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

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.

Publikationsverlauf

Eingereicht: 05. Februar 2021

Angenommen: 18. Mai 2021

Accepted Manuscript online:
21. Mai 2021

Artikel online veröffentlicht:
04. Juli 2021

• References

• 1 Tripodi A, Primignani M, Mannucci PM, Caldwell SH. Changing concepts of cirrhotic coagulopathy. Am J Gastroenterol 2017; 112 (02) 274-281
• 2 Lisman T, Porte RJ. Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases. Res Pract Thromb Haemost 2017; 1 (02) 150-161
• 3 Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol 2013; 11 (09) 1064-1074
• 4 Lisman T, Bongers TN, Adelmeijer J. et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006; 44 (01) 53-61
• 5 Mandorfer M, Schwabl P, Paternostro R. et al; Vienna Hepatic Hemodynamic Lab. Von Willebrand factor indicates bacterial translocation, inflammation, and procoagulant imbalance and predicts complications independently of portal hypertension severity. Aliment Pharmacol Ther 2018; 47 (07) 980-988
• 6 O'Leary JG, Greenberg CS, Patton HM, Caldwell SH. AGA clinical practice update: coagulation in cirrhosis. Gastroenterology 2019; 157 (01) 34.e1-43.e1
• 7 Intagliata NM, Argo CK, Stine JG, Lisman T, Caldwell SH, Violi F. faculty of the 7th International Coagulation in Liver Disease. Concepts and controversies in haemostasis and thrombosis associated with liver disease: Proceedings of the 7th International Coagulation in Liver Disease Conference. Thromb Haemost 2018; 118 (08) 1491-1506
• 8 D'Amico G, Pasta L, Morabito A. et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment Pharmacol Ther 2014; 39 (10) 1180-1193
• 9 LeVeen HH, Ip M, Ahmed N, Hutto RB, LeVeen EG. Coagulopathy post peritoneovenous shunt. Ann Surg 1987; 205 (03) 305-311
• 10 Agarwal S, Joyner Jr KA, Swaim MW. Ascites fluid as a possible origin for hyperfibrinolysis in advanced liver disease. Am J Gastroenterol 2000; 95 (11) 3218-3224
• 11 Scott-Coombes DM, Whawell SA, Vipond MN, Crnojevic L, Thompson JN. Fibrinolytic activity of ascites caused by alcoholic cirrhosis and peritoneal malignancy. Gut 1993; 34 (08) 1120-1122
• 12 Berckmans RJ, Sturk A, van Tienen LM, Schaap MC, Nieuwland R. Cell-derived vesicles exposing coagulant tissue factor in saliva. Blood 2011; 117 (11) 3172-3180
• 13 Hell L, Wisgrill L, Ay C. et al. Procoagulant extracellular vesicles in amniotic fluid. Transl Res 2017; 184: 12-20
• 14 Berckmans RJ, Nieuwland R, Tak PP. et al. Cell-derived microparticles in synovial fluid from inflamed arthritic joints support coagulation exclusively via a factor VII-dependent mechanism. Arthritis Rheum 2002; 46 (11) 2857-2866
• 15 Franz C, Böing AN, Hau CM. et al. Procoagulant tissue factor-exposing vesicles in human seminal fluid. J Reprod Immunol 2013; 98 (1-2): 45-51
• 16 Akay S, Ozutemiz O, Kilic M. et al. Reabsorption of ascites and the factors that affect this process in cirrhosis. Transl Res 2008; 152 (04) 157-164
• 17 Prentice TC, Siri W, Joiner EE. Quantitative studies of ascitic fluid circulation with tritium-labeled water. Am J Med 1952; 13 (06) 668-673
• 18 Flessner MF. Peritoneal transport physiology: insights from basic research. J Am Soc Nephrol 1991; 2 (02) 122-135
• 19 European Association for the Study of the Liver. Electronic address: [e-mail], European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018; 69 (02) 406-460
• 20 McKEE FW, Wilt Jr WG. et al. The circulation of ascitic fluid; interchange of plasma and ascitic fluid protein as studied by means of C14-labeled lysine in dogs with constriction of the vena cava. J Exp Med 1950; 91 (02) 115-122
• 21 Ardevol A, Ibañez-Sanz G, Profitos J. et al. Survival of patients with cirrhosis and acute peptic ulcer bleeding compared with variceal bleeding using current first-line therapies. Hepatology 2018; 67 (04) 1458-1471
• 22 de Franchis R, Baveno VIF. Baveno VI Faculty. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol 2015; 63 (03) 743-752
• 23 Bennett C, Klingenberg SL, Langholz E, Gluud LL. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database Syst Rev 2014; 2014 (11) CD006640
• 24 Collaborators H-IT. HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet 2020; 395 (10241): 1927-1936
• 25 Martí-Carvajal AJ, Solà I. Antifibrinolytic amino acids for upper gastrointestinal bleeding in people with acute or chronic liver disease. Cochrane Database Syst Rev 2015; 2015 (06) CD006007
• 26 Heidet M, Amathieu R, Audureau E. et al. Efficacy and tolerance of early administration of tranexamic acid in patients with cirrhosis presenting with acute upper gastrointestinal bleeding: a study protocol for a multicentre, randomised, double-blind, placebo-controlled trial (the EXARHOSE study). BMJ Open 2018; 8 (08) e021943
• 27 Spadaro A, Tortorella V, Morace C. et al. High circulating D-dimers are associated with ascites and hepatocellular carcinoma in liver cirrhosis. World J Gastroenterol 2008; 14 (10) 1549-1552
• 28 Saray A, Mesihovic R, Gornjakovic S. et al. Association between high D-dimer plasma levels and ascites in patients with liver cirrhosis. Med Arh 2012; 66 (06) 372-374
• 29 Henderson JM, Stein SF, Kutner M, Wiles MB, Ansley JD, Rudman D. Analysis of Twenty-three plasma proteins in ascites. The depletion of fibrinogen and plasminogen. Ann Surg 1980; 192 (06) 738-742
• 30 Medved L, Nieuwenhuizen W. Molecular mechanisms of initiation of fibrinolysis by fibrin. Thromb Haemost 2003; 89 (03) 409-419
• 31 Gitto S, Romanelli RG, Cellai AP. et al. Altered clot formation and lysis are associated with increased fibrinolytic activity in ascites in patients with advanced cirrhosis. Intern Emerg Med 2021; 16 (02) 339-347
• 32 Zemel D, Koomen GC, Hart AA, ten Berge IJ, Struijk DG, Krediet RT. Relationship of TNF-alpha, interleukin-6, and prostaglandins to peritoneal permeability for macromolecules during longitudinal follow-up of peritonitis in continuous ambulatory peritoneal dialysis. J Lab Clin Med 1993; 122 (06) 686-696
• 33 Zemel D, Betjes MG, Dinkla C, Struijk DG, Krediet RT. Analysis of inflammatory mediators and peritoneal permeability to macromolecules shortly before the onset of overt peritonitis in patients treated with CAPD. Perit Dial Int 1995; 15 (02) 134-141
• 34 Tripodi A, Salerno F, Chantarangkul V. et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005; 41 (03) 553-558
• 35 van der Pol E, Sturk A, van Leeuwen T, Nieuwland R, Coumans F. ISTH-SSC-VB Working group. Standardization of extracellular vesicle measurements by flow cytometry through vesicle diameter approximation. J Thromb Haemost 2018; 16 (06) 1236-1245