Pathophysiological role of prostanoids in coagulation of the portal venous system in liver cirrhosis

Autoři: Alexander Queck aff001;  Dominique Thomas aff002;  Christian Jansen aff003;  Yannick Schreiber aff004;  Sabrina Rüschenbaum aff001;  Michael Praktiknjo aff003;  Katharina Maria Schwarzkopf aff001;  Marcus Maximilian Mücke aff001;  Robert Schierwagen aff001;  Frank Erhard Uschner aff001;  Carsten Meyer aff006;  Joan Clària aff007;  Stefan Zeuzem aff001;  Gerd Geisslinger aff002;  Jonel Trebicka aff001;  Christian Markus Lange aff001
Působiště autorů: Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany aff001;  Institute of Clinical Pharmacology, University Hospital Frankfurt, Frankfurt, Germany aff002;  Department of Internal Medicine 1, University Hospital Bonn, Bonn, Germany aff003;  Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany aff004;  Clinic for Gastroenterology and Hepatology, University Hospital Essen and University Duisburg-Essen, Essen, Germany aff005;  Department of Radiology, University Hospital Bonn, Bonn, Germany aff006;  Department of Biochemistry and Molecular Genetics, Hospital Clinic-IDIBAPS and Department of Biomedical Science, University of Barcelona, Barcelona, Spain aff007;  European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain aff008;  Institute of Clinical Research, Odense University Hospital, University of Southern Denmark, Odense, Denmark aff009;  Institute for Bioengineering of Catalonia, Barcelona, Spain aff010
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222840



Prostanoids are important regulators of platelet aggregation and thrombotic arterial diseases. Their involvement in the development of portal vein thrombosis, frequent in decompensated liver cirrhosis, is still not investigated.


Therefore, we used pro-thrombotic venous milieu generation by bare metal stent transjugular intrahepatic portosystemic shunt insertion, to study the role of prostanoids in decompensated liver cirrhosis. Here, 89 patients receiving transjugular intrahepatic portosystemic shunt insertion were included in the study, and baseline levels of thromboxane B2, prostaglandin D2 and prostaglandin E2 were measured in the portal and the hepatic vein.


While the hepatic vein contained higher levels of thromboxane B2 than the portal vein, levels of prostaglandin E2 and D2 were higher in the portal vein (all P<0.0001). Baseline concentrations of thromboxane B2 in the portal vein were independently associated with an increase of portal hepatic venous pressure gradient during short term follow-up, as an indirect sign of thrombogenic potential (multivariable P = 0.004). Moreover, severity of liver disease was inversely correlated with portal as well as hepatic vein levels of prostaglandin D2 and E2 (all P<0.0001).


Elevated portal venous thromboxane B2 concentrations are possibly associated with the extent of thrombogenic potential in patients with decompensated liver cirrhosis.

Trial registration identifier: NCT03584204.

Klíčová slova:

Cirrhosis – Liver diseases – Platelets – Thrombosis – Veins – Portal veins – Prostaglandin – Thromboxane


1. Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. The New England journal of medicine. 2011;365(2):147–56. doi: 10.1056/NEJMra1011170 21751907

2. Nery F, Chevret S, Condat B, de Raucourt E, Boudaoud L, Rautou P-EE, et al. Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study. Hepatology (Baltimore, Md). 2015;61(2):660–7.

3. Funk C. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science (New York, NY). 2001;294(5548):1871–5.

4. Ding X, Murray PA. Cellular mechanisms of thromboxane A2-mediated contraction in pulmonary veins. American journal of physiology Lung cellular and molecular physiology. 2005;289(5):L825–33. doi: 10.1152/ajplung.00177.2005 15964897

5. Bustos M, Coffman T, Saadi S, Platt J. Modulation of eicosanoid metabolism in endothelial cells in a xenograft model. Role of cyclooxygenase-2. The Journal of clinical investigation. 1997;100(5):1150–8. doi: 10.1172/JCI119626 9276732

6. Alshbool FZ, Karim ZA, Espinosa EV, Lin OA, Khasawneh FT. Investigation of a Thromboxane A2 Receptor-Based Vaccine for Managing Thrombogenesis. Journal of the American Heart Association. 2018;7(13).

7. Huang S-WW, Kuo H-LL, Hsu M-TT, Tseng YJ, Lin S-WW, Kuo S-CC, et al. A novel thromboxane receptor antagonist, nstpbp5185, inhibits platelet aggregation and thrombus formation in animal models. Thrombosis and haemostasis. 2016;116(2):285–99. doi: 10.1160/TH15-12-0993 27173725

8. de Franchis R, Faculty BV. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. Journal of hepatology. 2015;63(3):743–52. doi: 10.1016/j.jhep.2015.05.022 26047908

9. for the of the E, for the of the Liver E. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. Journal of hepatology. 2018;69(2):406–60. doi: 10.1016/j.jhep.2018.03.024 29653741

10. Bureau C, Pagan JC, Layrargues GP, Metivier S, Bellot P, Perreault P, et al. Patency of stents covered with polytetrafluoroethylene in patients treated by transjugular intrahepatic portosystemic shunts: long-term results of a randomized multicentre study. Liver international: official journal of the International Association for the Study of the Liver. 2007;27(6):742–7.

11. Trebicka J, Krag A, Gansweid S, Schiedermaier P, runk H, Fimmers R, et al. Soluble TNF-alpha-receptors I are prognostic markers in TIPS-treated patients with cirrhosis and portal hypertension. PloS one. 2013;8(12):e83341. doi: 10.1371/journal.pone.0083341 24386183

12. Trebicka J, Krag A, Gansweid S, Appenrodt B, Schiedermaier P, Sauerbruch T, et al. Endotoxin and tumor necrosis factor-receptor levels in portal and hepatic vein of patients with alcoholic liver cirrhosis receiving elective transjugular intrahepatic portosystemic shunt. European journal of gastroenterology & hepatology. 2011;23(12):1218–25.

13. Berres M-LL, Asmacher S, Lehmann J, Jansen C, Görtzen J, Klein S, et al. CXCL9 is a prognostic marker in patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt. Journal of hepatology. 2015;62(2):332–9. doi: 10.1016/j.jhep.2014.09.032 25457205

14. O’Brien AJ, Fullerton JN, Massey KA, Auld G, Sewell G, James S, et al. Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. Nature medicine. 2014;20(5):518–23. doi: 10.1038/nm.3516 24728410

15. Graupera M, March S, Engel P, Rodés J, Bosch J, García-Pagán J-CC. Sinusoidal endothelial COX-1-derived prostanoids modulate the hepatic vascular tone of cirrhotic rat livers. American journal of physiology Gastrointestinal and liver physiology. 2005;288(4):G763–70. doi: 10.1152/ajpgi.00300.2004 15550559

16. Gracia-Sancho J, Laviña B, Rodríguez-Vilarrupla A, García-Calderó H, Bosch J, García-Pagán JC. Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers. Journal of hepatology. 2007;47(2):220–7. doi: 10.1016/j.jhep.2007.03.014 17459512

17. Rosado E, Rodríguez-Vilarrupla A, Gracia-Sancho J, Monclús M, Bosch J, García-Pagán J-CC. Interaction between NO and COX pathways modulating hepatic endothelial cells from control and cirrhotic rats. Journal of cellular and molecular medicine. 2012;16(10):2461–70. doi: 10.1111/j.1582-4934.2012.01563.x 22436078

18. Steib CJ, Gerbes AL, Bystron M, den Winkel M, Härtl J, Roggel F, et al. Kupffer cell activation in normal and fibrotic livers increases portal pressure via thromboxane A(2). Journal of hepatology. 2007;47(2):228–38. doi: 10.1016/j.jhep.2007.03.019 17573142

19. Parise L, Venton D, Breton LG. Arachidonic acid-induced platelet aggregation is mediated by a thromboxane A2/prostaglandin H2 receptor interaction. The Journal of pharmacology and experimental therapeutics. 1984;228(1):240–4. 6319669

20. Stueck AE, Wanless IR. Hepatocyte buds derived from progenitor cells repopulate regions of parenchymal extinction in human cirrhosis. Hepatology (Baltimore, Md). 2015;61(5):1696–707.

21. Wishart DS, Feunang YD, Marcu A, Guo AC, Liang K, Vázquez-Fresno R, et al. HMDB 4.0: the human metabolome database for 2018. Nucleic acids research. 2018;46(D1):D608–17. doi: 10.1093/nar/gkx1089 29140435

22. Akimova E. Prostacyclin and thromboxane A2 levels in children and adolescents with an inherited predisposition to coronary heart disease: a family study. Coronary artery disease. 1994;5(9):761–5. 7858766

23. Laleman W, Landeghem L, der Elst I, Zeegers M, Fevery J, Nevens F. Nitroflurbiprofen, a nitric oxide-releasing cyclooxygenase inhibitor, improves cirrhotic portal hypertension in rats. Gastroenterology. 2007;132(2):709–19. doi: 10.1053/j.gastro.2006.12.041 17258737

24. Urade Y, Eguchi N. Lipocalin-type and hematopoietic prostaglandin D synthases as a novel example of functional convergence. Prostaglandins & other lipid mediators. 2002;68–69:375–82.

25. Park JY, Pillinger MH, ramson S. Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases. Clinical immunology (Orlando, Fla). 2006;119(3):229–40.

26. Robinson MW, Harmon C, O’Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cellular & molecular immunology. 2016;13(3):267–76.

27. Queck A, Carnevale R, Uschner FE, Schierwagen R, Klein S, Jansen C, et al. Role of portal venous platelet activation in patients with decompensated cirrhosis and TIPS. Gut. 2019;

28. Friedman EA, Ogletree ML, Haddad EV, Boutaud O. Understanding the role of prostaglandin E2 in regulating human platelet activity in health and disease. Thrombosis research. 2015;136(3):493–503. doi: 10.1016/j.thromres.2015.05.027 26077962

29. Noor MT, Manoria P. Immune Dysfunction in Cirrhosis. Journal of clinical and translational hepatology. 2017;5(1):50–8. doi: 10.14218/JCTH.2016.00056 28507927

30. Schwarzkopf K, Bojunga J, Rüschenbaum S, Martinez Y, Mücke MM, Seeger F, et al. Use of Antiplatelet Agents Is Inversely Associated With Liver Fibrosis in Patients With Cardiovascular Disease. Hepatology communications. 2018;2(12):1601–9. doi: 10.1002/hep4.1254 30556044

31. Yoshida S, Ikenaga N, Liu SB, Peng Z-WW, Chung J, Sverdlov DY, et al. Extrahepatic platelet-derived growth factor-β, delivered by platelets, promotes activation of hepatic stellate cells and biliary fibrosis in mice. Gastroenterology. 2014;147(6):1378–92. doi: 10.1053/j.gastro.2014.08.038 25173753

32. Iannacone M, Sitia G, Isogawa M, Marchese P, Castro MG, Lowenstein PR, et al. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nature medicine. 2005;11(11):1167–9. doi: 10.1038/nm1317 16258538

33. Sitia G, Iannacone M, Guidotti LG. Anti-platelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma. Journal of hepatology. 2013;59(5):1135–8. doi: 10.1016/j.jhep.2013.05.040 23742914

34. Elia C, Graupera I, Barreto R, Solà E, Moreira R, Huelin P, et al. Severe acute kidney injury associated with non-steroidal anti-inflammatory drugs in cirrhosis: A case-control study. Journal of hepatology. 2015;63(3):593–600. doi: 10.1016/j.jhep.2015.04.004 25872166

35. Clària J, Kent JD, López-Parra M, Escolar G, Ruiz-Del-Arbol L, Ginès P, et al. Effects of celecoxib and naproxen on renal function in nonazotemic patients with cirrhosis and ascites. Hepatology (Baltimore, Md). 2005;41(3):579–87.

36. Ginès P, Arroyo V, Rodés J, Schrier R. Drug-induced renal failure in cirrhosis. Ascites and Renal Dysfunction in Liver Disease. 2005;372.

37. Klein S, Beuge MM, Granzow M, Beljaars L, Schierwagen R, Kilic S, et al. HSC-specific inhibition of Rho-kinase reduces portal pressure in cirrhotic rats without major systemic effects. Journal of hepatology. 2012;57(6):1220–7. doi: 10.1016/j.jhep.2012.07.033 22878469

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