Characterization of circulating thrombin in patients with septic shock: a prospective observational study

  • Tobias BecherEmail author
  • Jens Müller
  • Ibrahim Akin
  • Stefan Baumann
  • Ksenija Stach
  • Martin Borggrefe
  • Bernd Pötzsch
  • Dirk Loßnitzer


Septic shock is characterized by a dysregulated response to infection, hypotension and activation of the coagulation system. Markers of coagulation activation are commonly used to diagnose and monitor ensuing coagulopathies. In this study, we sought to determine levels of circulating thrombin in patients with septic shock. To characterize levels of circulating, active thrombin in patients with septic shock. 48 patients with septic shock were included in this prospective, observational study. Blood samples were obtained on admission, day 1, day 3 and day 6. Levels of active thrombin were measured using a standardized, clinically applicable oligonucleotide (aptamer)-based enzyme-capture assay (OECA). Thrombin levels were correlated with established indirect thrombin parameters, conventional coagulation tests, laboratory parameters, patient characteristics and outcome. Elevated levels of thrombin were detected in 27 patients (56.3%) during the course of the study. Thrombin levels were positively correlated with thrombin-antithrombin complexes (r = 0.30, p < 0.05) and negatively associated with FVII levels (r = − 0.28, p < 0.05). Thrombin levels on admission did not predict 30-day mortality (OR 0.82, 95% CI 0.23–2.92, p = 0.77). Circulating levels of active thrombin can be measured in a subset of patients with septic shock. Although thrombin levels are correlated with established markers of coagulation, they do not provide additional prognostic information.


Hemostasis Mortality Sepsis Shock, septic Thrombin 



Analysis of variance


Acute physiology and chronic health evaluation II


Activated protein C


Activated partial thromboplastin time




C-reactive protein




Disseminated intravascular coagulation

F1 + F2

Prothrombin activation fragment F1 + 2


Coagulation factor VII


Intensive care unit


International normalized ratio


Interquartile range


Lower limit of quantification


New oral anticoagulant


Oligonucleotide (aptamer)-based enzyme-capture assay


Protein C




Simplified Acute Physiology Score


Septic coagulopathy


Standard deviation


Tissue factor


Thrombin-antithrombin complexes


Vitamin K antagonist


White blood cell count



The authors thank the Klaus Tschira Charitable Foundation for its kind support. The authors further thank Simone Gasper for expert technical assistance.

Authors’ contributions

TB, SB and DL designed the study and drafted the manuscript. JM and KS analysed and interpreted the data. IA was a major contributor in writing the manuscript. BP, DL, JM and MB revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript


This study was funded by the Klaus Tschira Charitable Foundation (Grant No. 00.271.2015).

Compliance with ethical standards

Conflict of interest

Martin Borggrefe declares financial relations, including speaker honoraria and research grants, with Boston Scientific, Medtronic, Impulse Dynamics, St. Jude Medical, CVRx, Biotronic, Pfizer, Bayer and Böhringer-Ingelheim. All other authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (University of Heidelberg, Germany; reference number 2015-526N-MA) and with the 1964 Helsinki declaration and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Lelubre C, Vincent JL (2018) Mechanisms and treatment of organ failure in sepsis. Nat Rev Nephrol 14(7):417–427CrossRefGoogle Scholar
  2. 2.
    Rhee C, Dantes R, Epstein L et al (2017) Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014. JAMA 318(13):1241–1249CrossRefGoogle Scholar
  3. 3.
    de Grooth HJ, Postema J, Loer SA, Parienti JJ, Oudemans-van Straaten HM, Girbes AR (2018) Unexplained mortality differences between septic shock trials: a systematic analysis of population characteristics and control-group mortality rates. Intensiv Care Med 44(3):311–322CrossRefGoogle Scholar
  4. 4.
    Lyons PG, Micek ST, Hampton N, Kollef MH (2018) Sepsis-associated coagulopathy severity predicts hospital mortality. Crit Care Med 46(5):736–742CrossRefGoogle Scholar
  5. 5.
    Saracco P, Vitale P, Scolfaro C, Pollio B, Pagliarino M, Timeus F (2011) The coagulopathy in sepsis: significance and implications for treatment. Pediatr Rep. 3(4):e30CrossRefGoogle Scholar
  6. 6.
    Mesters RM, Mannucci PM, Coppola R, Keller T, Ostermann H, Kienast J (1996) Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients. Blood 88(3):881–886CrossRefGoogle Scholar
  7. 7.
    Becher T, Muller J, Akin I et al (2018) The evolution of activated protein C plasma levels in septic shock and its association with mortality: a prospective observational study. J Crit Care 47:41–48CrossRefGoogle Scholar
  8. 8.
    Ruhl H, Muller J, Harbrecht U et al (2012) Thrombin inhibition profiles in healthy individuals and thrombophilic patients. Thromb Haemost 107(5):848–853CrossRefGoogle Scholar
  9. 9.
    Muller J, Becher T, Braunstein J et al (2011) Profiling of active thrombin in human blood by supramolecular complexes. Angew Chem Int Ed Engl 50(27):6075–6078CrossRefGoogle Scholar
  10. 10.
    Ruhl H, Winterhagen FI, Berens C, Muller J, Oldenburg J, Potzsch B (2018) In vivo thrombin generation and subsequent APC formation are increased in factor V Leiden carriers. Blood 131(13):1489–1492CrossRefGoogle Scholar
  11. 11.
    Dellinger RP, Levy MM, Rhodes A et al (2013) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 41(2):580–637CrossRefGoogle Scholar
  12. 12.
    Muller J, Becher T, Mayer G, Potzsch B (2016) Aptamer-based enzyme capture assay for measurement of plasma thrombin levels. Methods Mol Biol 1380:179–189CrossRefGoogle Scholar
  13. 13.
    Muller J, Friedrich M, Becher T et al (2012) Monitoring of plasma levels of activated protein C using a clinically applicable oligonucleotide-based enzyme capture assay. J Thromb Haemost 10(3):390–398CrossRefGoogle Scholar
  14. 14.
    Konigsbrugge O, Koder S, Riedl J, Panzer S, Pabinger I, Ay C (2017) A new measure for in vivo thrombin activity in comparison with in vitro thrombin generation potential in patients with hyper- and hypocoagulability. Clin Exp Med 17(2):251–256CrossRefGoogle Scholar
  15. 15.
    Koyama K, Madoiwa S, Nunomiya S et al (2014) Combination of thrombin-antithrombin complex, plasminogen activator inhibitor-1, and protein C activity for early identification of severe coagulopathy in initial phase of sepsis: a prospective observational study. Crit Care 18(1):R13CrossRefGoogle Scholar
  16. 16.
    Simmons J, Pittet JF (2015) The coagulopathy of acute sepsis. Curr Opin Anaesthesiol 28(2):227–236CrossRefGoogle Scholar
  17. 17.
    Takahashi H, Wada K, Niwano H, Shibata A (1992) Comparison of prothrombin fragment 1 + 2 with thrombin-antithrombin III complex in plasma of patients with disseminated intravascular coagulation. Blood Coagul Fibrinolysis 3(6):813–818CrossRefGoogle Scholar
  18. 18.
    Franco RF, de Jonge E, Dekkers PE et al (2000) The in vivo kinetics of tissue factor messenger RNA expression during human endotoxemia: relationship with activation of coagulation. Blood 96(2):554–559CrossRefGoogle Scholar
  19. 19.
    Pawlinski R, Wang JG, Owens AP 3rd et al (2010) Hematopoietic and nonhematopoietic cell tissue factor activates the coagulation cascade in endotoxemic mice. Blood 116(5):806–814CrossRefGoogle Scholar
  20. 20.
    Gando S, Nanzaki S, Sasaki S, Aoi K, Kemmotsu O (1998) Activation of the extrinsic coagulation pathway in patients with severe sepsis and septic shock. Crit Care Med 26(12):2005–2009CrossRefGoogle Scholar
  21. 21.
    Kinasewitz GT, Yan SB, Basson B et al (2004) Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569]. Crit Care 8(2):R82–R90CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.First Department of Medicine, Faculty of Medicine Mannheim, University Medical Center Mannheim (UMM)University of HeidelbergMannheimGermany
  2. 2.Institute for Experimental Haematology and Transfusion Medicine, University of Bonn Medical Center (UKB)BonnGermany

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