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CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(03): 353-362
DOI: 10.1055/a-1515-9529
Coagulation and Fibrinolysis

Intraperitoneal Activation of Coagulation and Fibrinolysis in Patients with Cirrhosis and Ascites

Johannes Thaler 
1   Division of Haematology and Haemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
,
Ton Lisman
2   Department of Surgery, Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Peter Quehenberger
3   Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
,
Lena Hell
1   Division of Haematology and Haemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
,
Philipp Schwabl
4   Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
5   Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
,
Bernhard Scheiner
4   Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
5   Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
,
Theresa Bucsics
4   Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
5   Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
,
Rienk Nieuwland
6   Laboratory of Experimental Clinical Chemistry, Vesicle Observation Centre, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Cihan Ay
1   Division of Haematology and Haemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
,
Michael Trauner
4   Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
5   Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
,
Ingrid Pabinger
1   Division of Haematology and Haemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
,
Thomas Reiberger
4   Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
5   Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
,
Mattias Mandorfer 
4   Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
5   Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
› Author Affiliations Funding This work was supported by a grant from the Medical Scientific Fund of the Major of the City of Vienna (No. 15062), the Austrian Science Fund (FWF) Special Research Program SFB-F54, and by an unrestricted travel grant from the European Hematology Association (EHA).
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Abstract

Development of ascites is the most common form of decompensation of cirrhosis. We aimed to investigate the coagulation system in ascitic fluid and plasma of patients with cirrhosis. We determined coagulation parameters and performed clotting and fibrinolysis experiments in ascitic fluid and plasma of thoroughly characterized patients with cirrhosis and ascites (n = 25) and in plasma of patients with cirrhosis but without ascites (n = 25), matched for severity of portal hypertension. We also investigated plasma D-dimer levels in an independent cohort of patients (n = 317) with clinically significant portal hypertension (HVPG ≥ 10 mmHg), grouped according to ascites severity. Ascitic fluid was procoagulant in a clotting assay. The procoagulant potential of ascitic fluid was abolished by depletion of extracellular vesicles from ascitic fluid by filtration or by addition of a tissue factor-neutralizing antibody. Compared with plasma, extracellular vesicle-associated tissue factor activity was high in ascitic fluid, while activities of other coagulation factors were low. The extracellular vesicle-depleted fraction of ascitic fluid induced fibrinolysis, which was prevented by aprotinin, indicating the presence of plasmin in ascitic fluid. Plasma peak thrombin generation and parameters reflecting fibrinolysis were independently associated with the presence of ascites. Finally, plasma D-dimer levels were independently linked to ascites severity in our second cohort comprising 317 patients. In conclusion, coagulation and fibrinolysis become activated in ascites of patients with cirrhosis. While tissue factor-exposing extracellular vesicles in ascitic fluid seem unable to pass the peritoneal membrane, fibrinolytic enzymes get activated in ascitic fluid and may re-enter the systemic circulation and induce systemic fibrinolysis.

Keywords

cirrhosis - ascites - coagulation - fibrinolysis

Author Contributions

J.T. and M.M. have contributed to the conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, supervision, validation, visualization, writing––original draft, as well as writing—review and editing, and J.T. additionally acquired funding specific to this study. T.L., P.Q., L.H., P.S., B.S., T.B., R.N., C.A., M.T., I.P., and T.R have contributed to data curation, investigation, methodology, resources, and writing—review and editing.


Supplementary Material



Publication History

Received: 05 February 2021

Accepted: 18 May 2021

Accepted Manuscript online:
21 May 2021

Article published online:
04 July 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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