Gastroenterology 2019;156:1582–1599 PERSPECTIVES EIW AND REVIEWS REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Douglas J. Robertson and Vincent W. Yang, Section Editors Diagnosis, Development, and Treatment of Portal in Patients With and Without Nicolas M. Intagliata,1 Stephen H. Caldwell,1 and Armando Tripodi2

1Division of Gastroenterology and Hepatology, University of Virginia Medical CenterCharlottesville, Virginia; and 2Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milano, Italy

Portal vein thrombosis unrelated to solid malignancy is also central to estimating prognosis and to aid therapeutic common in patients with cirrhosis, but less frequently decision-making. observed in patients without cirrhosis. Prompt diagnosis and management of acute symptomatic portal vein throm- bosis are essential. Failure to detect and treat thromboses Pathophysiology and Risk Factors of can result in mesenteric ischemia, chronic cavernous Cirrhotic and Non-Cirrhotic Portal Vein transformation, and complications of portal . Thrombosis In patients with cirrhosis, development of portal vein The low-pressure, slow-flow, and high-volume hemody- thrombosis is often insidious and remains undetected until its incidental detection. Management of portal vein throm- namics of the portal venous system results in a unique bosis in patients with cirrhosis is more controversial. vascular environment. All venous thromboses are ’ — However, there are data to support treatment of specific multifactorial due to components of Virchow s triad patients with anticoagulation agents. We review the com- hypercoagulability, endothelial injury, and reduced blood mon and distinct features of portal vein thromboses in pa- flow. Dominant risks for PVT in patients with or without tients without tumors, with and without cirrhosis. cirrhosis can be broadly classified into risks arising from local or systemic processes (Table 1). In patients without cirrhosis, a systemic hypercoagulable Keywords: Hepatic; Therapy; Fibrosis; Anticoagulation. state is often implicated in PVT.5,6 Local risk factors in this setting include malignancy, intra-abdominal infections, abdominal trauma, and intra-abdominal surgery (eg, sple- istorically, clinicians in the late 19th and early 20th nectomy). In patients with cirrhosis, development of PVT is H century recognized the association of portal vein closely associated with static portal blood flow from thrombosis (PVT) with a variety of disorders, including advancing PH, coupled with spontaneous development of cirrhosis and (PH), malignancy, intra- portosystemic shunts. PV velocity is associated with risk of abdominal infection, and as a sequela of abdominal sur- PVT in cirrhosis and consequently as patients develop – gery.1 3 The liver has a unique circulatory system evolved to advancing PH, thrombosis becomes more likely.7 Other local protect against ischemic injury. However, when portal blood inciting factors common to cirrhosis (eg, infection, surgery, flow is impeded, considerable consequences can ensue or large portosystemic shunts) can enhance this risk. (Figure 1). At the sinusoidal level, deprivation of blood flow from portal venous microthrombi is proposed as a cause of Biology of Hypercoagulability in Portal Vein fi 4 brosis, organ atrophy, and PH. Termed parenchymal Thrombosis extinction, this concept emphasizes the consequences of defines a condition characterized by ischemia to the liver from interruption of blood flow via the inherited or acquired hypercoagulability secondary to splanchnic mesenteric . Non-tumoral thrombosis of the PV and associated splanchnic tributaries can occur from a variety of underly- ing etiologies, including PH, hypercoagulability, and vascular Abbreviations used in this paper: CT, computed tomography; DOAC, endothelial injury (Table 1). At initial diagnosis, it is direct-acting oral ; EASL, European Association for the Study of Liver Disease; FVIII, factor VIII; LMWH, low-molecular-weight important to distinguish between the common cirrhosis- heparin; MPN, myeloproliferative neoplasm; MRI, magnetic resonance related PVT and the uncommon non-cirrhotic PVT. This imaging; PC, protein C; PH, portal hypertension; PS, protein S; PVT, portal vein thrombosis; TIPS, transjugular intrahepatic portosystemic shunt; US, distinction is critical, as the evaluation, prognosis, and ultrasound; VKA, vitamin K antagonist. treatment are different. Careful evaluation for associated Most current article primary hepatic malignancy is essential. Establishing the © 2019 by the AGA Institute timing of thrombosis (acute vs chronic) and the anatomical 0016-5085/$36.00 extent within the splanchnic mesenteric venous system are https://doi.org/10.1053/j.gastro.2019.01.265 May 2019 PVT in Patients With and Without Cirrhosis 1583 REVIEWS AND PERSPECTIVES

Figure 1. Types of portal vein thrombosis. hemostasis defects leading to venous (rarely arterial) throm- demonstrated by in vitro thrombin generation studies.19–21 bosis. Hypercoagulability is evident in both non-cirrhotic and This balance is mainly due to decreased levels of PC and cirrhotic PVT, but is often dominated by different pathways. increased levels of factor VIII (FVIII).19,22,23 Activated PC is Inherited genetic mutations, such as and the physiological inhibitor to FVIII, the latter being the most prothrombin gene G20210A polymorphisms are more potent driver of thrombin generation. Therefore, high common in patients with both cirrhotic8,9 and non-cirrhotic levels of FVIII, low levels of PC, and the FVIII/PC ratio are an PVT.10,11 These common mutations are relatively weak index of hypercoagulability in cirrhosis. These changes are pro-coagulant factors compared to inherited deficiencies of associated with unfavorable outcome in patients with anticoagulant factors, such as antithrombin, protein C (PC), cirrhosis.24 Furthermore, patients with cirrhosis who are and protein S (PS). Among acquired thrombophilic condi- resistant to the anticoagulant action of thrombomodulin tions, the anti-phospholipid syndrome is characterized by (in vitro) are more likely to develop de novo PVT.25 persistent positivity of lupus anticoagulant and/or solid- Thrombophilia may occur via other mechanisms, phase antibodies to cardiolipin or b2-glycoprotein-I.12 including increased levels of circulating cell-derived micro- Deficiencies of the naturally occurring ,13 particles containing negatively charged phospholipids or high levels of procoagulant factors,14 or the presence of tissue factor derived from the parent cells (eg, platelets or – the anti-phospholipid syndrome15 17 in patients with PVT monocytes). In addition, activated neutrophils in areas are reported. However, the phenotypic activity of naturally of inflammation cause release of neutrophil external traps occurring anticoagulants cannot be easily measured in that can increase thrombin generation without affecting cirrhotic PVT due to impaired synthetic capacity of the liver. levels of the pro- or anticoagulant factors.26,27 Neutrophil Similarly, tests of lupus anticoagulants in anti-phospholipid external traps have been associated with increased risk of syndrome may be prolonged beyond the upper limit of the thrombosis in both non-cirrhotic subjects28,29 and in reference range in cirrhosis. Moreover, the solid-phase an- cirrhosis.30 High levels of gut-derived bacterial lipopolysac- tibodies to cardiolipin or b2-glycoprotein-I have been charide are common in cirrhosis and could also contribute to measured only sporadically in patients with PVT and not hypercoagulability31 and platelet hyperactivity.32 according to the most recent standards.18 Thus, these Isolated assessment of any of the individual components associations remain uncertain. of the Virchow’s triad is insufficient to entirely define Evidence is accumulating that the rebalanced hemostasis individual risk.25 Nonetheless, there are shared features system in cirrhosis is prone to hypercoagulability, as between cirrhotic and non-cirrhotic PVT beyond anatomical 1584 Intagliata et al Gastroenterology Vol. 156, No. 6

Table 1.Risk Factors for Portal Vein Thrombosis PERSPECTIVES EIW AND REVIEWS Common risk factors in non-cirrhotic PVTa Common risk factors in cirrhosis PVTb

Systemic disorder (approximately 50%–60% of cases) Systemic disorder MPNsa (, essential thrombocytemia, primary Advanced portal hypertension with reduced portal flow velocity myelofibrosis) Steal syndrome from large spontaneous portosystemic shunts JAK2 V617F mutation Malignancy Malignancy Inherited thrombophiliab Inherited thrombophilia Factor V Leiden Factor V Leiden Prothrombin gene G20210A mutation Prothrombin gene G20210A mutationa Acquired thrombophilia Protein C and S deficiency Increased Factor VIII Antithrombin deficiency Protein C and S deficiency, antithrombin deficiency Acquired thrombophilia Other systemic risk factors Antiphospholipid syndromea Non-alcohol steatohepatitis Paroxysmal nocturnal hemoglobinuria Other extrinsic factors Other systemic risk factors Local Autoimmune disease and Abdominal malignancy (HCC) Inflammatory bowel disease Intrabdominal surgery (hepatectomy, surgical shunt) Local regional therapy for HCC (TACE, radioembolization) Exogenous hormone supplementation TIPS Local (approximately 20%–25% of cases) Intra-abdominal infection (eg, , umbilical vein sepsis, cholecystitis, ) Trauma Abdominal malignancy Surgery (splenectomy, Whipple, gastric bypass, hepatectomy/ )

HCC, ; TACE, transarterial chemoembolization. aRisk estimates based mainly on largest prospective study and EASL guidelines.5,6 Patients may have more than 1 risk factor at diagnosis (patients with a local risk factor may also have a systemic risk factor). Approximately 25% of patients have no causal risk factor identified.6 The most common systemic hypercoagulable risk factors are in bold type—MPNs (21%), anti- phospholipid syndrome (9%), and inherited mutations in prothrombin gene G20210A (15%).6 bEtiologic risk factors in cirrhosis are less clearly defined (see text). Patients often have multiple risk factors simultaneously. The role of inherited thrombophilia is controversial in cirrhosis and routine testing should be individualized.

location. For example, patients with and without cirrhosis examining non-cirrhotic PVT were MPN (21%), pro- with PVT respond to anticoagulation with low-molecular- thrombin gene G20210A mutation (15%), and anti- weight heparin (LMWH), vitamin K antagonists (VKA), or phospholipid syndrome (8%).6 direct-acting oral anticoagulants (DOAC), when administered for primary prophylaxis33 or therapy34–40 (Supplementary Figure 1). This response pattern supports a role of hyperco- Hypercoagulability in Cirrhotic Portal Vein agulability in both major forms of non-tumoral PVT. Thrombosis All components of Virchow’s triad, including reduced portal flow, hypercoagulability, and endothelial injury, Hypercoagulability in Non-Cirrhotic Portal Vein contribute to the development of PVT in cirrhosis. Studies Thrombosis have not clearly shown benefit from genetic thrombophilia Myeloproliferative neoplasms (MPNs), including poly- testing in cirrhosis and the cost–benefit of screening pa- cythemia vera, essential thrombocythemia, and primary tients with venous thromboembolism is increasingly being myelofibrosis, are common risk factors for non-cirrhotic questioned.47 Testing high-risk populations can be useful, PVT.6 MPNs promote increased platelet aggregation and such as in cirrhotic patients with family histories of pro- heightened thrombin generation.41,42 MPNs can be diag- thrombotic defects, patients with multiple sites of throm- nosed with peripheral blood and bone marrow testing. bosis, recurrent thrombosis, or when treatment decisions The presence of the gain-of-function mutation JAK2V617F (ie, anticoagulation duration) may be affected. Vascular (JAK2) is closely linked to MPNs and has been associated endothelial dysfunction is common in liver disease, but is with splanchnic vein thromboses.43,44 Searching for not easily assessed by available tests. While evaluation of the somatic mutation in the gene for calreticulin may vascular endothelium via endothelial markers, such as von be useful in certain circumstances.45,46 Overall, the most Willebrand factor and/or circulating endothelial micro- common underlying hypercoagulable associated risk particles, is promising, the clinical utility remains factors identified in the largest prospective series unclear.48,49 May 2019 PVT in Patients With and Without Cirrhosis 1585

Diagnosis and Characterization of imaging can provide timeline clues and are reviewed elsewhere in greater detail.56 In non-cirrhotic patients, Portal Vein Thrombosis the presence of a cavernoma, venous collateralization, or Ultrasound features of PH implies a long-standing thrombosis. In both REVIEWS AND Ultrasound (US) imaging with Doppler is used patients with and without cirrhosis, obliteration of the PV PERSPECTIVES commonly in clinical practice and in screening cirrhotic and cavernous replacement are consistent with a more patients for hepatocellular carcinoma. US can initially distant event. diagnose clinically silent PVT or can be used initially to 50 evaluate more symptomatic patients. In US gray-scale Determination of the Presence or Absence of imaging, thrombus is apparent as hypo- or iso-echoic Cirrhosis material occupying the lumen of a mildly dilated vein in Defining the presence or absence of cirrhosis is funda- acute PVT or hyperechoic material in chronic PVT after mental, due to prognostic and long-term management clot organization. Doppler is used to estimate flow rate. implications. Cirrhotic PVT may be clearly evident by his- The detection of flow in multiple small vessels in the tory or imaging, although contour nodularity may be pre- usual PV location is characteristic of “cavernous trans- sent in chronic non-cirrhotic PVT.57 Transient elastography formation” of a thrombosed PV. While usually a marker may be helpful, but has limitations.58 In many cases, a liver of chronicity, cavernous transformation may form in as biopsy is essential. The presence of on imaging does few as 6 days.51 US has a reported sensitivity of 89%–93% not indicate cirrhosis per se. Transient ascites can be pre- and specificity of 92%–99% in 2 separate studies.52,53 sent on imaging in up to 40% of patients with acute non- There are numerous variables that limit accuracy of the cirrhotic PVT.6 Characteristics on fluid analysis would be US, including obesity, ascites, bowel gas, and operator expected to be high serum albumin ascites gradient (>1.1) experience. Slow blood flow can also limit interpreta- with preservation of protein in the ascites as sinusoidal tion.52 Normal PV flow excludes PVT, but a positive result function is preserved.59 Ascites can also be a complicating warrants further cross-sectional imaging. Modifications feature of chronic non-cirrhotic PVT due to pre-sinusoidal that may enhance US include the use of microbubble- PH.60 In contrast, PVT in cirrhotic patients may exacerbate enhanced contrasted Doppler US and endoscopic ascites, and characteristic features of ascites are typical of ultrasound.54,55 cirrhosis with high serum albumin ascites gradient with low total protein.61 Cross-Sectional Imaging Multi-phase abdominal computed tomography (CT) Distinguishing Tumor Thrombus From Benign effectively evaluates the portal-mesenteric venous system (Figure 2). Oral contrast obscures vasculature and should be Thrombus avoided. Advantages of CT include visualization of the entire It is important to maintain a high clinical suspicion for mesenteric venous system, wide availability, and ease of malignant thrombus in newly diagnosed PVT. This is visualization by clinicians. Disadvantages include radiation particularly important in cirrhosis, and requires clinical fi exposure, risk of contrast nephropathy, and technical vari- history, laboratory studies, and careful identi cation of 62–64 ations that can limit interpretation. important cross-sectional imaging characteristics. In Multiphase contrast enhanced magnetic resonance cases of hepatocellular carcinoma, distinguishing between “ ” imaging (MRI) has replaced CT as the first-line diagnostic benign or bland thrombus and malignant invasion is test after US at many institutions. The advantages of MRI essential. Criteria combining imaging characteristics and a– include absence of radiation exposure and possibly greater fetoprotein levels have been proposed recently based on 65 sensitivity for detecting concurrent biliary disease or ma- a small single-center retrospective cohort analysis. The lignancy. Disadvantages of MRI include expense, center criteria used included venous expansion, thrombus expertise, risk of motion artifact, and variable image quality enhancement, neovascularity, tumor adjacent to the a– > secondary to ascites or obesity. thrombus or an fetoprotein of 1000 ng/dL. When 3 or more criteria are present the presence of tumoral PVT was determined with confidence (sensitivity 100%, specificity Determination of the Chronicity of Portal Vein 94%, positive predictive value 80%, negative predictive Thrombosis value 100%). However, these criteria require further study Determining when the thrombotic event occurred is and have not been validated outside of the original popu- important, but can be challenging. A detailed clinical his- lation. In equivocal cases a biopsy of the thrombus may be tory to review inciting events or possible symptoms, necessary. including abdominal pain or new-onset ascites, is impor- tant. When diagnosed in asymptomatic patients on routine imaging, careful comparison with prior imaging Non-Cirrhotic Portal Vein Thrombosis may establish a historical timeline. Often times in Non-cirrhotic PVT can present acutely with or without cirrhosis, a “recent” PVT will be diagnosed on routine symptoms or after chronic progression of thrombus that hepatocellular carcinoma screening and the timing may be leads to sequelae of PH. When a PVT occurs, the liver inferred from review of the prior US. Specificfeatureson compensates with increased hepatic arterial flow and 1586 Intagliata et al Gastroenterology Vol. 156, No. 6 PERSPECTIVES EIW AND REVIEWS

Figure 2. (A) Patient without cirrhosis with acute PVT after splenec- tomy. Arrow indicates thrombus within the main PV. Note the perfusional changes in liver paren- chyma. (B) Patient without cirrhosis with long- standing chronic PVT and cavernous transformation. Arrow indicates cav- ernoma. (C) Patient with cirrhosis and acute PVT. Arrow indicates thrombus in the main PV. (D) Patient with cirrhosis and chronic PVT. Arrow indicates cav- ernoma and collaterals.

thereby preserves normal hepatic function.66 If undetected bowel ischemia and infarction.72 While normal liver func- or left untreated, this may progress to involve more prox- tion is generally maintained even in extensive PVT, the imal mesenteric veins that can result in intestinal ischemia. development of intestinal ischemia is associated with high Furthermore, the thrombosed PV may undergo cavernous morbidity and mortality. transformation. This can result in porto–portal, meso– portal, and/or portosystemic collaterals that can lead to Natural History and Treatment of Acute Non- gastrointestinal bleeding from varices, ascites, portal bilio- Cirrhotic Portal Vein Thrombosis pathy, and portosystemic encephalopathy.5,67,68 Knowledge of the natural history of non-cirrhotic acute PVT is limited.73 The immediate goal of treatment at pre- Epidemiology of Non-Cirrhotic Portal Vein sentation is to prevent propagation of the thrombus and to 5 Thrombosis promote recanalization. Resolution without intervention is Knowledge surrounding the incidence and prevalence exceedingly rare. Small-volume ascites on imaging are a 6 of non-cirrhotic PVT in the general population is limited by common, yet transient feature. The presence of clinically its infrequency, and epidemiologic studies vary tremen- detectable ascites may be an ominous sign and may repre- 74,75 dously in design.69–71 A large Swedish study found a sent a risk factor for bowel ischemia and infarction. population prevalence of PVT of 1% with the majority of Progressive thrombus extension into more proximal veins, cases associated with cirrhosis and hepatobiliary malig- such as the superior mesenteric vein and smaller tribu- nancy.69 Similarly, a subsequent multicenter study found taries, is associated with higher risk of intestinal ischemia 72 an incidence rate of 0.7 per 100,000 inhabitants per year and mortality. However, in the largest prospective study and prevalence rate of 3.7 per 100,000 inhabitants.70 A to date, intestinal infarction occurred in only 2% of patients – 6 more recent study in Italy examined 3535 patients 6 12 days after beginning anticoagulation. An earlier admitted to the hospital for firstincidentPVTfrom2002to retrospective study compared patients with isolated 2012. The overall incident rates of PVT in this cohort were mesenteric vein thrombosis to patients with PVT and 76 3.8 per 100,000 inhabitants in males and 1.7 per 100,000 mesenteric vein involvement. Isolated mesenteric vein inhabitants in females.71 thrombosis with involvement of small vascular arcades of the mesenteric system was a distinct risk factor for bowel ischemia and infarction. A more recent analysis corrobo- Acute Non-Cirrhotic Portal Vein Thrombosis rated this observation and identified extension of throm- Patients with acute PVT most commonly complain of bosis into smaller radicle vessels as a useful prognostic mild to severe abdominal pain and fever.6 The severity of indicator.74 presentation is predicated on the etiology and extent of Anticoagulation is the cornerstone of therapy for acute thrombosis, with acute extension of the thrombus into the non-tumoral PVT and should be initiated at diagnosis superior mesenteric vein much more likely to produce (Table 2).5,6,72,73,77,78 In the acute setting, LMWH or a 09PTi ainsWt n ihu iroi 1587 Cirrhosis Without and With Patients in PVT 2019 May

Table 2.Anticoagulation in Patients With Non-Tumoral Portal Vein Thrombosis Without Cirrhosis

Study, first author, year n Period Type Therapy Dose Duration Efficacy Bleeding

Acute or recent PVTa Condat, 200077 141 total PVT 1983–1999 Retrospective UFH, LMWH, NR At least 4 mo 80.6% recanalization 2 bleeding events (1 EV, 33 acute PVT VKA (complete 10, partial 15) 1 abdominal) 31 anticoagulated Amitrano, 200772 121 total PVT 1998–2005 Retrospective LMWH followed 200 IU/kg 6 mo minimum 45.4% recanalization 2 minor bleeds (1 epistaxis, 21 acute PVT by VKA (complete 10) 1 gingival) 41 anticoagulated Plessier, 20106 102 acute PVT 2003–2005 Prospective UFH, LMWH, NR Median 234 d 38% recanalization of main 9 events (5%) 95 anticoagulated VKA PV, 61% SMV, 54% (7 GI and nasal, 1 abdominal, 1 splenic bone marrow biopsy) Turnes, 200878 38 acute PVT 1995–2003 Retrospective UFH/LMWH NR; INR 2–3 6 mo minimum 44% recanalization (complete 1 major bleeding event 27 anticoagulated then VKA 6, partial 6) Chronic PVTb Condat, 200193 136 total PVT 1983–1998 Retrospective UFH, LMWH NR Median 46 mo Incidence rate thrombosis Incidence rate 35% (84 103 chronic PVT and VKA 5.5% (2 recurrent episodes of GI bleed in 84 anticoagulated mesenteric thrombosis on 42 patients) AC [9 total]) Orr, 2007c,91 60 total PVT 1973–2005 Retrospective VKA INR 2–3 NR NR 50% with variceal bleeding (9/ 50 chronic PVT 18) (5 prior to AC, 4 primary 18 anticoagulated bleed on AC) Spaander, 201394 120 total PVT 1985–2008 Retrospective UFH, LMWH, NR Median 1.9 y AC reduced recurrent VTE 58 bleeding episodes in 71 chronic PVT and VKA (HR, 0.2; P ¼.1) patients on AC; 33 anticoagulated 2 deaths from bleeding in AC patients Noronha Ferreira, 178 total PVT 1983–2014 Retrospective LMWH NR NR NR 15 patients on AC with GI 201692 141 chronic PVT VKA bleed (57 total initial GI 127 anticoagulated bleed)

AC, anticoagulation; EV, esophageal variceal; GI, gastrointestinal; HR, hazard ratio; INR, international normalized ratio; NR, not reported; SMV, superior mesenteric ; VTE, venous thromboembolism. aAcute or recent PVT determined by symptoms, presentation, and lack of cavernoma and portal hypertension. bIncluded studies are widely variable in cohort selection and outcome definition. Data reported according to cohort that received anticoagulation when possible. In studies above cohort sample size was altered in some cases to exclude certain patients. Several studies were not included in this table secondary to variable and undefined cohort inclusion outcome end points. cIncluded cirrhosis and tumoral-related PVT; reported n reflects these subjects excluded.

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unfractionated heparin are the preferred agents, typically Natural History and Outcome in Chronic Non- PERSPECTIVES EIW AND REVIEWS followed by VKA. Early retrospective studies established the Cirrhotic Portal Vein Thrombosis efficacy of anticoagulation, revealing rates of recanalization Survival in patients with chronic non-cirrhotic PVT 72,78 from 40%–45%. Notably, successful anticoagulation depends on the underlying etiology, but generally has a – was dependent on early initiation of therapy and untreated good prognosis.70,72,78,91 94 In a large prospective study of 78 patients did not develop recanalization. A subsequent 178 such patients, death was rare during follow-up and large prospective study examined outcomes of anti- 5-year survival was 96%.92 Earlier studies report overall 6 coagulation in 95 patients with non-cirrhotic acute PVT. 5-year survival of 70%–78%.91,94 The most common The majority of patients were initiated on LMWH or symptomatic presentation is gastroesophageal variceal unfractionated heparin and 38% achieved complete recan- hemorrhage.92 In patients without varices at baseline, the alization. Thrombus involving more proximal portions of the probability of developing varices was 2% at 1 year and 22% splanchnic mesentery was more likely to recanalize in this at 5 years.92 Other complications of PH, including ascites cohort. Nine patients developed gastrointestinal bleeding and portosystemic encephalopathy, are less common.95 and 2 patients developed progressive thrombosis and un- Progression of thrombosis may exacerbate PH or increase derwent surgical therapy for intestinal infarction. Recent risk for mesenteric ischemia. Chronic compression of the reports of the successful use of DOAC in non-cirrhotic acute bile ducts from collaterals (or ischemia from thrombosis in 79,80 PVT are encouraging. Current guidelines from the biliary venules) may lead to portal biliopathy, but is usually European Association for the Study of the Liver (EASL) asymptomatic and does not tend to progress.96,97 recommend a minimum treatment duration for 6 months, commensurate with guidelines for unprovoked venous 81,82 thromboembolism, however the underlying etiology Complications of Chronic Non-Cirrhotic Portal may necessitate indefinite therapy.5 A prospective multi- Vein Thrombosis center observational study recently found that patients with As the major from chronic PVT is gastro- non-cirrhotic PVT are at high risk to develop recurrent 94 thrombotic events and have similar risks of bleeding esophageal bleeding, anticoagulation can be complicated. compared to patients treated for non-abdominal venous Current EASL guidelines and Baveno VI consensus state- fi thromboembolism.83 ment both support inde nite anticoagulation in patients If there is progression of thrombus despite medical with chronic PVT after prophylaxis of gastrointestinal bleeding and according to underlying prothrombotic risks therapy, or when there are features of imminent bowel 5,67 infarction, endovascular thrombolysis or surgical interven- and history of thrombotic events. fi tion are neccessary.5,67 Thrombolysis is performed by the The ef cacy and risks of anticoagulation for chronic PVT transjugular access with or without transjugular intra- have been reported in mainly retrospective analyses that fi hepatic portal shunt (TIPS) placement or via direct trans- vary in cohort characteristics, outcome de nitions, treat- ment, and follow-up (Table 2).72,92–94,98 An early seminal hepatic or trans-splenic approaches. Early case reports and 93 series were small and described varying success rates, with study by Condat et al evaluated 103 patients with non- some studies revealing a high rate of complications.84–87 A cirrhotic, non-tumoral chronic PVT (84 who received anti- recent retrospective report of 17 patients undergoing coagulation). Patients with underlying thrombotic disorders transjugular thrombolysis showed a recanalization rate of who did not receive anticoagulation were more likely to 94%, with patency maintained at 2 years in 88% of cases.88 develop thrombosis, and anticoagulation did not increase Surgery was averted in 15 of the 17 cases and no patients the risk of bleeding. While subsequent studies support the safety of anticoagulation, prospective and properly powered went on to develop PH complications. Combined surgical 92,94 and endovascular approaches have also been reported with studies are lacking. Recent registry trials have examined high rates of success.89 anticoagulation in all types of patients with splanchnic vein thrombosis.83,98 These studies provide important data regarding the natural history of splanchnic vein thrombosis, Chronic Non-Cirrhotic Portal Vein Thrombosis efficacy and safety of anticoagulation therapy, and out- Patients with an unrecognized and untreated acute PVT comes. However, they are limited by heterogeneous cohorts or who do not respond to treatment are at risk to develop (eg, inclusion of cirrhotic, non-cirrhotic, and tumoral-related portal cavernoma78 (Figures 1 and 2). This is defined as PVT) and do not clearly distinguish between acute and extrahepatic PV obstruction and includes chronic throm- chronic thrombosis. bosis of the main PV alone with or without thrombus in The presence of ascites or at diagnosis is the intrahepatic and/or more proximal portions of the independently associated with the presence of gastro- splanchnic mesenteric venous system.5,67,68 The obstruction esophageal variceal, however, absence of ascites or spleno- causes increased presinusoidal pressure and forces blood megaly does not exclude gastroesophageal variceal.92 flow back into the splanchnic mesenteric veins.51,68,90 Once Primary (nonselective b-blocker or esophageal band PH develops, blood flows either hepatopetal through porto– ligation and secondary prophylaxis (nonselective b-blocker portal collaterals or hepatofugal from the liver through and esophageal band ligation) for bleeding are recom- portosystemic collaterals that contribute to gastroesopha- mended.5,67,99 TIPS can be utilized in patients with geal, ectopic, or rectal variceal bleeding. refractory bleeding, however, the presence of a cavernoma May 2019 PVT in Patients With and Without Cirrhosis 1589 can be technically challenging.100,101 Surgical considerations allows for a clearer clinical description and may improve for the management of PH include the mesoenterico-Rex research in the field through a comprehensive description shunt and other surgical portosystemic shunts and are for cohort selection and analyses (Supplementary Table 1). reviewed elsewhere.68,102 Symptomatic portal biliopathy is REVIEWS AND

managed endoscopically with endoscopic retrograde chol- PERSPECTIVES angiopancreatography.103 Surgical shunts or TIPS can Epidemiology of Cirrhotic Portal Vein Thrombosis decompress portal collaterals and improve portal chol- Because PVT is common in cirrhosis and patients if endoscopic management is insufficient.103,104 frequently undergo imaging on a regular basis for hepato- There is a risk over time of secondary sclerosing chol- cellular carcinoma screening, our knowledge of the preva- angitis developing, with need for liver transplantation.105 lence of PVT in cirrhosis is much more clearly defined 113,114 Extensive splanchnic mesenteric thrombosis is an compared to non-cirrhotic PVT. The majority of emerging indication for multivisceral transplantation at studies have been conducted in the transplantation popu- 115 specialized centers.106,107 Candidacy is determined by lation. It is particularly important to consider cohort multiple factors, including the overall extent of porto- characteristics in these studies, as patients with more mesenteric thrombosis. When advanced PVT is present advanced disease will have a higher prevalence of PVT. and non-physiologic approaches are used for trans- A systematic review of PVT in the transplant population plantation (eg, PV arterialization or cavoportal hemi- evaluated 41 studies and found a prevalence of PVT of 10% 115 transposition), patients have worse outcomes and PH may (2%–23%). Another prospective cross-sectional study persist. Multivisceral transplantation, therefore, offers the consisting of 43 centers in Italy identified PVT with ultra- 113 benefit of reinstating a normal vascular system and elimi- sound in 17% of patients with cirrhosis. The incidence of nating PH. PVT in cirrhosis has also been examined in prospective studies. Francoz et al36 found an incidence of PVT in 7% of patients listed for liver transplantation. A prospective trial Cirrhotic Portal Vein Thrombosis of patients with Child-Turcotte-Pugh B cirrhosis over 1 year PVT in patients with cirrhosis is a more controversial randomized patients without PVT to prophylactic enox- area that has recently garnered significant attention. We aparin for the prevention of PVT and found an incidence of 33 now understand that patients with cirrhosis have a “reba- 17% in the control arm over 1 year. A multicenter pro- lanced” coagulation system that can shift to promote spective study in France of Child-Turcotte-Pugh A and B bleeding or thrombotic tendency.108 Thrombotic risk is patients without PVT found an incidence rate of PVT of 5% driven by stasis of blood flow from PH, hypercoagulability, at 1 year, 8% at 3 years, and 11% at 5 years. Based on and endothelial injury. currently available data, we conclude that patients with It is important to distinguish between the effect of PVT advanced cirrhosis likely have an annual incidence of on transplantation and the role of PVT in outcomes in pa- approximately 10%–15%. tients with cirrhosis. There is evidence to support a role of anticoagulation in patients who are transplantation candi- dates in order to recanalize the PV prior and preserve Natural History and Outcome of Cirrhotic Portal physiologic portal flow to the new allograft. Although data Vein Thrombosis to support anticoagulation outside the context of trans- PVT in cirrhosis is most often detected incidentally on plantation are less clear, evidence is accumulating that routine ultrasound, but should be suspected in any patient certain patients may benefit from recanalization of the with worsening hepatic decompensation. Patients with PV.109 Unfortunately, patients with cirrhosis are routinely acute PVT may develop abdominal discomfort or worsening excluded from anticoagulation trials. Consequently, esti- ascites, but are most often asymptomatic. Ultrasound diag- mating the risks and benefits of anticoagulation in patients nosis necessitates follow-up imaging with cross-sectional CT fi with cirrhosis is a major challenge (Tables 3 and 4). or MRI to con rm the diagnosis and assess for tumor thrombus. Spontaneous resolution of PVT occurs in approximately Classification and Definitions of Portal Vein 40% of cases and is an important consideration when Thrombosis in Cirrhosis making treatment decisions.116 A longitudinal study exam- Early attempts at classification of PVT focused mainly on ining well-compensated patients with cirrhosis over time the anatomical location of the thrombus.110,111 The most found that a detected PVT (101 of 118 were non-occlusive) widely used system proposed by Yerdel et al110 in 2000, was subsequently not detected thereafter in 70% of relies on 4 separate grades of PVT defined solely by cases.114 This observation highlights the variable and anatomical location. Recent guidelines (EASL and American spontaneous progression and regression of PVT in cirrhosis Association for the Study of Liver Disease) adhere to past over time. The degree of PVT at diagnosis (non-occlusive vs nomenclature (eg, recent, acute, and chronic) and to occlusive) or extent of the thrombus in the portal system in anatomical descriptors.5,75 However, an “anatomico-func- 1 small study did not predict future spontaneous recanali- tional classification system” that incorporates anatomic zation.117 To date, there are no clearly identified clinical descriptors, timing of the thrombosis, and the relationship predictors of spontaneous recanalization. Future studies to clinical sequelae, has now been proposed.112 This system must control for spontaneous recanalization to better 1590 Intagliata et al Gastroenterology Vol. 156, No. 6

Table 3.The Special Case of Anticoagulation in Patients With Cirrhotic Portal Vein Thrombosis PERSPECTIVES EIW AND REVIEWS Unfractionated heparin (UFH) Mechanism: UFH is a fast-acting inhibitor to thrombin and factor Xa. UFH activity is accelerated many-fold by antithrombin, making UFH questionable in patients with cirrhosis and PVT, as antithrombin in cirrhosis is reduced. Dosage and monitoring: Full therapeutic UFH dose in non-cirrhotic patients requires adjustment by the activated partial thromboplastin time (APTT). In general, the APTT should be maintained from 1.5 to 2.5 times clotting time prolongation over baseline.148 Contraindications and caution: Because the APTT in cirrhosis is frequently prolonged over the upper limit of normal, UFH in these patients could be under-dosed. Furthermore, neither the APTT nor the anti-FXa activity assay (used instead of the APTT) are standardized and results may vary across laboratories. Low-molecular-weight heparin (LMWH) Mechanism: LMWH is a fast-acting inhibitor to FXa (and to a limited extent thrombin). Like UFH, LMWH works through antithrombin, hence dosages used in non-cirrhotic patients could be ineffective in cirrhosis. Dosage and monitoring: In non-cirrhotic patients, LMWH can be given subcutaneously at fixed (prophylaxis) or weight-adjusted (treatment) dose. Presently, there is little information on proper LMWH doses in cirrhosis and whether laboratory measurement with anti-FXa assays is useful. In vitro studies have shown conflicting results149–151 and in vivo studies are not properly designed to answer the question.152 Expert consensus suggests using LWMH in cirrhosis at fixed weight-adjusted or fixed unadjusted doses for PVT treatment and prophylaxis. Contraindications and caution: Adjustments are necessary in obesity, pregnancy, and renal insufficiency, for which the dosage should be adjusted to maintain an anti-FXa activity from 0.6 to 1.0 U/mL (treatment), but this target depends on the brand of LMWH and on the method used for testing.148 Vitamin K antagonists (VKA) Mechanism: VKA ( and congeners) are slow-acting anticoagulants interfering with the post-ribosomal carboxylation of vitamin K– dependent coagulation factors (VII, X, II, IX, PC, and PS). Dosage and monitoring: The indicated therapeutic interval is from 2.0 to 3.0 international normalized ratio (INR) units.153 Expert consensus indicates that patients with cirrhosis, who are on VKA for PVT or other indications, should be managed by INR aimed at a therapeutic interval from 2.0 to 3.0. A recent study showed that patients with cirrhosis and PVT while on VKA at a therapeutic interval from to 2.0 to 3.0 have taken (during the period of observation) weekly VKA dosages similar to those taken by a control group of patients on VKA for atrial fibrillation.154 Contraindications and caution: One of the limitations in cirrhosis and PVT is the baseline prolongation of the prothrombin time, which could make VKA based on the regular prothrombin time–INR underdosed in cirrhosis. Two groups, while addressing this issue independently concluded that INR, calibrated for non-cirrhotic patients on VKA, should not be used in patients with cirrhosis. A revised calibration system (called INRliver) valid for patients with cirrhosis has been proposed.155 Direct-acting oral anticoagulants (DOAC) Mechanism: DOAC inhibit thrombin or FXa without the mediation of antithrombin or carboxylation. DOAC would have theoretical ad- vantages over VKA or LMWH in cirrhosis and PVT. Dosage and monitoring: DOAC are widely used in non-cirrhotic patients for the same indications as for VKA,153 except for patients with mechanical heart valves156 or for patients with thrombotic antiphospholipid syndrome.157 Unlike LMWH, DOACs can be administered orally and do not require antithrombin (dramatically reduced in cirrhosis). Unlike VKA, DOACs do not require dose adjustment by laboratory testing (a major limitation of the INR scale in this setting (see above) and finally, DOACs do not reduce the naturally occurring anticoagulants protein C or protein S (which are already dramatically reduced in cirrhosis) as VKA do. Contraindications and caution: There is currently insufficient information on use in cirrhosis. A recent randomized trial showed that rivaroxaban at dose lower than that used in non-cirrhotic patients was more effective than warfarin to treat cirrhotic PVT, without causing significant bleeding events.39 However, larger clinical trials are needed. DOACs are currently used in non-cirrhotic patients at fixed dose based on patient characteristics and laboratory testing is needed only in special situations.158 Clinical trials should determine whether patients with cirrhosis and PVT require dose adjustment and whether the laboratory may be useful for patient management in this setting.

understand the natural history of PVT and to focus on pa- population, current available guidelines (EASL and Baveno tients that will benefit from therapy. VI) based on expert opinion support the use of anti- The presence of an advanced PVT increases surgical coagulation for the treatment of PVT in patients with complexity and decreases survival after transplantation cirrhosis who are candidates for transplantation.5,67 How- compared to patients without PVT.118 However, patients ever, clinical judgement and individualized treatment who are listed for transplantation and awaiting surgery do decision-making are always necessary (Table 4). The goal of not appear to have a higher risk of mortality before trans- treatment in the context of transplantation is to prevent plantation secondary to PVT. Data from single-center thrombus progression and/or promote recanalization of the studies36,119 and larger national databases120,121 indicate PV to allow for normal physiologic blood flow to the graft at that more advanced and higher-grade PVT at time of sur- the time of transplantation (end to end portal–portal gery increases the risk of graft loss and mortality after anastomosis). transplantation. However, if physiologic flow to the graft is The contribution of PVT to hepatic decompensation and maintained during surgery, mortality is similar, irrespective overall mortality in cirrhosis is less clear. Compelling evi- of the presence of PVT during the operation.122 While no dence from one prospective trial treating patients without randomized, prospective trial has been performed in this PVT with prophylactic LMWH showed that prevention of May 2019 PVT in Patients With and Without Cirrhosis 1591

Table 4.General Management Considerations for Anticoagulation in Cirrhotic Acute Portal Vein Thrombosis

Who? Patients with acute or recent PVT who are potential liver transplantation candidates or patients listed for liver transplantation. Patients with symptomatic acute occlusive PVT (eg, worsening portal hypertension). REVIEWS AND

Patients with progression of PVT on imaging (particularly when proximal veins, such as the superior mesenteric vein, PERSPECTIVES become involved). Patients where there is concern for risk of mesenteric ischemia. When? After confirmation no spontaneous resolution by observing for period and reimaging (1–3 mo) to determine whether patient will develop spontaneous recanalization. After detailed clinical history is taken for medical contraindications to anticoagulation (eg, bleeding risk assessment). After esophagogastroduodenoscopy for assessment of portal hypertension or other mucosal lesions and subsequent prophylaxis (esophageal band ligation or non-selective b-blocker for high-risk varices). With What? Selection of the type of anticoagulation should be individualized. The limitations and benefits of each medication should be reviewed with the patient. Often a multidisciplinary approach with hematology is advised. Why? In patients who are transplantation candidates: the goal is recanalization with the intent to allow physiologic anastomosis. In patients who are not transplantation candidates: the goal is recanalization, but data are less clear as to overall benefit. In patients with cirrhosis, there is not current evidence to justify routine hypercoagulable investigations in every patient. Individualized approach is essential. How Long? There is not current evidence to determine therapy duration. However, expert consensus recommendations generally support a minimum of 6 mo duration of therapy based on retrospective studies in the literature and extrapolation from general medical guidelines. In cases of underlying hypercoagulability or when the patient is listed for transplantation, indefinite anticoagulation may be considered. Interval imaging to assess for response to anticoagulation every 3 mo on therapy is advised. If anticoagulation is stopped, close follow-up with imaging at 3–6 mo intervals is advised to assess for recurrence.

PVT is associated with decreased hepatic decompensation anticoagulation does not predict likelihood of response to and improved survival.33 Experimental studies in animal treatment.35,127 However, in other studies, more extensive models and case reports of improved liver function with PVT before therapy decreases likelihood of recanaliza- PVT recanalization and modulation of portal flow support tion.128,131 There is a clear association between treatment the premise that PVT may contribute to hepatic dysfunction success with early diagnosis and administration of early and worsening disease.123,124 Moreover, clinical data sug- anticoagulation (<6 months).131 However, this must be gest anticoagulation and recanalization of the PV are asso- interpreted in the context of the overall limitations stated, ciated with a reduction in PH-related events and improved including the lack of prospective controlled trials to mitigate survival.109 However, a large recent multicenter study the confounding effect of spontaneous recanalization. following the incidence of PVT in cirrhosis over time found In a seminal study, Delgado et al35 examined 55 patients no association between PVT and progression of hepatic with cirrhosis and PVT treated with LMWH and/or VKA. decompensation.114 Before anticoagulation, 75% of patients had partial PVT and 60% achieved either partial or complete recanalization. Bleeding events related to anticoagulation occurred in 9%. Pharmacological Treatment of Cirrhotic Portal Another study examined 2 separate doses of LMWH Vein Thrombosis (1.5 mg/kg daily and 1 mg/kg twice daily) in patients with The majority of studies conducted in patients with cirrhosis and PVT. Rates of complete recanalization were cirrhosis and PVT are retrospective and limited, secondary similar between groups, however, there was a significant to varied outcome definitions, inclusion criteria, and treat- increase in bleeding risk in the group that received higher ment timing (Table 5).34–37,109,125–131 To address the vari- dose of LMWH.127 ability in the literature, several systematic reviews and Two studies have examined anticoagulation in patients meta-analyses have now been published.38,115,132,133 awaiting transplantation and revealed that anticoagulation is Important end points to consider when interpreting these safe and effective.36,125 The timing of anticoagulation is an data include the magnitude of PVT (occlusive vs non- important factor and studies indicate that patients started on occlusive), timing and type of anticoagulation, degree of anticoagulation within 6 months of diagnosis are more likely PV recanalization, bleeding definitions, occurrence of to develop recanalization.35,37,131 A large systematic review hepatic decompensation, overall patient survival, and the analyzed 8 separate studies comparing 353 patients with role of transplantation. cirrhosis and PVT treated with either LMWH or VKA Studies to date contain cohorts with a majority of non- compared to patients who did not receive treatment. Overall, occlusive PVT compared to advanced occlusive PVT and 72% of patients on anticoagulation achieved recanalization do not control for spontaneous recanalization. Two retro- compared with 42% that did not receive treatment without spective studies indicate that the degree of PVT before significant differences in bleeding35 (Supplementary Figure 1).

PERSPECTIVES EIW AND REVIEWS

Table 5.Anticoagulation in Patients With Non-Tumoral Portal Vein Thrombosis With Cirrhosis al et Intagliata 1592

Study, first author, year n Period Type Therapy Dose Duration Recanalization GI bleed Other bleeding

Francoz, 200536 19 1996–2001 Prospective VKA INR goal 2–3 8.1 mo (mean) 42% 1 UGI bleed (post — Nadroparin 5700 IU/d as 8 complete banding ulcer) bridge 10 unchanged 1 progression Amitrano, 201034 28 2005–2006 Prospective Enoxaparin 200 IU/ kg/d At least 6 mo 82% — 2 anemia from portal (2 mg/kg/d) 9 complete hypertensive gastropathy 14 partial 5 unchanged Senzolo, 201237 33 2007–2008 Prospective Nadroparin 95 antiXa-U/kg/ 6 mo after 64% 1 EV bleed 1 epistaxis d (treatment) re-permeation 12 complete 1 hematuria 3800 antiXa-U/ 9 partial) 1 cerebral d (prophylaxis) 7 unchanged 5 progression Delgado, 201235 55 2003–2010 Retrospective LMWH or VKA No dose given, 6.8 mo (median) 60% 6 EV bleed 1 vaginal INR goal 2–3 25 complete 1 lower GI bleed 1 surgical wound 8 partial 1 “obscure” GI bleed 1 bleed after tooth extraction 22 unchanged Cai, 2013a,129 6 2006–2011 Retrospective Nadroparin 85 IU/kg/bid 3 mo 67% —— VKA INR goal 1.5–2 4 complete 1 unchanged Werner, 2013125 28 2005–2011 Retrospective VKA INR goal 2-3 302 d (mean) 82% — 1 significant vaginal 11 complete 12 partial 5 unchanged Chung, 2014126 14 2003–2014 Retrospective VKA No dose given 112 d (mean) 79% —— 6 complete 5 partial 3 unchanged Cui, 2015b,127 34 NR Prospective LMWH 1.5 mg/kg daily 6 mo 76% — 8 bleeds (injection site, 8 complete epistaxis or hematuria) 18 partial 8 unchanged Cui, 2015b,127 31 NR Prospective LMWH 1mg/kg bid 6 mo 81% — 2 bleeds (injection site, 9 complete epistaxis or hematuria) 6 No. 156, Vol. Gastroenterology 16 partial 6 unchanged Chen, 2016128 30 2002–2014 Retrospective VKA INR goal 2–3 7.6 mo (median) 50% 4 GI bleed 4 other bleeds 15 complete/ partial (epistaxis, gingival) 4 stable 3 progression Table 5.Continued 1593 Cirrhosis Without and With Patients in PVT 2019 May

Study, first author, year n Period Type Therapy Dose Duration Recanalization GI bleed Other bleeding

Kwon, 2018130 91 2013–2016 Retrospective Dalteparin 200 mg/kg daily 6 mo 62% 1 major ectopic variceal 13 clinically relevant bleeds Enoxaparin 1 mg/kg bid 20 complete 2 major bleeds (CNS, GI) 36 partial 28 unchanged 4 progression La Mura, 2018 109 63 2003–2015 Retrospective VKA INR 2–3 23.3 mo (mean) 70% 7 (5 major UGI, 3 major (CNS, hematoma, 31 complete 2 minor lower) hematuria) 13 partial 11 minor 19 unchanged Rodriguez-Castro, 65 2007–2015 Retrospective Enoxaparin Weight adjusted 12 mo maximum 72% 1 major GI (PHG) 1 major (CNS); 2 minor 2018131 28 complete (hematuria, epistaxis) 19 partial 18 unchanged Hanafy, 2018c,39 40 2014–2017 Prospective Rivaroxaban 10 mg twice daily 6 mo maximum 100% 00 34 complete 6 partial Hanafy, 2018c,39 40 2014–2017 Prospective VKA INR goal 2–2.5 6 mo maximum 100% 17 patients with — 18 complete “severe GI bleed” 0 partial Nagaoki, 2018d,138 20 2011–2016 Retrospective Danaproid 2500 U/d 6 mo 90% 3 GI bleeds (rectal varices, — Edoxaban 60 mg daily 14 complete intestinal, colon polyp) 4 partial 1 unchanged 1 progression Nagaoki, 2018d,138 30 2011–2016 Retrospective Danaproid 2500 U/d 6 mo 30% 2 EV bleed — VKA INR 1.5–2 6 complete 3 partial 7 unchanged 14 progression

CNS, central nervous system; EV, esophageal variceal; GI, gastrointestinal; INR, international normalized ratio; NR, not reported; PHG, portal hypertensive gastropathy. aPatients with PVT after splenic embolization. bSeparate cohorts presented in each row. cPatients with acute PVT after surgical splenectomy; each cohort presented separately in rows. dSome patients treated simultaneously with antithrombin when baseline activity <70% for 3 d; each cohort presented separately in rows.

REVIEWS AND PERSPECTIVES 1594 Intagliata et al Gastroenterology Vol. 156, No. 6

DOACs are now used more widely in clinical practice due a common problem based on the anatomical location only. PERSPECTIVES EIW AND REVIEWS to acceptable safety profile without need for monitoring by However, the 2 entities differ vastly in many important laboratory testing and reversibility. Studies examining ways. The dominant pathogenic mechanisms, clinical DOAC for the treatment of PVT in compensated cirrhosis are implications, and appropriate interventions are dependent emerging, but remain limited.39,134–138 Data regarding on whether one is addressing cirrhotic or non-cirrhotic PVT. pharmacodynamics of DOAC in patients with advanced liver Consequently, clinicians must establish the presence or disease are especially limited. Small in vitro studies using absence of cirrhosis as early as possible in the evaluation of thrombin generation assay suggest the anticoagulant effect PVT. While recent studies have greatly expanded our may be altered in more decompensated cirrhosis.139,140 knowledge in both non-cirrhotic and cirrhotic PVT, research Bleeding is a feared complication of anticoagulation and remains limited to mainly retrospective cohort studies. the overall risk in highly selected patient populations ap- Future research to expand our understanding of the natural pears relatively low (Table 5). Comparison of bleeding rates history and therapy of PVT is now needed and will likely between studies is challenging, however, because no stan- require multicenter collaboration. dard definition of bleeding is used. As patients with cirrhosis are at risk to bleed from PH, an upper endoscopy to risk stratify varices is advised, and appropriate prophy- Supplementary Material laxis with nonselective b-blocker or esophageal band To access the supplementary material accompanying this ligation is recommended.5,141 A recent study compared article, visit the online version of Gastroenterology at www. upper gastrointestinal bleeding in patients with cirrhosis on gastrojournal.org, and at https://doi.org/10.1053/j.gastro. anticoagulation (27% of cohort anticoagulated for PVT) to 2019.01.265. patients with cirrhosis not on anticoagulation and deter- mined that anticoagulation does not increase the severity of References bleeding or mortality.142 Importantly, the net risks and benefits should also be considered, as anticoagulation can 1. Elliot JW II. The operative relief of gangrene of intestine offer benefits that are not directly measured, which di- due to occlusion of the mesenteric vessels. 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100% 90% on Ɵ 80% 70%

coagula 60% Ɵ 50%

al + + complete) al 40% Ɵ 30% (par 20%

% response to an 10% 0% Rodriguez- La Mura V Kwon J Chen H Cui SB Chung JW Werner KT Senzolo M Delgado Amitrano Francoz C Castro K (2018) (2018) (2016) 108 (2015) (2014) (2013) (2012) MG (2012) L (2010) (2005) (2018) Failure 18 19 35 7 6 3 5 12 22 5 11 Successful 47 44 56 15 25 11 23 21 33 23 8

Supplementary Figure 1. Efficacy of LMWH and/or VKA in Cirrhotic PVT.

Supplementary Table 1.Anatomico-Functional Classification of Portal Vein Thrombosis in Cirrhosis

Site of PVT – (Type 1, 2a, 2b, 3) Type 1: Only trunk Type 2: Only branch: 2a, one branch; 2b, both branches Type 3: Trunk and branches Degree of portal venous system occlusion (O, NO) O: Occlusive: No flow visible in PV lumen on imaging/Doppler study NO: Nonocclusive: Flow visible in PV lumen through imaging/Doppler study Duration and Presentation (R, C) R: Recent (first time detected in previously patent PV, presence of hyperdense thrombus on imaging, absent or limited collateral circulation, dilated PV at the site of occlusion) Asymptomatic: (As) Symptomatic: (S), Acute PVT features (with or without ABI) Ch: Chronic (no hyperdense thrombus; previously diagnosed PVT on follow-up, portal cavernoma and clinical features of PHT) Asymptomatic Symptomatic: features of portal hypertension (with or without PHT) Extent of PV system occlusion (S, M, SM) Splenic vein, mesenteric vein or both Type and presence of underlying liver disease: Cirrhotic, noncirrhotic liver disease, post-liver transplant, HCC, local malignancies, and associated conditions

NOTE. Modified with permission from Sarin et al.112 ABI, acute bowel ischemia; HCC, hepatocellular carcinoma; IMV, inferior mesenteric vein; PHT, portal hypertension; PVT, portal vein thrombosis; PV, portal vein; SV, splenic vein.