Modern aspects of anticoagulant therapy in patients with liver cirrhosis: pathophysiology, pharmacokinetics and clinical management
N.A. Suvorova, V.V. Smirnova, V.A. Kokorin
ABSTRACT. Historically, the use of anticoagulant therapy (ACT) in liver cirrhosis (LC) was limited by the concept of “autoanticoagulation”. Current data support the “rebalanced hemostasis” paradigm, which posits that patients with LC are in a latent prothrombotic state and exhibit an increased incidence of venous thromboembolic complications. The practical use of ACT remains associated with altered drug pharmacokinetics, bleeding risk, and a lack of large, randomized trials. The aim of this review is to examine the evidence base, pharmacokinetic characteristics, and safety profiles of the main classes of anticoagulants, and propose algorithms for personalized ACT administration based on Child–Pugh score stratification. This article analyzes the potential use of ACT according to the degree of liver dysfunction and specifies the indications for ACT in thrombotic complications of LC. Particular attention is paid to new data (CIRROXABAN study) that indicate the potential role of factor Xa inhibitors in reducing the incidence of decompensation and modulating fibrogenesis. The choice of anticoagulant should be based on rigorous stratification using the Child–Pugh score, an assessment of clinical benefits, and comprehensive management of portal hypertension.
For citation: Suvorova NA, Smirnova VV, Kokorin VA. Modern aspects of anticoagulant therapy in patients with liver cirrhosis: Pathophysiology, pharmacokinetics and clinical management. Therapy (Moscow). 2026;12(5S):67–74.
https://doi.org/10.18565/ therapy.2026.5-s5.67-74
Ключевые слова
liver cirrhosis
rebalanced hemostasis
anticoagulant therapy
portal vein thrombosis
direct oral anticoagulants
low-molecular-weight heparins
Child–Pugh score
portal hypertension
Список литературы
1. Campello E, Fabris L, Simioni P. Anticoagulants in cirrhosis: Main concerns. Nat Rev Gastroenterol Hepatol. 2024;21(12):827–28.
PMID: 39394378. https://doi.org/10.1038/s41575-024-00998-x
2. Intagliata NM, Davis JPE, Caldwell SH. Coagulation pathways, hemostasis, and thrombosis in liver failure. Semin Respir Crit Care Med. 2018;39(5):598–608.
PMID: 30485890. https://doi.org/10.1055/s-0038-1673658
3. Ambrosino P, Tarantino L, Di Minno G, Paternoster M, Graziano V, Petitto M, et al. The risk of venous thromboembolism in patients with cirrhosis. A systematic review and meta-analysis. Thromb Haemost. 2017;117(1):139–48.
PMID: 27761574. https://doi.org/10.1160/TH16-06-0450
4. Lisman T, Hernandez-Gea V, Magnusson M, Roberts L, Stanworth S, Thachil J, Tripodi A. The concept of rebalanced hemostasis in patients with liver disease: Communication from the ISTH SSC working group on hemostatic management of patients with liver disease. J Thromb Haemost. 2021;19(4):1116–22.
PMID: 33792172. https://doi.org/10.1111/jth.15239
5. Rautou P, Caldwell S, Villa E. Bleeding and thrombotic complications in patients with cirrhosis: A state-of-the-art appraisal. Clinical Gastroenterology and Hepatology. 2023;21(8):2110–23.
PMID: 37121529. https://doi.org/10.1016/j.cgh.2023.04.016
6. Intagliata N, Davitkov P, Allen A. AGA technical review on coagulation in cirrhosis. Gastroenterology. 2021;161(5):1630–56.
PMID: 34579937. https://doi.org/10.1053/j.gastro.2021.09.004.
7. Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: Evidence and clinical consequences. Blood. 2010;116(6):878–85.
PMID: 20400681. https://doi.org/10.1182/blood-2010-02-261891
8. Franchini M, Mannucci PM. Coagulation abnormalities in chronic liver disease. Semin Thromb Hemost. 2025;52(3):335–41.
PMID: 39904369. https://doi.org/10.1055/a-2531-4712
9. Carlin S, Cuker A, Gatt A, Gendron N, Hernandez-Gea V, Meijer K, et al. Anticoagulation for stroke prevention in atrial fibrillation and treatment of venous thromboembolism and portal vein thrombosis in cirrhosis: Guidance from the SSC of the ISTH. J Thromb Haemost. 2024;22(9):2653–69.
PMID: 38823454. https://doi.org/10.1016/j.jtha.2024.05.023
10. Pradhan-Sundd T, Gudapati S, Kaminski T. Exploring the complex role of coagulation factor VIII in chronic liver disease. Cell Mol Gastroenterol Hepatol. 2021;12(3):1061–72.
PMID: 33705963. PMCID: PMC8342958. https://doi.org/10.1016/j.jcmgh.2021.02.014
11. Zhao Y, Zhu L, Yang Y, Gao H, Zhang R. Safety of direct oral anticoagulants in patients with liver disease: A systematic review and meta-analysis. Acta Clin Belg. 2023;78(3):234–44.
PMID: 35913111. https://doi.org/10.1080/17843286.2022.2108259
12. Northup PG, Lisman T, Roberts LN. Treatment of bleeding in patients with liver disease. J Thromb Haemost. 2021;19(7):1644–52.
PMID: 33974330. PMCID: PMC8362012. https://doi.org/10.1111/jth.15364
13. Biolato M, Vitale F, Galasso T, Gasbarrini A, Grieco A. Minimum platelet count threshold before invasive procedures in cirrhosis: Evolution of the guidelines. World J Gastrointest Surg. 2023;15(2):127–41.
PMID: 36896308. https://doi.org/10.4240/wjgs.v15.i2.127
14. Qamar A, Vaduganathan M, Greenberger NJ, Giugliano RP. Oral anticoagulation in patients with liver disease. J Am Coll Cardiol. 2018;71(19):2162–75.
PMID: 29747837. https://doi.org/10.1016/j.jacc.2018.03.023
15. Elkrief L, Hernandez-Gea V, Senzolo M, Albillos A, Baiges A, Berzigotti A, et al.; ERN RARE-LIVER and VALDIG, an EASL consortium. Portal vein thrombosis: Diagnosis, management, and endpoints for future clinical studies. Lancet Gastroenterol Hepatol. 2024;9(9):859–83.
PMID: 38996577. https://doi.org/10.1016/S2468-1253(24)00155-9
16. De Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C; Baveno VII Faculty. Corrigendum to ‘Baveno VII – renewing consensus in portal hypertension. J Hepatol. 2022;76(4):959–74.
PMID: 35431106. PMCID: PMC11090185. https://doi.org/10.1016/j.jhep.2021.12.022. Erratum in: J Hepatol. 2022;77(1):271. https://doi.org/10.1016/j.jhep.2022.03.024
17. Loffredo L, Pastori D, Farcomeni A. Effects of anticoagulants in patients with cirrhosis and portal vein thrombosis: A systematic review and meta-analysis. Gastroenterology. 2017;153(2):480–87.e1.
PMID: 28479379. https://doi.org/10.1053/j.gastro.2017.04.042
18. Zhang Z, Zhao Y, Han B, Zhu Z, Sun L, Cui X. The efficacy and safety of anticoagulants in the treatment of cirrhotic portal vein thrombosis: A systematic review and meta-analysis. Clin Appl Thromb Hemost. 2022;28:10760296221104797.
PMID: 35656719. PMCID: PMC9168872. https://doi.org/10.1177/10760296221104797
19. 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(8):1491–506.
PMID: 30060258. PMCID: PMC6202935. https://doi.org/10.1055/s-0038-1666861
20. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL clinical practice guidelines on vascular diseases of the liver. Journal of Hepatology. 2025;84(2):399–456.
PMID: 41224629. https://doi.org/10.1016/j.jhep.2025.08.001
21. Villa E, Camma C, Marietta M, Luongo M, Critelli R, Colopi S, et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology. 2012;143(5):1253–60.e4.
PMID: 22819864. https://doi.org/10.1053/j.gastro.2012.07.018
22. Yao C, Zhao M, Ibrahim B, Saab S. Anticoagulation for the treatment of portal vein thrombosis in cirrhosis: A systematic review and meta-analysis of comparative studies. J Clin Exp Hepatol. 2023;13(3):404–13.
PMID: 37250883. https://doi.org/10.1016/j.jceh.2022.12.016
23. Simonetto DA, Singal AK, Garcia-Tsao G, Caldwell SH, Ahn J, Kamath PS. ACG clinical guideline: disorders of the hepatic and mesenteric circulation. Am J Gastroenterol. 2020;115(1):18–40.
PMID: 31895720. https://doi.org/10.14309/ajg.0000000000000486
24. Levy JH, Spyropoulos AC, Samama CM, Douketis J. Direct oral anticoagulants: New drugs and new concepts. JACC Cardiovasc Interv. 2014;7(12):1333–51.
PMID: 25523529. https://doi.org/10.1016/j.jcin.2014.06.014
25. Onay M, Heilani M, Gulia C, Matthias C, Herrmann E, Koch V, et al. Sequential anticoagulation with LMWH and DOACs in cirrhotic portal vein thrombosis. Clin Res Hepatol Gastroenterol. 2026;50(4):102792.
PMID: 41740719. https://doi.org/10.1016/j.clinre.2026.102792
26. Menichelli D, Ronca V, Di Rocco A, Pignatelli P, Marco Podda G. Direct oral anticoagulants and advanced liver disease: A systematic review and meta-analysis. Eur J Clin Invest. 2021;51(3):e13397.
PMID: 32895926. https://doi.org/10.1111/eci.13397
27. Tham D, Yu W, Zhao L, Kou R, Kherani J, Li PY, et al. Safety and efficacy of direct oral anticoagulants in patients with liver cirrhosis: A meta-analysis. Res Pract Thromb Haemost. 2025;10(1):103296.
PMID: 41552757. https://doi.org/10.1016/j.rpth.2025.103296
28. McConn DJ 2nd, Lin YS, Mathisen TL, Blough DK, Xu Y, Hashizume T, et al. Reduced duodenal cytochrome P450 3A protein expression and catalytic activity in patients with cirrhosis. Clin Pharmacol Ther. 2009;85(4):387–93.
PMID: 19212316. https://doi.org/10.1038/clpt.2008.292
29. Bochanova EN, Gatskikh IV, Goncharova PS, Demko IV, Zimnitskaya OV, Kaskaeva DS, et al. [Pharmacogenetics of direct oral anticoagulants. Monograph. Ed. by Schneider NA, Petrova MM, Nasyrova RF. Saint Petersburg: DEAN Publishing House LLC. 2022; 208 pp. (In Russ.)].
EDN: BOAZLR. ISBN: 978-5-6047437-9-9.
30. Graff J, Harder S. Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment. Clin Pharmacokinet. 2013;52(4):243–54.
PMID: 23389892. https://doi.org/10.1007/s40262-013-0034-0
31. Akca M, Ketenci YB, Demiroz H, Avcioglu U. Concerns on rivaroxaban use in cirrhosis: Pharmacokinetic, safety, and bleeding risk considerations. J Hepatol. 2026;84(1):e31–e32.
PMID: 40972841. https://doi.org/10.1016/j.jhep.2025.08.041
32. Costache RS, Dragomirica AS, Gheorghe BE, Balaban VD, Stanciu SM, Jinga M, Costache DO. Oral anticoagulation in patients with chronic liver disease. Medicina (Kaunas). 2023;59(2):346.
PMID: 36837547. https://doi.org/10.3390/medicina59020346
33. U.S. Food and Drug Administration. Guidance for industry pharmacokinetics in patients with impaired hepatic function: Study design, data analysis, and impact on dosing and labeling. URL: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm072123.pdf (accessed May 24, 2026).
34. European Medicines Agency. Guidelines on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003122.pdf (accessed May 24, 2026).
35. U.S. Food and Drug Administration. Apixaban. URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf (accessed May 24, 2026).
36. Stangier J, Stahle H, Rathgen K, Roth W, Shakeri-Nejad K. Pharmacokinetics and pharmaсodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol. 2008;48(12):1411–19.
PMID: 18827075. https://doi.org/10.1177/0091270008324179
37. U.S. Food and Drug Administration. Dabigatran. URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022512s027lbl.pdf (accessed May 24, 2026).
38. Kubitza D, Roth A, Becka M, Alatrach A, Halabi A, Hinrichsen H, Mueck W. Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol. 2013;76(1):89–98.
PMID: 23294275. PMCID: PMC3703231. https://doi.org/10.1111/bcp.12054. Erratum in: Br J Clin Pharmacol. 2013;76(3):489.
39. U.S. Food and Drug Administration. Rivaroxaban.
URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202439s001lbl.pdf (accessed May 24, 2026).
40. 40. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on prevention and management of bleeding and thrombosis in patients with cirrhosis. J Hepatol. 2022;76(5):1151–84.
PMID: 35300861. https://doi.org/10.1016/j.jhep.2021.09.003
41. Abideen ZU, Waseem MH, Ramzan NUH, Raheel H, Hasan F, Thada PK, Jalal PK. Comparative effectiveness and safety of various anticoagulation regimens for portal venous thrombosis in cirrhosis: A systematic review and network meta-analysis. Clin Appl Thromb Hemost. 2025;31:10760296251405419.
PMID: 41348536. PMCID: PMC12682983. https://doi.org/10.1177/10760296251405419
42. Li HJ, Yin FQ, Ma YT, Gao TY, Tao YT, Liu X, et al. Administration of anticoagulation strategies for portal vein thrombosis in cirrhosis: Network meta-analysis. Front Pharmacol. 2025;15:1462338.
PMID: 39834816. https://doi.org/10.3389/fphar.2024.1462338
43. Davis J, Lim J, Francis F et al. AGA Clinical practice update on management of portal vein thrombosis in patients with cirrhosis: Expert review. Gastroenterology. 2024;168(2):396–404.e1.
PMID: 39708000. https://doi.org/10.1053/j.gastro.2024.10.038
44. Roberts LN, Hernandez-Gea V, Magnusson M, Stanworth S, Thachil J, Tripodi A, Lisman T. Thromboprophylaxis for venous thromboembolism prevention in hospitalized patients with cirrhosis: Guidance from the SSC of the ISTH. J Thromb Haemost. 2022;20(10):223745.
PMID: 35948998. https://doi.org/10.1111/jth.15829
45. Simon TG, Singer DE, Zhang Y, Mastrorilli JM, Cervone A, DiCesare E, Lin KJ. Comparative effectiveness and safety of apixaban, rivaroxaban, and warfarin in patients with cirrhosis and atrial fibrillation: A nationwide cohort study. Ann Intern Med. 2024;177(8):1028–38.
PMID: 38976880. https://doi.org/10.7326/M23-3067
46. Li Z, Xu W, Wang L, Chai L, Ageno W, Romeiro FG, et al. Risk of bleeding in liver cirrhosis receiving direct oral anticoagulants: A systematic review and meta-analysis. Thromb Haemost. 2023;123(11):1072–88.
PMID: 37336474. https://doi.org/10.1055/s-0043-1770100
47. Northup PG, Garcia‐Pagan JC, Garcia‐Tsao G, Intagliata NM, Superina RA, Roberts LN, et al. Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 Practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021;73(1):366–413.
PMID: 33219529. https://doi.org/10.1002/hep.31646
48. Puente A, Turon F, Martinez J, Fortea JI, Guerra MH, Alvarado E, et al. Rivaroxaban to prevent complications of portal hypertension in cirrhosis: The CIRROXABAN study. J Hepatol. 2025;83(5):1069–76.
PMID: 40691992. https://doi.org/10.1016/j.jhep.2025.06.035
49. Lawal OD, Aronow HD, Hume AL, Shobayo F, Matson KL, Barbour M, et al. Venous thromboembolism, chronic liver disease and anticoagulant choice: Effectiveness and safety of direct oral anticoagulants versus warfarin. Res Pract Thromb Haemost. 2023;8(1):102293.
PMID: 38268519. https://doi.org/10.1016/j.rpth.2023.102293
Об авторах / Для корреспонденции
Natalya A. Suvorova, MD, PhD (Medicine), associate professor of the Department of hospital therapy named after academician P.E. Lukomsky of the Institute of clinical medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation.E-mail: natalia-suvorova@inbox.ru
ORCID: https://orcid.org/0000-0001-5959-6759. Scopus ID: 57224593022. eLibrary SPIN: 2582-3709
Veronika V. Smirnova, MD, postgraduate student of the Department of hospital therapy named after academician P.E. Lukomsky of the Institute of clinical medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation.
E-mail: miss.smirnova_veronika@mail.ru
ORCID: https://orcid.org/0000-0003-1181-0060
Valentin A. Kokorin, MD, Dr. Sci. (Medicine), associate professor, head of the Department of hospital therapy with courses in endocrinology, hematology, and clinical diagnostics of the Medical institute, RUDN University; professor of the Department of hospital therapy named after academician P.E. Lukomsky of the Institute of clinical medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation.
E-mail: kokorin-va@rudn.ru
ORCID: https://orcid.org/0000-0001-8614-6542. Scopus ID: 60478883000. eLibrary SPIN: 9772-2288
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