摘要
门静脉血栓(PVT)是肝硬化患者最常见的血栓性疾病,常出现在进展期肝病患者中。PVT使肝脏血供进一步减少,肝功能恶化;同时加重门脉高压症,使静脉曲张出血风险增加、腹水加重。但是临床中,大部分PVT患者起病隐匿,无特殊症状,在肝硬化随访中被偶然发现。PVT对肝硬化自然病程的确切影响尚不清楚。PVT的治疗包括:药物治疗、介入治疗和手术治疗,方法的选择与应用多依据各诊疗中心的临床经验,尚无基于循证医学证据的指南。针对肝硬化患者抗凝治疗的适应证、药物选择、疗程及安全性监测等方面亦无共识意见。本文就当前肝硬化PVT患者抗凝治疗的现状与进展做一简单回顾,以期对临床工作有所帮助。
Portal vein thrombosis( PVT) is the most common thrombotic disease in patients with liver cirrhosis,most in patients with advanced liver disease. PVT reduces the blood supply to the liver and worsens the liver function. It also aggravates portal hypertension,increases the risk of variceal bleeding and worsens ascites. However,most patients with PVT have occult onset and have no special symptoms. They were incidentally discovered during follow-up. The exact effect of PVT on the natural course of cirrhosis is unknown. The treatment of PVT includes drug therapy,interventional therapy and surgical treatment. The choice and application of different methods are based on the clinical experience of each clinic,and there is no guideline based on evidence-based medical evidence. There is no consensus on the indications,drug selection,course of treatment and safety monitoring of anticoagulant therapy in patients with liver cirrhosis. In this paper,the status and progress of anticoagulant therapy for PVT in patients with cirrhosis are reviewed briefly,thus providing help for clinical work.
引文
1 Okuda K,Ohnishi K,Kinura K,et al.Incidence of portal vein thromhosis in liver cirrhosis.An angiographic study in 708 patients[J].Gastroenterology,1985,89(1):279-286.
2 Francoz C,Belghiti J,Vilgrain V,et al.Splanchnic vein thrombosis in candidates for liver transplantation:usefulness of screening and anticoagulation[J].Gut,2005,54(5):691-697.
3 Orlando G,Luca LD,Totil,et al.Liver Transplantation in the Presence of Portal Vein Thrombosis:Report From a Single Center[J].Transplantation Proceeding,2004,36(1):199-202.
4 Maruyama H,Okugawa H,Takahashi M,et al.De novo portal vein thrombosis in virusrelated cirrhosis:predictive factors and long-term outcomes[J].Am J Gastroenterol,2013,108(4):568-574.
5 Chen H,Liu L,Qi X,et al.Efficacy and safety of anticoagulation in more advanced portal vein thrombosis in patients with liver cirrhosis[J].Eur J Gastroenterol Hepatol,2016,28(1):82-89
6 Girleanu I,Stanciu C,Cojocariu C,et al.Natural course of nonmalignant partial portal vein thrombosis in cirrhotic patients[J].Saudi J Gastroenterol,2014,20(5):288-292.
7 Chung JW,Kim GH,Lee JH,et al.Safety,efficacy,and response predictors of anticoagulation for the treatment of nonmalignant portalveinthrombosis in patients with cirrhosis:propensity score matching analysis[J].Clin Mol Hepatol,2014,20(4):384-391.
8 John BV.Konjeti R,Aggarwal A,et al.Impact of untreated portal vein thrombosis on pre and post liver transplant outcomes in cirrhosis[J].Ann Hepatol,2013,12(6):952-958.
9 Luca A,Caruso S,Milazzo M,et al.Natural course of extrahepatic nonmalignant partial portal vein thrombosis in patients with cirrhosis[J].Radiology,2012,265(1):124-132.
10 Senzolo M,M Sartori T,Rossetto V,et al.Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis[J].Liver Int,2012,32(6):919-927.
11 De Santis A.Portal vein thrombosis(PVT)in cirrhotic patients:prevalence and associated factors[J].Dig Liver Dis,2001,33(Suppl.1):A61.
12 Ferreira CN,Rodrigues T,Alexandrino P,et al.Portal vein thrombosis in cirrhotic patients is associated with advanced liver disease and predicts poor long-term prognosis[J].Hepatology,2010,52(3):1072A.
13 D'Amico G,De Franchis R.Upper digestive bleeding in cirrhosis Post-therapeutic outcome and prognostic indicators[J].Hepatology,2003,38(3):599-612.
14 Amitrano L,Guardascione MA,Scaglione M,et al.Splanchnic vein thrombosis and varicealrebleeding in patients with cirrhosis[J].Eur JGastroenterol Hepatol,2012,24(12):1381-1385.
15 Nery F,Chevret S,Condat B,et al.Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis:results of a longitudinal study[J].Hepatology,2015,61(2):660-667.
16 Berry K,Taylor J,Liou IW,et al.Portal vein thrombosis is not associated with increased mortality among patients with cirrhosis[J].Clin Gastroenterol Hepatol,2015,13(3):585-593.
17 Englesbe MJ,Schaubel DE,Cai S,et al.Portal vein thrombosis and liver transplant survival benefit[J].Liver Transpl,2010,16(8):999-1005.
18 Ravaioli M,Zanello M,Grazi GL,et al.Portal vein thrombosis and liver transplantation:evolution during 10 years of experience at the University of Bologna[J].Ann Surg,2011,253(8):378-384.
19 Doenecke A,Tsui TY,Zuelke C,et al.Pre-existent portal vein thrombosis in liver transplantation:influence of preoperative disease severity[J].Clin Transplant,2010,24(1):48-55.
20 Ghabril M1,Agarwal S,Lacerda M,et al.Portal Vein Thrombosis Is a Risk Factor for Poor Early Outcomes After Liver Transplantation:Analysis of Risk Factors and Outcomes for Portal Vein Thrombosis in Waitlisted Patients[J].Transplantation,2016,100(1):126-133.
21 Gao PJ,Gao J,Li Z.et al.Liver transplantation in adults with portal vein thrombosis:Data from the China Liver Transplant Registry[J].Clin Res Hepatol Gastroenterol,2016,40(3):327-332.
22 Amitrano L,Guardascione MA,Menchise A,et al.Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis[J].J Clin Gastroenterol,2010,44(6):448-451.
23 Bento L.Antihrombotic therapy in non-neoplastic chronic portal venous thrombosis in cirrhosis:Recanalization and liver function evaluation[J].Blood,2011,118(21):3358A.
24 Delgado MG,Seijo S,Yepes I,et al.Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis[J].Clin Gastroenterol Hepatol,2012,10(1):776-783.
25 Maruyama H,Takahashi M,Shimada T,et al.Emergency anticoagulation treatment for cirrhosis patients with portal vein thrombosis and acute variceal bleeding[J].Scand J Gastroenterol,2012,47(6):686-691.
26 Werner KT,Sando S,Carey EJ,et al.Portal vein thrombosis in patients with end stage liver disease awaiting liver transplantation:outcome of anticoagulation[J].Dig Dis Sci,2013,58(6):1776-1780.
27 Copaci I,Ismail G,Micu L,et al.Anticoagulant therapy with sulodexidum for portal vein thrombosis in patients with liver cirrhosis[J].Hepatology,2013,58(3):867A-868A.
28 Takatori H,Hayashi T,Sunagozaka H,et al.Danaparoid sodium monotherapy for portal vein thrombosis in cirrhotic patients is as effective as combination therapy with antithrombinⅢ[J].Hepatology,2013,58(3):894A.
29 Cui SB,Shu RH,Yan SP,et al.Efficacy and safety of anticoagulation therapy with different doses of enoxaparin for portal vein thrombosis in cirrhotic patients with hepatitis B[J].Eur J Gastroenterol Hepatol,2015,27(8):914-919.
30 Naeshiro N,Aikata H,Hyogo H,et al.Efficacy and safety of the anticoagulant drug,danaparoid sodium,in the treatment of portal vein thrombosis in patients with liver cirrhosis[J].Hepatol Res,2015,45(6):656-662.
31 de Franchis R,Baveno VIFaculty.Expanding consensus in portal hypertension:Report of the Baveno VI Consensus Workshop:Stratifying risk and individualizing care for portal hypertension[J].JHepatol,2015,63(3):743-752.
32 Villa E,CammàC,Marietta M,etal.Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis[J].Gastroenterology,2012,143(5):1253-1260.
33 Zecchini RFA,Bernabucci V,Lei B,etal.Anticoagulant therapy is safe and effective in preventing portal vein thrombosis(PVT)in advanced cirrhotic patients:a prospective randomized controlled study[J].J Hepatol,2010,52:S460.
34 Senzolo M,Rodriguez Kryssia I,Rossetto V,et al.Increased anticoagulant response to low molecular weight heparin in plasma from patients with advanced cirrhosis[J].J Thromb Haemost,2012,10(9):1823-1829.
35 Basili S,Raparelli V,Violi F,et al.The coagulopathy of chronic liver disease:is there a causal relationship with bleeding?Yes[J].Eur JIntern Med,2010,21(2):62-64.
36 Potze W,Arshad F,Adelmeijer J,et al.Routine coagulation assays underestimate levels of antithrombin-dependent drugs but not of direct anticoagulant drugs in plasma from patients with cirrhosis[J].Br J Haematol,2013,163(5):666-673.
37 Valla DC.Thrombosis and anticoagulation in liver disease[J].Hepatology,2008,47(4):1384-1393.
38 Porte RJ,Lisman T,Tripodi A,et al.The International Normalized Ratio(INR)in the MELD score:problems and solutions[J].Am JTransplant,2010,10(6):1349-1353.
39 Bechmann LP,Sichau M,Wichert M,et al.Low-molecular-weight heparin in patients with advanced cirrhosis[J].Liver Int,2011,31(1):75-82.
40 Webster GJ,Burroughs AK,Riordan SM,et al.Review article:portal vein thrombosis-new insights into aetiology and management[J].Aliment Pharmacol Ther,2005,21(1):1-9.
41 Pollack Jr CV,Reilly PA,Eikelboom J,et al.darucizumab for dabigatran reversal[J].N Engl J Med,2015,373(6):511-520.
42 Potze W,Arshad F,Adelmeijer J,et al.Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis[J].PLo S One,2014,9D2:e88390.
43 Mueck W,Schwers S,Stampfuss J,et al.Rivaroxaban and other novel oral anticoagulants:pharmacokinetics in healthy subjects,specific patient populations and relevance of coagulation monitoring[J].Thromb J,2013,11(1):10.
44 Eerenberg ES,Kamphuisen PW,Sijpkens MK,et al.Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate:a randomized,placebo-controlled,crossover study in healthy subjects[J].Circulation,2011,124(14):1573-1579.
45 Marlu R,Hodaj E,Paris A,et al.Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban:a randomised crossover ex vivo study in healthy volunteers[J].Thromb Haemost,2012,108(2):217-224.
46 Martinez M,Tandra A,Vuppalanchi R,et al.Treatment of acute portal vein thrombosis by nontraditional anticoagulation[J].Hepatology,2014,60(1):425-426.
47 Pannach S,Babatz J,Beyer-Westendorf J,et al.Successful treatment of acute portal vein thrombosis with rivaroxaban[J].Thromb Haemost,2013,110(4):626-627.
48 Lenz K,Dieplinger B,Buder R,et al.Successful treatment of partial portal vein thrombosis(PVT)with low dose rivaroxaban[J].ZGastroenterol,2014,52(10):1175-1177.
49 Deleve ID,Val La DC,Garcia-Tsao G,et al.Vascular disorders of the liver[J].Hepatology,2009,49(5):1729-1764.
50 Qi X,Zhang C,Han G,et al.Prevalence of the JAK2V617F mutation in Chinese patients with Budd-Chiari syndrome and portal vein thrombosis:a prospective study[J].J Gastroenterol Hepatol,2012,27(6):1036-1043.
51 Tripodi M,Primignani V,Chantarangkul,et al.An imbalance of provs anti-coagulation factors in plasma from patients with cirrhosis[J].Gastroenterology,2009(137),pp:2105-2111.
52 Borensztajn K,Stiekema J,Nijmeijer S,et al.Factor Xa stimulates proinflammatory and profibrotic responses in fibroblasts via proteaseactivated receptor-2 activation[J].Am J Pathol,2008,172(2):309-320.
53 Duplantier JG,Dubuisson L,Senant N,et al.A role for thrombin in liver fibrosis[J].Gut,2004,53(11):1682-1687.
54 Abe W,Ikejima K,Lang T,et al.Low molecular weight heparin prevents hepatic fibrogenesis caused by carbon tetrachloride in the rat[J].J Hepatol,2007,46(2):286-294.
55 Kopec AK,Joshi N,Towery KL,et al.Thrombin inhibition with dabigatran protects against high-fat diet-induced fatty liver disease in mice[J].J Pharmacol Exp Ther,2014,351(2):288-297.
56 Anstee QM,Dhar A,Thursz MR.The role of hypercoagulability in liver fibrogenesis[J].Clin Res Hepatol Gastroenterol,2011,35(8-9):526-533.
57 Nevens F,Bustami R,Scheys I,et al.Variceal pressure is a factor predicting the risk of a first variceal bleeding:a prospective cohort study in cirrhotic patients[J].Hepatology,1998,27(1):15-19.
58 De Santis A,Moscatelli R,Catalano C,et al.Systemic thrombolysis of portal vein thrombosis in cirrhotic patients:a pilot study[J].Dig Liver Dis,2010,42(6):451-455.
