actabiomedicaActa Biomedica ScientificaActa Biomedica Scientifica2541-94202587-9596Scientific Centre for Family Health and Human Reproduction Problems10.29413/ABS.2019-4.2.3actabiomedica-2041Research ArticleВНУТРЕННИЕ БОЛЕЗНИINTERNAL DISEASESАнтикоагулянтная терапия у больных с циррозом печени (обзор литературы)Anticoagulation in Patients with Liver Cirrhosis (Literature Review)https://orcid.org/0000-0002-9069-3570ЕнисееваЕ. С.EniseevaE. S.

Енисеева Елена Сергеевна – кандидат медицинских наук, доцент кафедры кардиологии и функциональной диагностики; доцент кафедры госпитальной терапии

664049, г. Иркутск, Юбилейный, 100; 664003, г. Иркутск, ул. Красного Восстания, 1

Elena S. Eniseeva – Cand. Sc. (Med.), Associate Professor at the Department of Cardiology and Functional Diagnostics; Associate Professor at the Department of Hospital Therapy

Yubileynyy 100, Irkutsk 664049; ul. Krasnogo Vosstaniya 1, Irkutsk 664003

eniseeva-irk@yandex.ruИркутская государственная медицинская академия последипломного образования – филиал ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России; ФГБОУ ВО «Иркутский государственный медицинский университет» Минздрава РоссииIrkutsk State Medical Academy of Postgraduate Education – Branch Campus of the Russian Medical Academy of Continuing Professional Education; Irkutsk State Medical University201923052019422328Copyright © Енисеева Е.С., 20192019Енисеева Е.С.Eniseeva E.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.actabiomedica.ru/jour/article/view/2041

Цирроз печени сопровождается сложными нарушениями гемостаза с увеличением риска как геморрагических, так и тромботических осложнений. Снижение синтеза коагуляционных белков, таких как факторы II, VII, IX, X и тромбоцитопения ассоциируются с повышенным риском кровотечений. Нарушение синтеза антикоагулянтов: протеина С, протеина S, антитромбина III сопровождается усилением генерации тромбина, что ведёт к прокоагулянтному статусу, увеличению риска венозных тромбозов, тромбоэмболии лёгочной артерии, а также тромбоза воротной вены. Активация коагуляционного каскада не только повышает риск тромбозов, но и играет большую роль в повреждении печени, способствуя прогрессированию фиброза. Цирроз печени увеличивает риск тромбоэмболических осложнений фибрилляции предсердий.

Для профилактики тромбозов и тромбоэмболических осложнений необходимы антикоагулянты. Однако большие проспективные исследования эффективности антикоагулянтной терапии у больных с циррозом отсутствуют. Недостаточно данных о безопасности антикоагулянтной терапии при циррозе. Имеются трудности мониторирования антикоагуляции при применении антагонистов витамина К и низкомолекулярных гепаринов.

В обзоре представлены имеющиеся данные по применению варфарина, нефракционированного гепарина, низкомолекулярных гепаринов и прямых оральных антикоагулянтов у больных с циррозом печени, свидетельствующие о необходимости профилактики венозных тромбозов у больных с факторами риска, возможности предупреждения декомпенсации цирроза, снижении частоты кардиоэмболических инсультов при фибрилляции предсердий у больных циррозом печени.

Liver cirrhosis is accompanied by complex hemostatic disorders with an increase in the risk of both hemorrhagic and thrombotic complications. Reduced coagulation protein synthesis, such as factors II, VII, IX, X and thrombocytopenia are associated with an increased risk of bleeding. Reducing the synthesis of such anticoagulants as protein C, protein S, antithrombin III is accompanied by increased generation of thrombin, which leads to procoagulant status, increased risk of venous thrombosis, pulmonary embolism, and portal vein thrombosis. Activation of the coagulation cascade increases the risk of thrombosis, and also plays an important role in liver damage, contributing to the progression of fibrosis. Cirrhosis increases the risk of thromboembolic complications of atrial fibrillation.

Anticoagulants are necessary for the prevention of thrombosis and thromboembolic complications. However, there are no large prospective studies. There is insufficient data on the safety of anticoagulant therapy in cirrhosis. There are difficulties in monitoring anticoagulation in the application of vitamin K antagonists and low molecular weight heparins.

The review presents the available data on the use of warfarin, unfractionated heparin, low molecular weight heparins and direct oral anticoagulants in patients with liver cirrhosis, indicating the need for prevention of venous thrombosis in patients with risk factors, the possibility of preventing decompensation of cirrhosis, reducing the frequency of cardioembolic strokes in patients with atrial fibrillation.

цирроз печенитромбозытромбоэмболииантикоагулянтыliver cirrhosisthrombosisthromboembolismanticoagulantsReferencesTripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005; 41(3): 553-558. doi: 10.1002/hep.20569Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005; 41(3): 553-558. doi: 10.1002/hep.20569Ponziani FR, De Stefano V, Gasbarr A. Viral Cirrhosis: an Overview of Haemostatic Alterations and Clinical Consequences. Medit J Hemat Infect Dis. 2009; 1(3): e2009033. doi: 10.4048/mjhid.2009.033Ponziani FR, De Stefano V, Gasbarr A. Viral Cirrhosis: an Overview of Haemostatic Alterations and Clinical Consequences. Medit J Hemat Infect Dis. 2009; 1(3): e2009033. doi: 10.4048/mjhid.2009.033Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol. 2013; 11(9): 1064-1074. doi: 10.1016/j.cgh.2013.02.026Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol. 2013; 11(9): 1064-1074. doi: 10.1016/j.cgh.2013.02.026Borensztajn K, von der Thüsen JH, Peppelenbosch MP, Spek CA. The coagulation factor Xa/protease activated receptor-2 axis in the progression of liver fibrosis: a multifaceted paradigm. J Cell Mol Med. 2010; 14(1-2): 143-153. doi: 10.1111/j.1582-4934.2009.00980.xBorensztajn K, von der Thüsen JH, Peppelenbosch MP, Spek CA. The coagulation factor Xa/protease activated receptor-2 axis in the progression of liver fibrosis: a multifaceted paradigm. J Cell Mol Med. 2010; 14(1-2): 143-153. doi: 10.1111/j.1582-4934.2009.00980.xTripodi A, Primignani M, Lemma L, Chantarangkul V, Dell’Era A, Iannuzzi F , et al. Detection of the imbalance of procoagulant versus anticoagulant factors in cirrhosis by a simple laboratory method. Hepatology. 2010; 52(1): 249-255. doi: 10.1002/hep.23653Tripodi A, Primignani M, Lemma L, Chantarangkul V, Dell’Era A, Iannuzzi F , et al. Detection of the imbalance of procoagulant versus anticoagulant factors in cirrhosis by a simple laboratory method. Hepatology. 2010; 52(1): 249-255. doi: 10.1002/hep.23653Leonardi F, Maria N, Villa E. Anticoagulation in cirrhosis: a new paradigm? Clin Mol Hepatol. 2017; 23(1): 13-21. doi: 10.3350/cmh.2016.0110Leonardi F, Maria N, Villa E. Anticoagulation in cirrhosis: a new paradigm? Clin Mol Hepatol. 2017; 23(1): 13-21. doi: 10.3350/cmh.2016.0110Hugenholtz GCG, Northup PG, Porte RJ, Lisman T. Is there a rationale for treatment of chronic liver disease with antithrombotic therapy? Blood Reviews. 2015; 29(2): 127-136. doi: 10.1016/j.blre.2014.10.002Hugenholtz GCG, Northup PG, Porte RJ, Lisman T. Is there a rationale for treatment of chronic liver disease with antithrombotic therapy? Blood Reviews. 2015; 29(2): 127-136. doi: 10.1016/j.blre.2014.10.002Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. The New England Journal of Medicine. 2011; 365 (2): 147-156. doi: 10.1056/NEJMra1011170Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. The New England Journal of Medicine. 2011; 365 (2): 147-156. doi: 10.1056/NEJMra1011170Gatt A, Riddell A, Calvaruso V, Tuddenham EG, Makris M, Burroughs AK. Enhanced thrombin generation in patients with cirrhosis-induced coagulopathy. J Thromb Haemost. 2010; 8(9): 1994-2000. doi: 10.1111/j.1538-7836.2010.03937.xGatt A, Riddell A, Calvaruso V, Tuddenham EG, Makris M, Burroughs AK. Enhanced thrombin generation in patients with cirrhosis-induced coagulopathy. J Thromb Haemost. 2010; 8(9): 1994-2000. doi: 10.1111/j.1538-7836.2010.03937.xAnstee QM, Dhar A, Thursz MR. The role of hypercoagulability in liver fibrogenesis. Clin Res Hepatol Gastroenterol. 2011; 35(8-9): 526-533. doi: 10.1016/j.clinre.2011.03.011Anstee QM, Dhar A, Thursz MR. The role of hypercoagulability in liver fibrogenesis. Clin Res Hepatol Gastroenterol. 2011; 35(8-9): 526-533. doi: 10.1016/j.clinre.2011.03.011Gulley D, Teal E, Suvannasanka A, Chalasani N, Liangpunsakul S. Deep vein thrombosis and pulmonary embolism in cirrhosis patients. Dig Dis Sci. 2008; 53(11): 3012-3017. doi: 10.1155/2013/807526Gulley D, Teal E, Suvannasanka A, Chalasani N, Liangpunsakul S. Deep vein thrombosis and pulmonary embolism in cirrhosis patients. Dig Dis Sci. 2008; 53(11): 3012-3017. doi: 10.1155/2013/807526Dabbagh O, Oza A, Prakash S, Sunna R, Saettele TM. Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. Chest. 2010; 137(5): 1145-49. doi: 10.1378/chest.09-2177Dabbagh O, Oza A, Prakash S, Sunna R, Saettele TM. Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. Chest. 2010; 137(5): 1145-49. doi: 10.1378/chest.09-2177Bogari H, Patanwala AE, Cosgrove R, Katz M. Risk assessment and pharmacological prophylaxis of venous thromboembolism in hospitalized patients with chronic liver disease. Thromb Res. 2014; 134(6): 1220-1223. doi: 10.1016/j.thromres.2014.09.031Bogari H, Patanwala AE, Cosgrove R, Katz M. Risk assessment and pharmacological prophylaxis of venous thromboembolism in hospitalized patients with chronic liver disease. Thromb Res. 2014; 134(6): 1220-1223. doi: 10.1016/j.thromres.2014.09.031Søgaard KK, Horva´th-Puho´ E, Grønbaek H, Jepsen P, Vilstrup H, Sørensen H. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-controlstudy. Am J Gastroenterol. 2009; 104(1): 96-101. doi: 10.1038/ajg.2008.34Søgaard KK, Horva´th-Puho´ E, Grønbaek H, Jepsen P, Vilstrup H, Sørensen H. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-controlstudy. Am J Gastroenterol. 2009; 104(1): 96-101. doi: 10.1038/ajg.2008.34Wu H, Nguyen GC. Liver cirrhosis is associated with venous thromboembolism among hospitalized patients in a nationwide US study. Clin Gastroenterol Hepatol. 2010; 8(9): 800-805. doi: 10.1016/j.cgh.2010.05.014Wu H, Nguyen GC. Liver cirrhosis is associated with venous thromboembolism among hospitalized patients in a nationwide US study. Clin Gastroenterol Hepatol. 2010; 8(9): 800-805. doi: 10.1016/j.cgh.2010.05.014Northup PG, McMahon MM, Ruhl AP, Altschuler SE, Volk-Bednarz A, Caldwell SH et al. Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism. Am J Gastroenterol. 2006; 101(7): 1524-1528. doi: 10.1111/j.1572-0241.2006.00588.xNorthup PG, McMahon MM, Ruhl AP, Altschuler SE, Volk-Bednarz A, Caldwell SH et al. Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism. Am J Gastroenterol. 2006; 101(7): 1524-1528. doi: 10.1111/j.1572-0241.2006.00588.xDhar A, Mullish BH, Thursz MR. Grand Round: anticoagulation in chronic liver disease. Journal of Hepatology. 2017; 66(6): 1313-1326. doi: 10.1016/j.jhep.2017.01.006Dhar A, Mullish BH, Thursz MR. Grand Round: anticoagulation in chronic liver disease. Journal of Hepatology. 2017; 66(6): 1313-1326. doi: 10.1016/j.jhep.2017.01.006Turon F, Hernández-Gea V, García-Pagán JC. Portal vein thrombosis: yes or no on anticoagulation therapy. Curr Opin Organ Transplant. 2018; 23(2): 250-256. doi: 10.1097/MOT.0000000000000506Turon F, Hernández-Gea V, García-Pagán JC. Portal vein thrombosis: yes or no on anticoagulation therapy. Curr Opin Organ Transplant. 2018; 23(2): 250-256. doi: 10.1097/MOT.0000000000000506Nery F, Chevret S, Condat B de Raucourt E, Boudaoud L, Rautou PE, Plessier A, et al. Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: Results of a longitudinal study. Hepatology. 2015; 61(2): 660-667. doi: 10.1002/hep.27546Nery F, Chevret S, Condat B de Raucourt E, Boudaoud L, Rautou PE, Plessier A, et al. Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: Results of a longitudinal study. Hepatology. 2015; 61(2): 660-667. doi: 10.1002/hep.27546Plompen EP, Murad SD, Hansen BE, Loth DW, Schouten JN, Taimr P, et al. Prothrombotic genetic risk factors are associated with an increased risk of liver fibrosis in the general population: The Rotterdam Study. J Hepatol. 2015; 63(6): 1459-1465. doi: 10.1016/j.jhep.2015.07.026Plompen EP, Murad SD, Hansen BE, Loth DW, Schouten JN, Taimr P, et al. Prothrombotic genetic risk factors are associated with an increased risk of liver fibrosis in the general population: The Rotterdam Study. J Hepatol. 2015; 63(6): 1459-1465. doi: 10.1016/j.jhep.2015.07.026European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Vascular diseases of the liver. J Hepatol. 2016; 64(1): 179-202. doi: 10.1016/j.jhep.2015.07.040European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Vascular diseases of the liver. J Hepatol. 2016; 64(1): 179-202. doi: 10.1016/j.jhep.2015.07.040Cohen AT, Tapson VF, Bergmann JF, Goldhaber SZ, Kakkar AK, Deslandes B, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet. 2008; 371(9610): 387-394. doi: 10.1016/S0140-6736(08)60202-0Cohen AT, Tapson VF, Bergmann JF, Goldhaber SZ, Kakkar AK, Deslandes B, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet. 2008; 371(9610): 387-394. doi: 10.1016/S0140-6736(08)60202-0Dabbagh O, Oza A, Prakash S, Sunna R, Saettele TM. Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. Chest. 2010; 137(5): 1145-1149. doi: 10.1378/chest.09-2177Dabbagh O, Oza A, Prakash S, Sunna R, Saettele TM. Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. Chest. 2010; 137(5): 1145-1149. doi: 10.1378/chest.09-2177Smith CB, Hurdle AC, Kemp LO, Sands C, Twilla JD. Evaluation of venous thromboembolism prophylaxis in patients with chronic liver disease. J Hosp Med. 2013; 8(10): 569-573. doi: 10.1002/jhm.2086Smith CB, Hurdle AC, Kemp LO, Sands C, Twilla JD. Evaluation of venous thromboembolism prophylaxis in patients with chronic liver disease. J Hosp Med. 2013; 8(10): 569-573. doi: 10.1002/jhm.2086Barclay SM, Jeffres MN, Nguyen K, Nguyen T. Evaluation of pharmacologic prophylaxis for venous thromboembolism in patients with chronic liver disease. Pharmacotherapy. 2013; 33(4): 375-382. doi: 10.1002/phar.1218Barclay SM, Jeffres MN, Nguyen K, Nguyen T. Evaluation of pharmacologic prophylaxis for venous thromboembolism in patients with chronic liver disease. Pharmacotherapy. 2013; 33(4): 375-382. doi: 10.1002/phar.1218Pincus KJ, Tata AL, Watson K. Risk of venous thromboembolism in patients with chronic liver disease and the utility of venous thromboembolism prophylaxis. Annals of Pharmacotherapy. 2012; 46(6): 873-878. doi: 10.1345/aph.1Q726Pincus KJ, Tata AL, Watson K. Risk of venous thromboembolism in patients with chronic liver disease and the utility of venous thromboembolism prophylaxis. Annals of Pharmacotherapy. 2012; 46(6): 873-878. doi: 10.1345/aph.1Q726Lisman T, Kamphuisen PW, Northup PG, Porte RJ. Established and new-generation antithrombotic drugs in patients with cirrhosis – possibilities and caveats. J Hepatol. 2013; 59(2): 358-366. doi: 10.1016/j.jhep.2013.03.027Lisman T, Kamphuisen PW, Northup PG, Porte RJ. Established and new-generation antithrombotic drugs in patients with cirrhosis – possibilities and caveats. J Hepatol. 2013; 59(2): 358-366. doi: 10.1016/j.jhep.2013.03.027Tripodi A, Primignani M, Braham S, Chantarangkul V, Clerici M, Moia M, et al. Coagulation parameters in patients with cirrhosis and portal vein thrombosis treated sequentially with low molecular weight heparin and vitamin K antagonists. Dig Liver Dis. 2016; 48(10): 1208-1213. doi: 10.1016/j.dld.2016.06.027Tripodi A, Primignani M, Braham S, Chantarangkul V, Clerici M, Moia M, et al. Coagulation parameters in patients with cirrhosis and portal vein thrombosis treated sequentially with low molecular weight heparin and vitamin K antagonists. Dig Liver Dis. 2016; 48(10): 1208-1213. doi: 10.1016/j.dld.2016.06.027Potze W, Arshad F, Adelmeijer J, Blokzijl H, van den Berg AP, Porte RJ, et al. Routine coagulation assays underestimate levels of antithrombin-dependent drugs but not of direct anticoagulant drugs in plasma from patients with cirrhosis. Br J Haematol. 2013; 163(5): 666-673. doi: 10.1111/bjh.12593Potze W, Arshad F, Adelmeijer J, Blokzijl H, van den Berg AP, Porte RJ, et al. Routine coagulation assays underestimate levels of antithrombin-dependent drugs but not of direct anticoagulant drugs in plasma from patients with cirrhosis. Br J Haematol. 2013; 163(5): 666-673. doi: 10.1111/bjh.12593Huard G, Bilodeau M. Management of anticoagulation for portal vein thrombosis in individuals with cirrhosis: a systematic review. International Journal of Hepatology. 2012; 2012: 672986. doi: 10.1155/2012/672986Huard G, Bilodeau M. Management of anticoagulation for portal vein thrombosis in individuals with cirrhosis: a systematic review. International Journal of Hepatology. 2012; 2012: 672986. doi: 10.1155/2012/672986Intagliata NM, Henry ZH, Shah N, Lisman T, Caldwell SH, Northup PG. Prophylactic anticoagulation for venous thromboembolism in hospitalized cirrhosis patients is not associated with high rates of gastrointestinal bleeding. Liver Int. 2014; 34(1): 26-32. doi: 10.1111/liv.12211Intagliata NM, Henry ZH, Shah N, Lisman T, Caldwell SH, Northup PG. Prophylactic anticoagulation for venous thromboembolism in hospitalized cirrhosis patients is not associated with high rates of gastrointestinal bleeding. Liver Int. 2014; 34(1): 26-32. doi: 10.1111/liv.12211Reichert JA, Hlavinka PF, Stolzfus JC. Risk of hemorrhage in patients with chronic liver disease and coagulopathy receiving pharmacologic venous thromboembolism prophylaxis. Pharmacotherapy. 2014; 34(10): 1043-1049. doi: 10.1002/phar.1464Reichert JA, Hlavinka PF, Stolzfus JC. Risk of hemorrhage in patients with chronic liver disease and coagulopathy receiving pharmacologic venous thromboembolism prophylaxis. Pharmacotherapy. 2014; 34(10): 1043-1049. doi: 10.1002/phar.1464Villa 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): 1253-1260. doi: 10.1053/j.gastro.2012.07.018Villa 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): 1253-1260. doi: 10.1053/j.gastro.2012.07.018Fuentes A, Gordon-Burroughs S, Hall JB, Putney DR, Monsour HP Jr. Comparison of anti-Xa and activated partial thromboplastin time monitoring for heparin dosing in patients with cirrhosis. Ther Drug Monit. 2015; 37(1): 40-44. doi: 10.1097/FTD.0000000000000105Fuentes A, Gordon-Burroughs S, Hall JB, Putney DR, Monsour HP Jr. Comparison of anti-Xa and activated partial thromboplastin time monitoring for heparin dosing in patients with cirrhosis. Ther Drug Monit. 2015; 37(1): 40-44. doi: 10.1097/FTD.0000000000000105Amitrano L, Guardascione MA, Menchise A, Martino R, Scaglione M, Giovine S, et al. Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis. J Clin Gastroenterol. 2010; 44(6): 448-451. doi: 10.1097/MCG.0b013e3181b3ab44Amitrano L, Guardascione MA, Menchise A, Martino R, Scaglione M, Giovine S, et al. Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis. J Clin Gastroenterol. 2010; 44(6): 448-451. doi: 10.1097/MCG.0b013e3181b3ab44Delgado MG, Seijo S, Yepes I, Achécar L, Catalina MV, García-Criado Á, et al. Efficacy and safety of anticoagulation of patients with cirrhosis and portal vein thrombosis. Clin Gastroenterol Hepatol. 2012; 10(7): 776-783. doi: 10.1016/j.cgh.2012.01.012Delgado MG, Seijo S, Yepes I, Achécar L, Catalina MV, García-Criado Á, et al. Efficacy and safety of anticoagulation of patients with cirrhosis and portal vein thrombosis. Clin Gastroenterol Hepatol. 2012; 10(7): 776-783. doi: 10.1016/j.cgh.2012.01.012Maruyama H, Takahashi M, Shimada T, Yokosuka O. Emergency anticoagulation treatment for cirrhosis patients with portal vein thrombosis and acute variceal bleeding. Scand J Gastroenterol. 2012; 47(6): 686-691. doi: 10.3109/00365521.2012.674972Maruyama H, Takahashi M, Shimada T, Yokosuka O. Emergency anticoagulation treatment for cirrhosis patients with portal vein thrombosis and acute variceal bleeding. Scand J Gastroenterol. 2012; 47(6): 686-691. doi: 10.3109/00365521.2012.674972Werner KT, Sando S, Carey EJ, Vargas HE, Byrne TJ, Douglas DD, et al. Portal vein thrombosis in patients with end stage liver disease awaiting liver transplantation: outcome of anticoagulation. Dig Dis Sci. 2013; 58(6): 1776-1780. doi: 10.1007/s10620-012-2548-yWerner KT, Sando S, Carey EJ, Vargas HE, Byrne TJ, Douglas DD, et al. Portal vein thrombosis in patients with end stage liver disease awaiting liver transplantation: outcome of anticoagulation. Dig Dis Sci. 2013; 58(6): 1776-1780. doi: 10.1007/s10620-012-2548-yCerini F, Gonzalez JM, Torres F, Puente Á, Casas M, Vinaixa C, et al. Impact of anticoagulation on upper-gastrointestinal bleeding in cirrhosis: a retrospective multicenter study. Hepatology. 2015; 62(2): 575-583. doi: 10.1002/hep.27783Cerini F, Gonzalez JM, Torres F, Puente Á, Casas M, Vinaixa C, et al. Impact of anticoagulation on upper-gastrointestinal bleeding in cirrhosis: a retrospective multicenter study. Hepatology. 2015; 62(2): 575-583. doi: 10.1002/hep.27783Dhar A, Anstee Q, Sadiq S, Levene A, Goldin R, Thursz M. A role for anticoagulation in fibrogenesis: suppression of human hepatic stellate cell contractility and liver fibrosis in vitro and vivo. J Hepatol. 2012; 56(2): S35-S36. doi: 10.1016/S0168-8278(12)60095-6Dhar A, Anstee Q, Sadiq S, Levene A, Goldin R, Thursz M. A role for anticoagulation in fibrogenesis: suppression of human hepatic stellate cell contractility and liver fibrosis in vitro and vivo. J Hepatol. 2012; 56(2): S35-S36. doi: 10.1016/S0168-8278(12)60095-6Dhar A, Tschotazis E, Brown R, Manousou P, Millson C, Aldersley M, et al. Warfarin anticoagulation for liver fibrosis in patients transplanted for hepatitis C (WAFT-C): results at one year. J Hepatol. 2015; 62: s268-s269. doi: 10.1016/S0168-8278(15)30165-3Dhar A, Tschotazis E, Brown R, Manousou P, Millson C, Aldersley M, et al. Warfarin anticoagulation for liver fibrosis in patients transplanted for hepatitis C (WAFT-C): results at one year. J Hepatol. 2015; 62: s268-s269. doi: 10.1016/S0168-8278(15)30165-3Yeh CH, Hogg K, Weitz JI. Overview of the new oralanticoagulants: opportunities and challenges. Arterioscler Thromb Vasc Biol. 2015; 35(5): 1056-1065. doi: 10.1161/ATVBAHA.115.303397Yeh CH, Hogg K, Weitz JI. Overview of the new oralanticoagulants: opportunities and challenges. Arterioscler Thromb Vasc Biol. 2015; 35(5): 1056-1065. doi: 10.1161/ATVBAHA.115.303397Intagliata NM, Maitland H, Caldwell SH. Direct oral anticoagulants in cirrhosis. Curr Treat Options Gastro. 2016; 14(2): 247-256. doi: 10.1007/s11938-016-0092-0Intagliata NM, Maitland H, Caldwell SH. Direct oral anticoagulants in cirrhosis. Curr Treat Options Gastro. 2016; 14(2): 247-256. doi: 10.1007/s11938-016-0092-0Stangier J, Stahle H, Rathgen J, Roth W, Shakeri-Nejad K. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor are not affected by moderate hepatic impairment. J Clin Pharmacol. 2008; 48(12): 1411-1419. doi: 10.1177/0091270008324179Stangier J, Stahle H, Rathgen J, Roth W, Shakeri-Nejad K. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor are not affected by moderate hepatic impairment. J Clin Pharmacol. 2008; 48(12): 1411-1419. doi: 10.1177/0091270008324179Potze W, Arshad F, Adelmeijer J, Blokzijl H, van den Berg A, Meijers JCM, et al. Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis. PLoS One. 2014; 9(2): e88390. doi: 10.1371/journal.pone.0088390Potze W, Arshad F, Adelmeijer J, Blokzijl H, van den Berg A, Meijers JCM, et al. Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis. PLoS One. 2014; 9(2): e88390. doi: 10.1371/journal.pone.0088390Kubitza D, Roth A, Becka M, Alatrach A, Halabi A, Hinrichsen H, et al. 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. doi: 10.1111/bcp.12054Kubitza D, Roth A, Becka M, Alatrach A, Halabi A, Hinrichsen H, et al. 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. doi: 10.1111/bcp.12054Martinez M, Tandra A, Vuppalanchi R. Treatment of acute portal vein thrombosis by non-traditional anticoagulation. Hepatology. 2014; 60(1): 425-426. doi: 10.1002/hep.26998Martinez M, Tandra A, Vuppalanchi R. Treatment of acute portal vein thrombosis by non-traditional anticoagulation. Hepatology. 2014; 60(1): 425-426. doi: 10.1002/hep.26998Intagliata NM, Henry ZH, Maitland H, Shah NL Argo CK, Northup PG, et al. Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when compared to traditional anticoagulation. Dig Dis Sci. 2016; 61(6): 1721-1727. doi: 10.1007/s10620-015-4012-2Intagliata NM, Henry ZH, Maitland H, Shah NL Argo CK, Northup PG, et al. Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when compared to traditional anticoagulation. Dig Dis Sci. 2016; 61(6): 1721-1727. doi: 10.1007/s10620-015-4012-2Seung-Jun Lee, Jae-Sun Uhm, Jong-Youn Kim, Hui-Nam Pak, Moon-Hyoung Lee, Boyoung Joung. The safety and efficacy of vitamin K antagonist in patients with atrial fibrillation and liver cirrhosis. International Journal of Cardiology. 2015; 180(1): 185-191. doi: 10.1016/j.ijcard.2014.11.183Seung-Jun Lee, Jae-Sun Uhm, Jong-Youn Kim, Hui-Nam Pak, Moon-Hyoung Lee, Boyoung Joung. The safety and efficacy of vitamin K antagonist in patients with atrial fibrillation and liver cirrhosis. International Journal of Cardiology. 2015; 180(1): 185-191. doi: 10.1016/j.ijcard.2014.11.183Lai H-C, Chien W-C, Chung C-H, Lee W-L, Wu T-J, Wang K-Y, et al. Atrial fibrillation, liver disease, antithrombotics and risk of cerebrovascular events: A population-based cohort study. International Journal of Cardiology. 2016; 223: 829-837. doi: 10.1016/j.ijcard.2016.08.297Lai H-C, Chien W-C, Chung C-H, Lee W-L, Wu T-J, Wang K-Y, et al. Atrial fibrillation, liver disease, antithrombotics and risk of cerebrovascular events: A population-based cohort study. International Journal of Cardiology. 2016; 223: 829-837. doi: 10.1016/j.ijcard.2016.08.297Pastori D, Lip GYH, Farcomeni A, Del Sole F, Sciacqua A, Perticone F, et al. Incidence of bleeding in patients with atrial fibrillation and advanced liver fibrosis on treatment with vitamin K or non-vitamin K antagonist oral anticoagulants. International Journal of Cardiology. 2018; 264: 58-63. doi: 10.1016/j.ijcard.2018.01.097Pastori D, Lip GYH, Farcomeni A, Del Sole F, Sciacqua A, Perticone F, et al. Incidence of bleeding in patients with atrial fibrillation and advanced liver fibrosis on treatment with vitamin K or non-vitamin K antagonist oral anticoagulants. International Journal of Cardiology. 2018; 264: 58-63. doi: 10.1016/j.ijcard.2018.01.097Kuo L, Chao TF, Liu CJ, Lin YJ, Chang SL, Lo LW, et al. Liver Cirrhosis in Patients With Atrial Fibrillation: Would Oral Anticoagulation Have a Net Clinical Benefit for Stroke Prevention? J Am Heart Assoc.2017; 6(6): e005307. doi: 10.1161/JAHA.116.005307Kuo L, Chao TF, Liu CJ, Lin YJ, Chang SL, Lo LW, et al. Liver Cirrhosis in Patients With Atrial Fibrillation: Would Oral Anticoagulation Have a Net Clinical Benefit for Stroke Prevention? J Am Heart Assoc.2017; 6(6): e005307. doi: 10.1161/JAHA.116.005307

The authors declare that there are no conflicts of interest present.