Nontumoral Portal Vein Thrombosis in Patients Awaiting Liver Transplantation

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1 LIVER TRANSPLANTATION 22: , 2016 REVIEW ARTICLE Nontumoral Portal Vein Thrombosis in Patients Awaiting Liver Transplantation Hui Chen, 1 Fanny Turon, 1,4 Virginia Hernandez-Gea, 1,4 Josep Fuster, 3 Angeles Garcia-Criado, 2 Marta Barrufet, 2 Anna Darnell, 2 Constantino Fondevila, 3 Juan Carlos Garcia-Valdecasas, 3 and Juan Carlos Garcia-Pagan 1,4 1 Barcelona Hepatic Hemodynamic Laboratory, Liver Unit; 2 Department of Radiology, Hospital Clinic, Institut d Investigacions Biomèdiques August Pi i Sunyer, and 3 HBP Surgery and Liver Transplantation Unit, University of Barcelona, Barcelona, Spain; and 4 Centro de Investigaci on Biom edica en Red de Enfermedades Hep aticas y Digestivas, Madrid, Spain Portal vein thrombosis (PVT) occurs in approximately 2%-26% of the patients awaiting liver transplantation (LT) and is no longer an absolute contraindication for LT. Nearly half of PVT cases are accidentally found during the LT procedure. The most important risk factor for PVT development in cirrhosis may be the severity of liver disease and reduced portal blood flow. Whether other inherited or acquired coagulation disorders also play a role is not yet clear. The development of PVT may have no effect on the liver disease progression, especially when it is nonocclusive. PVT may not increase the risk of wait-list mortality, but it is a risk factor for poor early post-lt mortality. Anticoagulation and transjugular intrahepatic portosystemic shunt (TIPS) are 2 major treatment strategies for patients with PVT on the waiting list. The complete recanalization rate after anticoagulation is approximately 40%. The role of TIPS to maintain PV patency for LT as the primary indication has been reported, but the safety and efficacy should be further evaluated. PVT extension and degree may determine the surgical technique to be used during LT. If a conventional end-to-end portal anastomotic technique is used, there is not a major impact on post-lt survival. Post-LT PVT can significantly reduce both graft and patient survival after LT and can preclude future options for re-lt. Liver Transpl 22: , VC 2015 AASLD. Received September 15, 2015; accepted November 25, Liver transplantation (LT) is the best and most common treatment for patients with end-stage liver disease. Because of better LT management, refined operative techniques, better organ preservation and immunosuppression, and specially trained surgeons, LT is a highly successful treatment for many patients. 1 Portal vein thrombosis (PVT) is defined by the formation of a thrombus within the main portal vein (PV) and intrahepatic portal branches which can extend into the splenic vein (SV) and/or superior mesenteric vein (SMV). 2 Classically, PVT was considered an absolute contraindication to LT and patients were not even evaluated for LT. The first successful LT in a patient with PVT was reported by the Pittsburgh group in Since that seminal experience, the development of various surgical and medical strategies have been proposed and conventional anastomotic techniques (end-to-end portal anastomosis) can be performed nowadays in the vast majority of PVT cases. 4 However, in patients with extensive portomesenteric thrombosis, LT is still technically challenging and associated with a poor prognosis. An impaired prognosis is due to the impossibility to perform LT, increased operative time, higher red blood cell transfusion requirements, higher rates of reintervention, and longer intensive care Abbreviations: CR, complete recanalization; CT, computed tomography; DDLT, deceased donor liver transplantation; DOAC, direct oral anticoagulant; FVL, factor V Leiden; GIB, gastrointestinal bleeding; HCC, hepatocellular carcinoma; HIT, heparin-induced thrombocytopenia; INR, international normalized ratio; JAK2, Janus kinase 2; IVC, inferior vena cava; LDLT, living donor liver transplantation; LMWH, low-molecular-weight heparin; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; MRI, magnetic resonance imaging; MTHFR, methylene tetrahydrofolate reductase; MVT, multivisceral transplantation; NA, not available; OPTN, Organ Procurement and Transplantation Network; PR, partial recanalization; PV, portal vein; PVT, portal vein thrombosis; SMV, superior mesenteric vein; SRS, splenorenal shunt; SV, splenic vein; TIPS, transjugular intrahepatic portosystemic shunt; US, ultrasonography; VKA, vitamin K antagonist. Address reprint requests to Juan Carlos Garcia-Pagan, Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Villarroel 170, Barcelona, Spain. Telephone: , ext. 2824; FAX: ; jcgarcia@clinic.ub.es DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2015 American Association for the Study of Liver Diseases.

2 LIVER TRANSPLANTATION, Vol. 22, No. 3, 2016 CHEN ET AL. 353 unit and hospital stay. 5 The potential impact of PVT modifying the prognosis of patients with cirrhosis while on the waiting list and the need for treatment is still a matter of debate. This review will focus on these issues. Pediatric patients or those with hepatocellular carcinoma (HCC) have their own characteristics and are not in the scope of this review. PREVALENCE, INCIDENCE, ETIOLOGY, DIAGNOSIS, AND CLASSIFICATION Prevalence and Incidence Prevalence and incidence of PVT often varies with different diagnostic methods and target populations. The prevalence was 1% on a necropsy study of the general population, 6 10%-25% in patients with cirrhosis without HCC submitted to ultrasound, 7 and 2%-26% in patients on the waiting list for LT. 5 Interestingly, up to 50% of patients with PVT at the time of LT were previously unrecognized. 8,9 The reported annual incidence of PVT in patients with cirrhosis is also variable, ranging from 4.6% to 17.9% (Table 1). For a population of Child A and B patients in the largest more recent prospective study, the 1-, 3-, and 5-year cumulative incidence rates of PVT were 4.6%, 8.2%, and 10.7%, respectively. 13 In patients with cirrhosis without PVT entering the LT waiting list, the 1-year reported de novo PVT varies between 7.4% 16 and 8.4%. 12 In another recent study using the Organ Procurement and Transplantation Network (OPTN) database, % of patients without PVT listed for a median waiting time of approximately 3 months had developed PVT at the moment of transplantation. Etiology Although there has been a lot of effort in recent years, the mechanisms involved in the development of PVT in patients with cirrhosis are not yet fully understood. Several predictive factors of PVT development have been identified. Decreased PV blood flow velocity (<15 cm/sec) has been found to be an independent predictor of PVT development in a longitudinal prospective study. 10 The potential value and the best cutoff value of PV blood flow velocity have not been determined yet. Other factors that have been found to be associated with the development of PVT, but that need prospective confirmation, are the presence of large portal-collateral vessels, 11 previous injury to the portal venous system (splenectomy, hepatectomy, surgical shunt, etc.), and focal inflammatory lesions (pancreatitis, cholecystitis, appendicitis, etc.). 18,19 Cirrhosis is characterized by a fragile hemostatic balance due to a decreased liver synthesis of procoagulant and anticoagulant factors. 20 In more detail, there is an increase in factor VIII, von Willebrand levels, and thrombin generation. 21 Coagulation abnormalities become more pronounced as the severity of the liver disease advances, and it has been suggested that this hypercoagulative state could facilitate the development of PVT. 22 However, 2 small nonlongitudinal studies partially evaluating this issue do not support this hypothesis, 23,24 and therefore, adequately designed prospective longitudinal large studies are needed. Although several studies have evaluated the potential implication of inherited thrombophilic disorders in the development of PVT in patients with cirrhosis, the results are still not conclusive 10,13,15,18,25-31 (Table 2). Only 3 studies were prospective and longitudinal, 10,13,15 and although not all inherited factors were evaluated, no clear relationship between the studied inherited factors and development of PVT was found. However, retrospective transversal studies suggest a potential role in increasing the risk of PVT for homozygous methylene tetrahydrofolate reductase (MTHFR) C677T gene mutation 25,28,29,32 as well as for the prothrombin G20210A 15,25-27 and factor V Leiden (FVL) 27 mutations, with the increase in the risk of PVT being more than 2.5-fold. 33 In another recent transversal retrospective study, plasminogen activator inhibitor type 1 4G-4G mutation together with MTHFR C677T gene mutation, but not prothrombin G20210A and FVL mutations, were independent predictors of PVT in patients with cirrhosis. 30 Antithrombin III, protein C, and protein S levels are reduced in patients with cirrhosis and correlate with liver disease severity but not with the risk of developing PVT. 34 However, in any of these studies, an attempt was made to differentiate real inherited deficiencies from acquired synthesis. Therefore, the potential role of these inherited factors still remains inconclusive, and more prospective longitudinal studies are needed. The potential role of various acquired prothrombotic disorders has also been evaluated. Antiphospholipid antibodies and antiphospholipid syndrome do not seem to be a major factors in PVT development. 35,36 Myeloproliferative disorders, which are commonly detected in noncirrhotic PVTs, have seldom been investigated in cirrhotic PVTs. The reported prevalence of Janus kinase 2 (JAK2) V617F mutation has been evaluated in 3 studies and ranges between 1.4% and 10%. 31,37,38 Once PVT develops, how the presence of associated prothrombotic disorders impacts the progression rate or response to treatment has never been properly evaluated and deserves further study. Overall, the above-mentioned data suggest that it may not be mandatory to screen for acquired or inherited thrombophilic disorders when a patient with cirrhosis develops PVT. Diagnosis Ultrasonography (US) is the first-line diagnostic approach when PVT is suspected; it is noninvasive, inexpensive, and repeatable. The diagnostic sensitivity and specificity for color Doppler ultrasound vary from 66% to 100% depending on the expertise of the individual examiner and the extent of PVT The value of US is reduced in the presence of bowel gas and obesity, and its main limitation is delimiting the extension of the thrombi to SV or SMV. The best time frame to perform US for the screening of PVT in patients with cirrhosis

3 354 CHEN ET AL. LIVER TRANSPLANTATION, March 2016 TABLE 1. Incidence of PVT in Patients With Liver Cirrhosis Patients Reference LT* (n) Child C (%) Diagnostic Tool New PVT (n) Partial/ Complete 1 Year 2 Year 3 Year 5 Year Reported Rate During the Indicated Follow-up Zocco et al. 10 (2009) No 73 25% US 12 8/3 16.4% NA NA NA 16.4% Maruyama et al. 11 No % US 42 31/ % 14.9% 18.6% 20% 28%, follow-up (2013) non-thrombosis group: 67.5 (range ) m; follow-up thrombosis group: 63.3 (range ) m John et al. 12 (2013) Yes 243 NA US, CT, MRI 23 NA 8.4% 17.3% NA NA NA Nery et al. 13 (2014) No % US /17 4.6% NA 8.2% 10.7% 9.4%, follow-up: range 47 m Abdel-Razik et al. 14 No % US 17 12/5 17.9% NA NA NA NA (2015) Amitrano et al. 15 (2002) Francoz et al. 16 (2005) Ghabril et al. 17 (2015) No % US 10 k 6/3 NA NA NA NA 16.4%, follow-up: 7.4 (range 2-11) m Yes % US, CT, MRI, during LT 17 14/3 NA NA NA NA 7.4%, follow-up: (range 4-27) m Yes NA During LT 2205 NA NA NA NA NA 4.9%, follow-up: days *The study was done among patients on the waiting list for LT. This percentage is about the entire initial group (n 5 100). 1 patient with portal cavernoma. 14 patients with obstruction that varied over time from partial to complete. k 1 patient had a right portal branch thrombosis.

4 LIVER TRANSPLANTATION, Vol. 22, No. 3, 2016 CHEN ET AL. 355 TABLE 2. Studies That Evaluated the Potential Role of Factor II Prothrombin G20210A Mutation, FVL G1691A Mutation, and Homozygous MTHFR 677TT Mutation in the Development of PVT in Liver Cirrhosis Reference Design Group Patients, n FII Mutation, n (%) P Value FV Mutation, n (%) P Value Homozygous MTHFR, n (%) P Value Amitrano et al. 25 (2000) Transversal PVT (34.8%) (13%) (43.5%) <0.001 PVT 40 1 (2.5%) 3 (7.5%) 2 (5%) Amitrano et al. 15 (2002) Longitudinal PVT (50%) < (0%) NA 2 (20%) NA PVT 51 1 (2%) 1 (2%) 2 (3.9%) Amitrano et al. 26 (2004) Transversal PVT (21.4%) (11.4%) (21.4%) 0.24 PVT 79 4 (5.1%) 4 (5.1%) 11 (14.1%) Mangia et al. 18 (2005) Transversal PVT (4.7%) > (2.3%) > (20.9%) >0.05 PVT (3.4%) 6 (3.4%) 39 (22.1%) Erkan et al. 27 (2005) Transversal PVT (29%) < (29%) < (0%) >0.05 PVT 57 2 (3.5%) 2 (3.5%) 2 (3.5%) Pasta et al. 28 (2006) Transversal PVT1 78 NA NA NA NA 19 (54%) 0.04 PVT 78 NA NA NA NA 9 (25%) Gabr et al. 29 (2010) Transversal PVT1 21 NA NA NA NA 7 (33.3%) 0.04 PVT 55 NA NA NA NA 6 (10.9%) D Amico et al. 30 (2015) Transversal PVT (5.3%) > (11.5%) > (26.7%) <0.001 PVT (3.2%) 38 (6.1%) 74 (11.9%) Saugel et al. 31 (2015) Transversal PVT (0%) > (5%) 0.65 NA NA PVT 43 1 (2%) 5 (12%) NA Total, n (%) PVT1 48/436 (11%) 41/436 (9.4%) 127/514 (24.7%) PVT 35/1068 (3.3%) 59/1068 (5.5%) 145/1158 (12.5%)

5 356 CHEN ET AL. LIVER TRANSPLANTATION, March 2016 has not been well defined. A recent study has shown that performing US every 3 months detects PVT more frequently than when US is performed every 6 months, 13 although surprisingly PVT had spontaneously disappeared at the following imaging study in a significant proportion of patients. Taking this into account, in the setting of the LT waiting list, it is probably wise to perform PVT screening with US every 3 months because of theimportanceofdetecting progression. 8 Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are both good options to delineate the extent, and the precise location of the thrombus providing valuable information regarding the patency of the SV/SMV junction, the distal SMV, and possible venous collaterals that could be used as potential inflow vessels when the PV is not available. 40,42 Both CT and MRI angiography have replaced conventional angiography in the preoperative evaluation and planning for LT. 43 It has to be remembered that the presence of calcification within the wall of the vessel or the thrombus, which can eventually add complexity to the LT procedure, can only be detected using US or CT but not MRI. 41 Classifications PVT is most commonly presented as an incidental finding at imaging techniques in the screening for HCC or for other nonrelated reasons. 26 PVT can be evaluated on its age (acute or chronic), degree (partial or complete), and extension (extended into SMV, SV, or the right/left portal branch). Characterization of the thrombus is of special relevance because all of these factors seem to correlate with the probability of thrombus disappearance under anticoagulation treatment. This is also helpful for the evaluation of response after certain treatments. Acute PVT may be diagnosed in the evaluation of abdominal pain, but it may be also asymptomatic and detected in a routine imaging study. It is usually difficult to accurately assess the age of the thrombus. However, a finding of a hyperdense thrombus within the PV on noncontrast-enhanced CT suggests that the thrombus is recent. 39 In patients without liver cirrhosis, the presence of a cavernoma may suggest that PVT is chronic. Nevertheless, development of portal cavernoma may develop very early after acute PVT. 44 In patients with cirrhosis, development of portal cavernoma is much less frequent. Some studies have divided PVT into asymptomatic and symptomatic. However, no clear definition of symptomatic PVT is provided given a broad spectrum of clinical presentations. Classifying PVT requires assessing the number of vessels of the splanchnic venous system that are involved and the percentage of the lumen that the thrombus is occupying. Several classifications of PVT have been proposed. 4,45,46 However, the most widely used is the one by Yerdel et al. 40 that has been demonstrated to have a prognostic value in patients who are submitted to LT: grade I, thrombus at main PV affecting less than 50% of the lumen with or without minimal extension into SMV; grade II, thrombus at PV affecting more than 50%, including complete thrombosis, with or without minimal extension into the SMV; grade III, complete PVT plus thrombosis extending to the proximal SMV with patent distal SMV; grade IV, complete PVT plus complete thrombosis of the SMV (proximal and distal; Fig. 1). IMPACT OF PORTAL VEIN THROMBOSIS ON NATURAL HISTORY OF LIVER CIRRHOSIS AND LIVER TRANSPLANTATION Impact of Portal Vein Thrombosis on the Natural History of Liver Cirrhosis To what extent the development of PVT has an impact on the natural history of liver cirrhosis is unclear. Several studies have shown that PVT is more frequently found in patients with more severe liver disease with a prevalence ranging from <1% in patients with well-compensated cirrhosis to > 25% in patients at the transplant waiting list. 10,13,26,40 However, whether PVT is the cause or the consequence of liver deterioration or if both are the consequence of a common pathophysiological mechanism that independently promotes liver impairment and the development of PVT is still a matter of debate. A recent prospective study including more than 1000 Child A and B patients with cirrhosis without PVT showed an annual incidence of PVT of <5%. In this study, the only independent factor predicting survival was the severity of liver cirrhosis, but not the development of PVT. 13 In addition, no relationship between PVT development and worsening of liver function during follow-up was found. However, it is important to remark that in this study, most patients developed only a partial nonocclusive PVT and the lack of impact in extensive/occlusive thrombosis remains elusive. Two previous retrospective studies also showed that the progression or regression of partial PVT had no clinical impact on the prognosis of patients with cirrhosis. 11,47 Additionally, in a recent study evaluating the effect of prophylactic doses of enoxaparin in patients with cirrhosis (B7-C10), no association between prevention of disease progression and prevention of PVT was observed. 48 On the other hand, several studies including a large number of patients with cirrhosis with acute variceal bleeding identified the presence of PVT as an independent predictor of 5-day treatment failure Impact of Portal Vein Thrombosis on the Wait- List Mortality and on Liver Transplantation Data from the Scientific Registry of Transplant Recipients and OPTN (n 5 22,291) and data from a singlecenter study 12 showed that the presence of PVT does not increase the risk of wait-list mortality. 52 Another study using the United Network for Organ Sharing registries (n 5 66,506) found that patients with PVT

6 LIVER TRANSPLANTATION, Vol. 22, No. 3, 2016 CHEN ET AL. 357 Figure 1. Yerdel classification of PVT for LT (Ref. 40). (A) Grade I: thrombus at main PV affecting less than 50% of the lumen with or without minimal extension into SMV; (B) Grade II: thrombus at PV affecting more than 50%, including complete thrombosis, with or without minimal extension into the SMV; (C) Grade III: complete PVT plus thrombosis extending to the proximal SMV with patent distal SMV; (D) Grade IV: complete PVT plus complete thrombosis of the SMV (proximal and distal). on LT waiting lists have lower mortality than patients without PVT. 53 Unfortunately, none of these analyses differentiated partial from occlusive PVT. The impact of PVT on survival after LT is also full of controversy, even in recent systematic reviews. 4,5,45 Survival may depend on the grade of PVT and the kind of surgery, 54 whereas incidentally discovered PVT during LT may have a limited effect on post-lt outcome. 9 According to Yerdel s classification, patients with grade I-III PVT have similar survival rates to those with PVT, and patients with grade IV PVT have a higher rate of mortality. 4 According to a recent meta-analysis, partial PVT seems to have no impact on post-lt survival rates, whereas patients suffering from complete PVT have inferior 1-year survival rates. However, complete PVT does not affect longterm survival. 8,45,52 This hypothesis was recently confirmed by a large study that used the database of OPTN (n 5 48,570). 17 This study found that the survival rates of patients with PVT at LT were significantly worse compared with those without PVT within the first 90 days after LT, but the results were similar in both groups for patients surviving longer than 6 months. 17 For physiologic portal anastomosis, the survival rates may be similar to those for patients without PVT regardless of its degree and extension, whereas the survival rate is decreased in those patients with nonanatomic portal anastomosis (cavoportal hemitransposition; renoportal anastomosis; PV arterialization). 8,55 MANAGEMENT OF PORTAL VEIN THROMBOSIS IN CANDIDATES FOR LIVER TRANSPLANTATION For patients with PVT awaiting LT, the main objective of treatment is to allow portal flow to the graft to be restored through conventional end-to-end PV

7 358 CHEN ET AL. LIVER TRANSPLANTATION, March 2016 anastomosis because (see below) this is associated with a better LT outcome in comparison with those transplants in which other surgical approaches for PV vascularization are needed. 8 Thus, in patients with PVT already extending to the SMV, the goal will be to achieve recanalization of at least this area, whereas in patients without compromise of this area, the goal will be to prevent the extension of the thrombus during waiting time. Emerging evidence has shown that spontaneous recanalization of the PV may occur. This has been evaluated in at least 8 studies, including 316 patients with cirrhosis, most of them with partial PVT 11-13,16,47,56-58 (Table 3). Complete or partial recanalization was reported in 141 (44.6%) of these patients with the reported recanalization rate ranging from 0% to 69%. However, progression of thrombosis was also reported in 64/316 (20.3%) patients with a progression rate ranging from 8.8% to 71.4%. Unfortunately, besides PVT extension factors, predictions of spontaneous improvement or progression of thrombosis remain unknown. The differences in the reported incidences of spontaneous recanalization or progression of the thrombus are probably related to different severity of the disease and, even more importantly, to different imaging techniques used to stage the extent of the thrombus. The heterogeneous rate of spontaneous recanalization or of progression makes it difficult to evaluate the real efficacy of the different treatments used for PVT. If no treatment is decided, a close imaging surveillance has to be adopted. When treatment is considered, 2 major strategies can be implemented: anticoagulation and/or transjugular intrahepatic portosystemic shunt (TIPS). Anticoagulation To date, 10 studies have evaluated the safety and efficacy of anticoagulation for PVT in liver cirrhosis 16,56-64 (Table 4). Most of them were retrospective, have small sample sizes, and the majority of patients had partial nonocclusive PVT. In total, 295 patients had been included and treated with different anticoagulation strategies. In 210 (71.2%) patients, improvement in PVT after anticoagulation was observed (complete recanalization [CR] in 44% of patients and partial in the remaining 56%). The reported improvement ranged between 42% and 100% in the different studies. Delay between PVT diagnosis and initiation of anticoagulation seems to be the most important factor predicting recanalization. 56,57,61 Indeed, an interval of <6 months was associated with a higher recanalization rate. 56,57 Withdrawal of anticoagulation is associated with recurrence in up to 38% of patients. 61 Recurrent thrombosis may occur early after stopping anticoagulation. This observation suggests that the prolongation of anticoagulation treatment after repermeation of the PV may prevent rethrombosis. Two studies evaluated the efficacy of anticoagulation, specifically in patients awaiting LT. The CR rate was 39% and 42.1% after a mean duration of 10 and 7.6 minutes, respectively. 16,62 TABLE 3. Studies That Evaluated the Outcome of PVT in Patients With Liver Cirrhosis Without Anticoagulation Improved, n (%) Stable, Progression, CR PR Overall n (%) n(%) Partial/ References LT* Patients, n Total, n (%) Francoz et al. 16 (2005) Yes (100)/0 (0) 0 (0) NA 0 (0) 4 (40) 6 (60) Senzolo et al. 56 (2012) No (66.7)/7 (33.3) 1 (4.8) NA 1 (4.8) NA 15 (71.4) Luca et al. 47 (2012) No (100)/0 (0) NA NA 19 (45.2) 9 (21.4) 14 (33.3) Maruyama et al. 11 (2013) No (81) /8 (19) NA NA 20 (47.6) 19 (45.2) 3 (7.1) John et al. 12 (2013) Yes 70 NA NA NA 22 (31.4) NA 3 (4.3) Chung et al. 57 (2014) No 14 NA 3 (21.4) 2 (14.3) 5 (35.7) 6 (42.9) 3 (21.4) Nery et al. 13 (2014) No (100)/0 (0) 70 (69.3) NA 70 (69.3) NA 14 (13.9) Chen et al. 58 (2015) No 16 6 (37.5)/10 (62.5) NA NA 4 (25) 6 (37.5) 6 (37.5) Total, n (%) (44.6) 64 (20.3) *The study was done among patients on the waiting list for LT. Thrombosis was considered to be occlusive when blood flow was absent or thrombus involved more than 90% of the vessel. At least half of the vascular lumen of the portal trunk was involved. Partial was considered when the thrombosis occupied < 75% of PV lumen while total was > 75%.

8 LIVER TRANSPLANTATION, Vol. 22, No. 3, 2016 CHEN ET AL. 359 TABLE 4. Studies That Evaluated the Outcome of PVT in Patients With Cirrhosis Treated With Anticoagulation Improved, n (%) Reference LT* Patients, n Drugs CR PR Overall Stable, n (%) Progression, n (%) Complications Francoz et al. 16 (2005) Amitrano et al. 59 (2010) Senzolo et al. 56 (2012) Maruyama et al. 60 (2012) Delgado et al. 61 (2012) Werner et al. 62 (2013) Naeshiro et al. 63 (2015) Chung et al. 57 (2014) Cui et al. 64 (2015), 1.5 mg/kg Cui et al. 64 (2015), 1 mg/kg Chen et al. 58 (2016) Yes 19 Nadroparin/ acenocoumarol 8 (42.1%) 0 (0) 8 (42.1%) 10 (52.6%) 1 (5.3%) No No 28 Enoxaparin 21 (75%) 2 (7.1%) 23 (82.1%) 3 (10.7%) 2 (7.1%) No No 33 Nadroparin 12 (36%) 9 (27%) 21 (63%) 7 (21%) 5 (15%) Epistaxis (n 5 1); haematuria (n 5 1); cerebral hemorrhage (n 5 1); HIT (n 5 1) No 5 LMWH 5 (100%) 0 (100%) 5 (100%) 0 (0%) 0 (0%) No No 55 LMWH/VKA 25 (45.5%) 8 (14.5%) 33 (60%) no improvement: 22 (40%) Lower GIB (n 5 1); oral bleeding (n 5 1); obscure GIB (n 5 1); vaginal bleeding (n 5 1); surgical wound hemorrhage (n 5 1) Yes 28 Warfarin 11 (39%) 12 (43%) 23 (82%) 5 (18%) 0 (0%) Vaginal bleeding (n 5 1) No 26 Danaparoid 4 (15%) 16 (62%) 20 (77%) 6 (23%) 0 (0%) No No 14 Warfarin 6 (42.9%) 5 (35.7) 11 (78.6%) 2 (14.3%) 1 (7.1%) No No 34 Enoxaparin 8 (23.5%) 18 (52.9%) 26 (76.5%) no improvement: 8 (23.5%) Injection-site hemorrhage (n 5 2); epistaxis (n 5 4); hematuria (n 5 2) No 31 Enoxaparin 9 (29%) 16 (51.6%) 25 (80.6%) no improvement: 6 (19.4%) Injection-site hemorrhage (n 5 1); epistaxis (n 5 1) No 22 Warfarin NA NA 15 (68.2%) 4 (18.2%) 3 (13.6%) Epistaxis (n 5 1); gingival hemorrhage (n 5 3); stomach upset (n 5 2) Total, n (%) 109/273 (39.9%) 86/273 (31.5%) 210/295 (71.2%) 37/175 (21.1%) 12/175 (6.9%) *The study was done among patients on the waiting list for LT.

9 360 CHEN ET AL. LIVER TRANSPLANTATION, March 2016 Low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKAs) were the 2 main anticoagulants used. There is no consensus about the superiority of one over the other. LMWH has the advantage of a fixed dose that does not require laboratory monitoring, and it does not affect international normalized ratio (INR) values. However, the inconvenience of daily subcutaneous injections may reduce compliance. LWMH is mainly eliminated by the kidney, so patients with decreased renal function may need dose adjustments. 65 A recent study compared the safety and efficacy of different dosages of enoxaparin (1.5 mg/kg per 24 hours versus 1 mg/kg per 12 hours) for cirrhotic PVT and showed comparable efficacy; however, there were significantly higher rates of injection-site hemorrhage, epistaxis, or hematuria in the 1.5 mg/kg group. 64 VKAs are still the choice for longterm anticoagulation with the limitation of regular monitoring of INR. Anticoagulant INR-induced changes will overestimate the Model for End-Stage Liver Disease (MELD) scores. Besides, INR does not correlate well with the degree of anticoagulation in patients with cirrhosis. 66 Recently, direct oral anticoagulants (DOACs) were approved for clinical use in indications different from PVT (ie, dabigatran, rivaroxaban, and apixaban). DOACs would offer the theoretical advantage of no need for laboratory monitoring However, the experience with DOACs in patients with cirrhosis is very limited, 70 and until more studies are available, they cannot be formally recommended for patients with cirrhosis. A common concern when patients with cirrhosis and portal hypertension are given anticoagulants is the risk of worsening variceal bleeding. If the decision of initiating anticoagulation is taken, it is wise to recommend screening for varices by endoscopy and initiation of standard primary or secondary prophylaxis of variceal bleeding before starting treatment. Nevertheless, a recent multicenter retrospective study in patients with cirrhosis having an episode of upper gastrointestinal bleeding (GIB) while being anticoagulated showed that anticoagulation is not associated with an increase in 5-day treatment failure or 6-week mortality. 51 The reported adverse events probably related with anticoagulation were symptomatic cerebral hemorrhage, lower GIB, oral bleeding, obscure GIB, vaginal bleeding, and surgical wound hemorrhage. However, no anticoagulation-related deaths were reported. 56,61,62 TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT Classically, PVT was considered a contraindication for TIPS but the increased expertise and improvement in radiological techniques have completely changed this concept. TIPS has been shown to be successfully placed in 75%-100% of patients with cirrhosis and PVT The feasibility of this procedure is reduced in patients with portal cavernoma or when imaging studies are unable to detect patent intrahepatic PV branches. 74 However, in centers with high-level technical expertise and with the introduction of the transhepatic and transsplenic route to access the PV, TIPS can finally be placed in a high percentage (48.1%-100%) of patients. 71,72,75 However, in most patients, TIPS was indicated to treat a severe complication of portal hypertension, and PVT was identified during the pre-tips workout. Only the study by Salem et al. 71 included patients in whom TIPS was specifically indicated to restore PVT patency to facilitate LT. In addition, the number of patients for whom TIPS was not even considered due to the presence and/or the extension of thrombosis in the portal venous axis is unknown. This makes it difficult to estimate the real applicability of TIPS in the management of PVT in patients with cirrhosis. When TIPS is successfully placed, the portal recanalization can be achieved in up to 80% of the patients, 73 and this seems to happen without the need of anticoagulation. 71,73 Indeed, in the study by Salem et al., 71 although persistence of thrombus was noted in 77% of the patients in whom TIPS was placed, the thrombus had disappeared in more than a third of them 1 month later without using anticoagulation. 71 This is thought to be due to clot dissolution promoted by the increased portal blood flow once TIPS reestablishes portal venous flow. From the perspective of LT, TIPS misplacement is a well-known condition that increases the technical difficulty of LT. 76 To reduce the transplantation difficulties, the stent should extend the shortest possible distance into the main PV in the proximal end and should not extend into the inferior vena cava (IVC; or atrium). 77 Thus, TIPS could represent an alternative to anticoagulation in patients with cirrhosis and PVT and offers the additional advantage of ameliorating portal hypertension related complications. Studies are needed that are specifically designed to compare the effectiveness of anticoagulation versus TIPS for the treatment of PVT in patients with cirrhosis. IMPACT OF PORTAL VEIN THROMBOSIS IN LIVER TRANSPLANTATION PROCEDURE From the first successful report of LT in patients with PVT in 1985, 3 different approaches to restore the PV patency at the time of LT have been suggested. Precise imaging evaluations of PVT before LT is necessary to plan for PV reconstruction, and conventional end-to-end portal anastomosis should always be the first-line option. The management of adult living donor liver transplantation (LDLT) is principally similar to deceased donor liver transplantation (DDLT), but LDLT in patients with PVT has its own difficulties, such as the need for distal dissection of the vascular pedicle of the hilum and restricted availability of a vein graft Technical issues have been extensively reviewed previously, and the algorithm for the management of PVT during LT has been proposed according to Yerdel classification. 55,81,82

10 LIVER TRANSPLANTATION, Vol. 22, No. 3, 2016 CHEN ET AL. 361 Briefly, management is similar for patients with grades I to III PVT and includes the resection of the short-affected PV segment, 40 removal of PVT by eversion thrombectomy, or thromboendovenectomy (ie, removal of the clot and the attached intimal layer of the vein). 4 If portal flow is insufficient, different options can be considered in order to establish an adequate portal flow, 82 like ligation of the portosystemic collaterals or the left renal vein if splenorenal shunt (SRS) exists, 83 additional PV arterialization, or an additional interposition graft between a patent splanchnic tributary and the PV. 81 If an adequate flow cannot be achieved or a low dissection of the retropancreatic PV or distal SMV part is required, a jump graft or polytetrafluoroethylene graft from the SMV to the donor PV will be necessary. 81,82,84 In grade IV patients, the PV can be anastomosed to a patent splanchnic tributary, for example, the coronary vein or a large collateral vein (diameter of 2 cm or more). 4,82,85-87 If the portal inflow after these methods was suboptimal or PV cannot be anastomosed, PV arterialization is a simple and effective method of augmenting suboptimal portal inflow in endto-end or end-to-side anastomosis. A disadvantage, however, is that it leaves the portal hypertension unchanged, and overarterialization of the liver can eventually lead to fibrosis. 88 For patients with a patent SRS (either spontaneous or surgically created), renoportal anastomosis can establish nearly physiologic flows, and it has become the technique of choice. 81 The 1- and 5-year survival rates can be as high as 83%- 100% and 60%, respectively. 89,90 Cavoportal hemitransposition is an anastomosis between the allograft PV and the suprarenal recipient IVC in an end-to-side or end-to-end manner. 81,82,91 Multivisceral transplantation (MVT) may be the ideal treatment for patients with extensive grade IV PVT. 92 MVT restores anatomical portal blood flow and completely reverses portal hypertension, but the experience with MVT in the setting of diffuse PVT is limited and only approximately 25 patients have been reported POSTLIVER TRANSPLANTATION PORTAL VEIN THROMBOSIS AND MANAGEMENT Post-LT PVT can significantly reduce both graft and patient survival after LT and can cause limitations or loss of future options for re-lt. 96,97 Pre-LT PVT is a risk factor for PVT recurrence in the recipient, which occurs, especially in the early period after LT. 5,98 The recurrence rate of PVT has reduced from 36% in the early experience to 2%-3% in recent years. 5 The rate of rethrrombosis may be related with a greater degree and extension of pre-lt PVT and nonanatomical anastomosis: 4% in partial PVT and 12.3% in complete PVT; 3.5%, 10.7%, 22.2%, and 17% in Yerdel grade I, II, III, and IV, respectively 4 ; 11.3% in patients with cavoportal hemitransposition 81 ; and 5.8%-10% in patients with renoportal anastomosis. 89,90 The incidence of vascular complications was reported to be higher among the LDLT group (7.2%) compared with the DDLT group (2.6%) without pre-lt PVT, especially for pediatrics. 99 Close follow-up with Doppler US in the first week immediately after LT is recommended for the early detection of PVT recurrence, which can be confirmed by CT or MRI. 100 It is necessary to perform short-term anticoagulation, like LMWH, for the prevention of post-lt PVT, especially for those with cavoportal hemitransposition, renoportal anastomosis, and LDLT. 8,97,98,101 However, no consensus exists about the duration and the optimal dose of anticoagulants in this setting. In our center, we usually recommend 3 months of LMWH treatment. Once post-lt PVT occurs, treatment is more challenging because alternative portal inflow can be difficult to establish. 96 If PVT appears despite anticoagulation, treatment has to be started as soon as the diagnosis is made, and minimally invasive techniques should be considered depending on the characteristics of PVT (stage, degree, and extension), severity of symptoms, and the availability of local expertise. Catheter-directed percutaneous mechanical and/or pharmacologic thrombolysis or stent placement via a transjugular, transhepatic, and transsplenic approach can be both safe and effective. 97, If not effective, combination of TIPS, mechanical thrombectomy, and angioplasty with or without local thrombolytic therapy may be an alternative. 106,107 Surgical treatment is considered to be the last therapeutic option. 108,109 CONCLUSION PVT remains an important and controversial issue for LT. Thrombophilia seems to play a limited role in the development of PVT, and strong evidence coming from randomized clinical trials is certainly needed. The causal relationship of PVT and liver deterioration is still a matter of debate, especially for occlusive PVT. Well-designed studies without selection bias are warranted for pre-lt PV recanalization-tips. The physiologic end-to-end portal anastomosis may have limited impact on prognosis, but the influence of nonphysiological methods should be further investigated. Post- LT PVT is a serious complication, and more evidence to guide its best management is greatly needed. Whether or not patients with occlusive PVT should get priority or a MELD exception on the waiting list needs further investigation. REFERENCES 1. Dutkowski P, Linecker M, DeOliveira ML, M ullhaupt B, Clavien PA. Challenges to liver transplantation and strategies to improve outcomes. Gastroenterology 2015; 148: Qi X, Han G, Fan D. Management of portal vein thrombosis in liver cirrhosis. Nat Rev Gastroenterol Hepatol 2014;11: Shaw BW Jr, Iwatsuki S, Bron K, Starzl TE. Portal vein grafts in hepatic transplantation. Surg Gynecol Obstet 1985;161: Rodrıguez-Castro KI, Porte RJ, Nadal E, Germani G, Burra P, Senzolo M. Management of nonneoplastic portal

11 362 CHEN ET AL. LIVER TRANSPLANTATION, March 2016 vein thrombosis in the setting of liver transplantation: a systematic review. Transplantation 2012;94: Ponziani FR, Zocco MA, Senzolo M, Pompili M, Gasbarrini A, Avolio AW. Portal vein thrombosis and liver transplantation: implications for waiting list period, surgical approach, early and late follow-up. Transplantation Rev (Orlando) 2014;28: Ogren M, Bergqvist D, Bj orck M, Acosta S, Eriksson H, Sternby NH. Portal vein thrombosis: prevalence, patient characteristics and lifetime risk: a population study based on 23,796 consecutive autopsies. World J Gastroenterol 2006;12: Tsochatzis EA, Senzolo M, Germani G, Gatt A, Burroughs AK. Systematic review: portal vein thrombosis in cirrhosis. Aliment Pharmacol Ther 2010;31: Francoz C, Valla D, Durand F. Portal vein thrombosis, cirrhosis, and liver transplantation. J Hepatol 2012;57: Koh PS, Chan SC, Chok KS, Sharr WW, Wong TC, Sin SL, Lo CM. The friendly incidental portal vein thrombus in liver transplantation. Liver Transpl 2015;21: Zocco MA, Di Stasio E, De Cristofaro R, Novi M, Ainora ME, Ponziani F, et al. Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development. J Hepatol 2009;51: Maruyama H, Okugawa H, Takahashi M, Yokosuka O. De novo portal vein thrombosis in virus-related cirrhosis: predictive factors and long-term outcomes. Am J Gastroenterol 2013;108: John BV, Konjeti R, Aggarwal A, Lopez R, Atreja A, Miller C, et al. Impact of untreated portal vein thrombosis on pre and post liver transplant outcomes in cirrhosis. Ann Hepatol 2013;12: Nery F, Chevret S, Condat B, de Raucourt E, Boudaoud L, Rautou PE, et al.; for Groupe d Etude et de Traitement du Carcinome Hepatocellulaire. Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study. Hepatology 2015;61: Abdel-Razik A, Mousa N, Elhelaly R, Tawfik A. De-novo portal vein thrombosis in liver cirrhosis: risk factors and correlation with the Model for End-Stage Liver Disease scoring system. Eur J Gastroenterol Hepatol 2015; 27: Amitrano L, Brancaccio V, Guardascione MA, Margaglione M, Sacco M, Martino R, et al. Portal vein thrombosis after variceal endoscopic sclerotherapy in cirrhotic patients: role of genetic thrombophilia. Endoscopy 2002;34: Francoz C, Belghiti J, Vilgrain V, Sommacale D, Paradis V, Condat B, et al. Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation. Gut 2005;54: Ghabril M, Agarwal S, Lacerda M, Chalasani N, Kwo P, Tector AJ. 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. Transplantation 2016;100: Mangia A, Villani MR, Cappucci G, Santoro R, Ricciardi R, Facciorusso D, et al. Causes of portal venous thrombosis in cirrhotic patients: the role of genetic and acquired factors. Eur J Gastroenterol Hepatol 2005;17: DeLeve LD, Valla DC, Garcia-Tsao G; for American Association for the Study Liver Diseases. Vascular disorders of the liver. Hepatology 2009;49: Lisman T, Caldwell SH, Burroughs AK, Northup PG, Senzolo M, Stravitz RT, et al.; for Coagulation in Liver Disease Study Group. Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol 2010;53: Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011;365: Tripodi A, Primignani M, Chantarangkul V, Dell Era A, Clerici M, de Franchis R, et al. An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology 2009;137: Chen H, Qi X, He C, Yin Z, Fan D, Han G. Coagulation imbalance may not contribute to the development of portal vein thrombosis in patients with cirrhosis. Thromb Res 2013;131: Tang W, Wang Y, Zhao X, Wang X, Zhang T, Ou X, et al. Procoagulant imbalance aggravated with falling liver function reserve, but not associated with the presence of portal vein thrombosis in cirrhosis. Eur J Gastroenterol Hepatol 2015;27: Amitrano L, Brancaccio V, Guardascione MA, Margaglione M, Iannaccone L, D Andrea G, et al. Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis. Hepatology 2000;31: Amitrano L, Guardascione MA, Brancaccio V, Margaglione M, Manguso F, Iannaccone L, et al. Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol 2004;40: Erkan O, Bozdayi AM, Disibeyaz S, Oguz D, Ozcan M, Bahar K, et al. Thrombophilic gene mutations in cirrhotic patients with portal vein thrombosis. Eur J Gastroenterol Hepatol 2005;17: Pasta L, Marrone C, D amico M, Virdone R, D amico G, Sammarco P, et al. MTHFR C677T mutations in liver cirrhosis with and without portal vein thrombosis. Liver Int 2006;26: Gabr MA, Bessa SS, El-Zamarani EA. Portal vein thrombosis in Egyptian patients with liver cirrhosis: Role of methylenetetrahydrofolate reductase C677T gene mutation. Hepatol Res 2010;40: D Amico M, Pasta F, Pasta L. Thrombophilic genetic factors PAI-1 4G-4G and MTHFR 677TT as risk factors of alcohol, cryptogenic liver cirrhosis and portal vein thrombosis, in a Caucasian population. Gene 2015;568: Saugel B, Lee M, Feichtinger S, Hapfelmeier A, Schmid RM, Siveke JT. Thrombophilic factor analysis in cirrhotic patients with portal vein thrombosis. J Thromb Thrombolysis 2015;40: Qi X, Yang Z, De Stefano V, Fan D. Methylenetetrahydrofolate reductase C677T gene mutation and hyperhomocysteinemia in Budd-Chiari syndrome and portal vein thrombosis: A systematic review and meta-analysis of observational studies. Hepatol Res 2014;44:E480- E Qi X, Ren W, De Stefano V, Fan D. Associations of coagulation factor V Leiden and prothrombin G20210A mutations with Budd-Chiari syndrome and portal vein thrombosis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2014;12: Qi X, Chen H, Han G. Effect of antithrombin, protein C and protein S on portal vein thrombosis in liver cirrhosis: a meta-analysis. Am J Med Sci 2013;346: Amitrano L, Ames PR, Guardascione MA, Lopez LR, Menchise A, Brancaccio V, et al. Antiphospholipid antibodies and antiphospholipid syndrome: role in portal vein thrombosis in patients with and without liver cirrhosis. Clin Appl Thromb Hemost 2011;17: Qi X, De Stefano V, Su C, Bai M, Guo X, Fan D. Associations of antiphospholipid antibodies with splanchnic vein thrombosis: a systematic review with meta-analysis. Medicine (Baltimore) 2015;94:e496.

12 LIVER TRANSPLANTATION, Vol. 22, No. 3, 2016 CHEN ET AL Qi X, Zhang C, Han G, Zhang W, He C, Yin Z, et al. Prevalence of the JAK2V617F mutation in Chinese patients with Budd-Chiari syndrome and portal vein thrombosis: a prospective study. J Gastroenterol Hepatol 2012;27: Karak ose S, Oruç N, Zengin M, Akarca US, Ers oz G. Diagnostic value of the JAK2 V617F mutation for latent chronic myeloproliferative disorders in patients with Budd-Chiari syndrome and/or portal vein thrombosis. Turk J Gastroenterol 2015;26: Chawla Y, Duseja A, Dhiman RK. Review article: the modern management of portal vein thrombosis. Aliment Pharmacol Ther 2009;30: Yerdel MA, Gunson B, Mirza D, Karayalçin K, Olliff S, Buckels J, et al. Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome. Transplantation 2000;69: Berzigotti A, Garcıa-Criado A, Darnell A, Garcıa-Pagan JC. Imaging in clinical decision-making for portal vein thrombosis. Nat Rev Gastroenterol Hepatol 2014;11: Kumar A, Sharma P, Arora A. Review article: portal vein obstruction--epidemiology, pathogenesis, natural history, prognosis and treatment. Aliment Pharmacol Ther 2015;41: Saad WE, Lin E, Ormanoski M, Darcy MD, Rubens DJ. Noninvasive imaging of liver transplant complications. Tech Vasc Interv Radiol 2007;10: Valla D. Splanchnic vein thrombosis. Semin Thromb Hemost 2015;41: Qi X, Dai J, Jia J, Ren W, Yang M, Li H, et al. Association between portal vein thrombosis and survival of liver transplant recipients: a systematic review and metaanalysis of observational studies. J Gastrointestin Liver Dis 2015;24: Ma J, Yan Z, Luo J, Liu Q, Wang J, Qiu S. Rational classification of portal vein thrombosis and its clinical significance. PloS One 2014;9:e Luca A, Caruso S, Milazzo M, Marrone G, Mamone G, Crino F, et al. Natural course of extrahepatic nonmalignant partial portal vein thrombosis in patients with cirrhosis. Radiology 2012;265: 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: D Amico G, De Franchis R; for Cooperative Study Group. Upper digestive bleeding in cirrhosis. Posttherapeutic outcome and prognostic indicators. Hepatology 2003;38: Amitrano L, Guardascione MA, Manguso F, Bennato R, Bove A, DeNucci C, et al. The effectiveness of current acute variceal bleed treatments in unselected cirrhotic patients: refining short-term prognosis and risk factors. Am J Gastroenterol 2012;107: Cerini F, Gonzalez JM, Torres F, Puente A, Casas M, Vinaixa C, et al. Impact of anticoagulation on uppergastrointestinal bleeding in cirrhosis. A retrospective multicenter study. Hepatology 2015;62: Englesbe MJ, Schaubel DE, Cai S, Guidinger MK, Merion RM. Portal vein thrombosis and liver transplant survival benefit. Liver Transpl 2010;16: Berry K, Taylor J, Liou IW, Ioannou GN. Portal vein thrombosis is not associated with increased mortality among patients with cirrhosis. Clin Gastroenterol Hepatol 2015;13: Fouzas I, Paul A, Becker C, Vernadakis S, Treckmann JW, Mathe Z, et al. Orthotopic liver transplantation in patients with portal vein thrombosis in the absence of hepatocellular carcinoma. Transplant Proc 2012;44: Hibi T, Nishida S, Levi DM, Selvaggi G, Tekin A, Fan J, et al. When and why portal vein thrombosis matters in liver transplantation: a critical audit of 174 cases. Ann Surg 2014;259: Senzolo M, M Sartori T, Rossetto V, Burra P, Cillo U, Boccagni P, et al. Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis. Liver Int 2012;32: Chung JW, Kim GH, Lee JH, Ok KS, Jang ES, Jeong SH, Kim JW. Safety, efficacy, and response predictors of anticoagulation for the treatment of nonmalignant portal-vein thrombosis in patients with cirrhosis: a propensity score matching analysis. Clin Mol Hepatol 2014;20: Chen H, Liu L, Qi X, He C, Wu F, Fan D, Han G. Efficacy and safety of anticoagulation in more advanced portal vein thrombosis in patients with liver cirrhosis. Eur J Gastroenterol Hepatol 2016;28: Amitrano 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: Maruyama 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: Delgado MG, Seijo S, Yepes I, Achecar L, Catalina MV, Garcıa-Criado A, et al. Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis. Clin Gastroenterol Hepatol 2012;10: Werner 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: Naeshiro N, Aikata H, Hyogo H, Kan H, Fujino H, Kobayashi T, et al. Efficacy and safety of the anticoagulant drug, danaparoid sodium, in the treatment of portal vein thrombosis in patients with liver cirrhosis. Hepatol Res 2015;45: Cui SB, Shu RH, Yan SP, Wu H, Chen Y, Wang L, Zhu Q. Efficacy and safety of anticoagulation therapy with different doses of enoxaparin for portal vein thrombosis in cirrhotic patients with hepatitis B. Eur J Gastroenterol Hepatol 2015;27: Bechmann LP, Sichau M, Wichert M, Gerken G, Kr oger K, Hilgard P. Low-molecular-weight heparin in patients with advanced cirrhosis. Liver Int 2011;31: Porte RJ, Lisman T, Tripodi A, Caldwell SH, Trotter JF; for Coagulation in Liver Disease Study Group. The International Normalized Ratio (INR) in the MELD score: problems and solutions. Am J Transplant 2010;10: Martinez M, Tandra A, Vuppalanchi R. Treatment of acute portal vein thrombosis by nontraditional anticoagulation. Hepatology 2014;60: Intagliata NM, Maitland H, Northup PG, Caldwell SH. Treating thrombosis in cirrhosis patients with new oral agents: ready or not? Hepatology 2015;61: Simonetto DA, Wysokinski WE, Kamath PS. Use of nontraditional anticoagulants in portal vein thrombosis: a note of caution. Hepatology 2015;61: De Gottardil A, Seijo S, Plessier A, Schouten J, Trebicka J, Terziroli B, et al. Use of direct oral anticoagulants (DOACs) in patients with splanchnic vein thrombosis and/or cirrhosis. J Hepatol 2015;62(suppl 2):S229.