS  Google Scholar 

  3. Vincent JL, Francois B, Zabolotskikh I, Daga MK, Lascarrou JB, Kirov MY, et al. Effect of a recombinant human soluble Thrombomodulin on mortality in patients with Sepsis-associated coagulopathy: the SCARLETRandomized clinical trial. JAMA. 2019.

    Article  CAS  Google Scholar 

  4. Zhang Z, Zhang G, Goyal H, Mo L, Hong Y. Identification of subclasses of sepsis that showed different clinical outcomes and responses to amount of fluid resuscitation: a latent profile analysis. Crit Care. 2018;22:347.

    Article  Google Scholar 

  5. Seymour CW, Kennedy JN, Wang S, Chang CH, Elliott CF, Xu Z, et al. Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA. 2019.

    Article  CAS  Google Scholar 

Download references


Not applicable.


This research did not receive any funding.

Author information

Authors and Affiliations



DH and ON were responsible for the conception of the letter. All authors drafted the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Osamu Nishida.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This comment refers to the article available at

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, 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 ( applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hasegawa, D., Nishida, O. Individualized recombinant human thrombomodulin (ART-123) administration in sepsis patients based on predicted phenotypes. Crit Care 23, 231 (2019).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: