Publications > Journals > Journal of Clinical and Translational Hepatology > Article Full Text

  • OPEN ACCESS

Update on Management of Portal Vein Thrombosis and the Role of Novel Anticoagulants

  • Matthew Wu1,
  • Michael Schuster2 and
  • Micheal Tadros*,3
Journal of Clinical and Translational Hepatology 2019;():-

DOI: 10.14218/JCTH.2018.00057

Received:

Accepted:

Published online:

 Author information

Abstract

The clinical management of portal vein thrombosis (PVT) remains ambiguous due to its heterogeneous presentations and its associations with liver disease, malignancy, and hypercoagulable states. The natural history and clinical outcome of PVT are highly variable, dependent upon size, extent and degree of the thrombotic occlusion, as well as the physiological impact of patient comorbidities. While existing clinical guidelines consistently recommend low molecular weight heparin or vitamin K antagonist anticoagulation in cirrhotic patients with symptomatic acute PVT, management of asymptomatic and chronic PVT may need to be determined on a case-by-case basis, factoring in the state of underlying liver disease. In general, patients with PVT and underlying malignancy should be anticoagulated to alleviate symptoms and prevent recurrences that could disrupt the cancer management. However, existing clinical data does not support routine anticoagulation of cirrhotic patients with asymptomatic PVT in the absence of underlying cancer. While low molecular weight heparin and vitamin K antagonist remain the most commonly used agents in PVT, an emerging body of clinical evidence now suggests that direct-acting oral anticoagulants may be used safely and effectively in PVT. As such, direct-acting oral anticoagulants may offer a more convenient anticoagulation alternative for PVT management in future practice.

Keywords

Portal vein, Thrombosis, Liver cirrhosis, Neoplasm, Anticoagulant

Risk factors and natural history

Since the first description of portal vein thrombosis (PVT) by Balfour and Stewart in 1869, in their report of a 20-year-old patient who died from complications of splenomegaly, ascites, and varicose dilation with associated PVT, the clinical manifestations and management of PVT have been met with great interest.1 PVT is classically defined as obstruction of the portal vein by thrombus, graded based upon the extent of vascular occlusion.2 As an entity, it has been included occasionally in splanchnic vein thrombosis (SPVT), referring to the thrombotic involvement of portal, mesenteric, splenic veins, and in Budd-Chiari syndrome, based on shared etiology and risk factors.35

The incidence rate of PVT is unknown. The population prevalence has been reported as 1% based on an autopsy series from Sweden6 and has been proposed to range between 0.6% to 26% in patients with liver cirrhosis,79 in which the incidence of PVT rises with severity of liver disease. In patients undergoing liver transplantation for end-stage liver diseases, for example, studies have reported 5.5% to 26% prevalence.10

Risk factors of PVT adhere to Virchow’s a triad of thrombus formation: stasis of blood flow, endothelial injury, and hypercoagulability (Table 1).11,12 In addition to cirrhosis, PVT is common with hepatobiliary cancers.13 For hepatocellular cancer (HCC), 23% and 44% of untreated and autopsy series of patients were found to have PVT, respectively.14,15 HCC alone confers >100-fold risk of PVT over that for the general population. In the absence of associated cirrhosis or malignancy, myeloproliferative neoplasms (MPNs) have been shown to be the most common underlying prothrombotic factor for acute PVT. In a meta-analysis of 32 studies assessing the prevalence of MPNs in PVT patients, MPNs were present in 166 out of 855 (31.5%) cases. Of these patients with MPN, 86.6% were found to have the JAK2V16F mutation.16 Thrombophilias (deficiency of antithrombin-III, protein C or protein S, and factor V Leiden mutation) are known risk factors for venous thromboembolism (VTE).17 These account for less than 10% of all recurrent VTE and confer only a modest increased risk (<5-fold) for PVT (Table 1).

Table 1.

Risk factors of PVT

Risk factorsRelative risk
General population prevalence61
Nonmalignant cirrhosis7,9,21,101
 Early cirrhosis4.2-4.6
 Advanced cirrhosis11.2-16.6
Nonmalignant with cirrhosis with portal hypertension1016.1
Malignancies102
 Overall5.3
 Hepatocellular124
 Cholangiocarcinoma77
 Pancreatic28
Hematologic disorders16,103
 Factor V-Leiden4.8
 All thrombophilia1.2
JAK2V617F-positive MPNs27.7
 All MPNs31.5
Inflammation102
 Autoimmune (ulcerative colitis, Crohn’s)2.5
 Autoimmune deficiency syndrome3.6

Hypercoagulability leading to a prothrombotic state is the primary pathophysiological factor leading to PVT, underscored by the high incidence of concomitant nonportal vein VTEs.18 Based on the report of Ögren et al.6, up to 70% of patients with noncirrhotic PVT may have underlying malignancy or MPN. Indeed, Sogaard et al.19 proposed the presence of SPVT as a marker for occult malignancy, as 3-month and 5-year absolute cancer risks were found to be 8.0% and 14.8%, respectively, in patients who presented with SPVT.

The natural history of PVT has not been well described due to the wide variability of underlying causes and patient-specific determinants, such as the associated prothrombotic state and vascular/liver physiology. In patients without underlying malignancy, the clinical course of PVT can vary in the different stages of liver disease. In a study population consisting of 40% alcohol users with good baseline liver function, being representative of PVT in the setting of early chronic liver disease, the natural history of PVT was indolent. In 85% of these patients with nonocclusive PVT, 70% showed spontaneous resolution and 19% showed resolution and reappearance with very few patients having received anticoagulation therapy. When PVT developed prior to progression of the liver disease, it was not statistically associated with increased risk of liver disease progression or decompensation.20 In contrast, an earlier series by Amitrano et al.7 in patients with more advanced cirrhosis reported 11.2% PVT incidence and 45% were symptomatic with portal hypertensive bleed, abdominal pain, and/or intestinal infarction. In this series, mesenteric vein involvement was always associated with symptoms. In another retrospective series, bleeding was found to be the main presenting symptom, in 82% of cirrhotic patients with PVT treated for portal hypertension.9 The incidence of PVT was 16.6% in this series. When taken together, PVT incidence markedly increases with cirrhosis and is significantly associated with symptoms of bleeding, abdominal pain, and intestinal infarction.

In patients with HCC and liver cirrhosis, using ultrasound as a screening methodology, Nery et al.21 found the overall 1-, 3- and 5-year cumulative PVT incidence to be 4.6%, 8.2% and 10.7%, respectively. The natural history of patients with PVT and underlying malignancy has not been described; however, the presence of PVT has been identified as an adverse predictor for survival.14,22

Clinical presentation

A new classification system of PVT, based on the site of thrombosis (portal venous trunk and/or its tributary branches), degree of occlusion, duration and presentation, and associated symptoms, has recently been proposed to delineate this relatively common clinical finding within a heterogenous set of diseases (Table 2).23,24 While adoption of this classification system will help to standardize nomenclature and reduce variation in clinical trials, it does not immediately provide instruction in clinical decision-making for patients with individualized risk factors and disease severities. The decision to intervene in PVT will vary, since the clinical objectives must be individualized for nonmalignant noncirrhotics, nonmalignant cirrhotic patients, patients with hepatobiliary cancer, and patients with hematologic disorders or solid tumor malignancies.

Table 2.

Proposed classification

Proposed classification of PVT in cirrhosis24
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 (on imaging/Doppler study)
 O: Occlusive
 NO: Nonocclusive
Duration and presentation (R, C)
 R: Recent (first time detected in previously patent portal vein, presence of hyperdense thrombus on imaging, absent or limited collateral circulation, dilated portal vein at the site of occlusion)
  -S: Symptomatic (acute PVT features with or without “ABI”)
  -AS: Asymptomatic
 C: Chronic (no hyperdense thrombus; previously diagnosed PVT on follow-up, portal cavernoma and clinical features of “PHT”)
  -S: Symptomatic (features of “PHT”)
  -AS: Asymptomatic

Usually, PVT presents without apparent symptoms, even in patients with advanced liver disease; however, patients with advanced liver disease are more likely to be symptomatic, especially with acute onset and complete thrombotic occlusion of the portal vein.25 In a prospective study of noncirrhotic patients, Plessier et al.26 reported that 91% presented with abdominal pain and that the majority demonstrated signs of systemic inflammation, fever (53%), and elevated C-reactive protein (84%). Intestinal infarction, which has been reported in up to 28% in another series27 was found in two (2/102) patients requiring surgery. Sepsis due to intraabdominal infection or phlebitis was not specifically addressed in this series but has been frequently reported as an early complication of acute PVT.28,29 Intestinal infarction is the most feared complication of acute PVT and is associated with a 60% mortality risk.30

In patients with cirrhosis, symptoms resulting from acute PVT can be highly variable, likely related to the cumulative effect of venous thrombosis on underlying portal hypertension and liver disease. Ascites and bleeding, or portal hypertensive gastropathy are found in 40-80% of cirrhotics who present with PVT.7,3133 Intestinal infarction is reported in 2-12% of these patients, correlating with involvement of the mesenteric vein.7,33,34 Hepatic decompensation is found both in high frequency at presentation and as a complication of PVT, and is likely a marker of advanced liver disease.3234 Encephalopathy is also common, occurring in 10-25% of patients.7,32,34

Chronic PVT occurs when acute PVT fails to resolve, resulting eventually in the formation of collateral vasculature bypassing the area of obstruction (known as cavernous transformation). Cavernous transformation of the portal vein has been shown to occur between 6-12 days from unresolved PVT with bypass of blood through the paracholedochal veins.35 The location of these cavernomas results in cholestasis in 50-90% of the patients but causes biliary obstruction only in the minority (6-25%) of these cases.36 However, in a case series of PVT in cirrhotics, Sogaard et al.31 found that chronic PVT did not differ significantly from acute PVT in clinical presentation; therefore, symptoms classically associated with acute PVT may still herald chronic PVT with incomplete or delayed resolution.

Evaluation

Serial screening with Doppler ultrasound has been recently proposed for patients with cirrhosis and portal hypertension, and in candidates on the waiting list for liver transplantation.37 Asymptomatic PVTs, however, are primarily found incidentally on initial computer tomography (commonly known as CT) or magnetic resonance imaging (commonly known as MRI) of the liver. Clinically suspected PVTs are generally established by conventional and Doppler ultrasound (Fig. 1). Color Doppler studies demonstrate an accuracy of 88-98% with sensitivity/specificity in the 80-100% range,38 and is considered sufficient for diagnosis (Fig. 2).

Filling defect in the portal vein on ultrasound.
Fig. 1.  Filling defect in the portal vein on ultrasound.
Ultrasound color Doppler.
Fig. 2.  Ultrasound color Doppler.

Contrast-enhanced sonography using microbubble contrast agents adds to the sensitivity of the color Doppler ultrasound and may be used to better characterize the nature of the thrombus.39,40 Bland versus tumor thrombus may be differentiated on the basis of contrast enhancement during the arterial phase of the study, especially in a thrombus that is noncontiguous with the tumor. Pathological confirmation is usually unnecessary by needle aspiration but may be clinically indicated in some situations, such as when the tumor involving the vessel up-stages the disease and precludes local regional therapy.41 Contrast-enhanced multi-phase CT (Fig. 3) or MRI (Fig. 4) may be reserved to further characterize PVT extension and to detect the presence of cavernomas, synchronous bowel ischemia, or suspected intra-abdominal malignancy.38

Computed tomography of the abdomen showing portal vein filling defects.
Fig. 3.  Computed tomography of the abdomen showing portal vein filling defects.
Filling defect in the right portal vein, coronal LAVA magnetic resonance imaging sequence.
Fig. 4.  Filling defect in the right portal vein, coronal LAVA magnetic resonance imaging sequence.

Measurement of the hepatic venous pressure gradient through transvenous balloon catheterization may be indicated to assess the portal venous pressure gradient in advanced cirrhotics, in whom intervention might be considered.42,43

It is important to remember that in the initial diagnosis of PVT, 10-15% of patients will present with no known risk factors (Table 1). In these noncirrhotic patients, the presence of myeloproliferative disorder, thrombophilia, or occult malignancy must be considered in the evaluation. Recently, the presence of JAK2 V617 mutation has been demonstrated to be highly suggestive of MPNs and has been found in 5-35% of patients presenting with PVT/SPVT.4446 In these patients, hematologic investigation that includes bone marrow biopsy should be considered to establish MPN diagnosis and guide subsequent treatment. Additionally, exon 9 deletion and/or insertion mutations in the calreticulin gene (CALR) have recently been associated with MPNs.47 However, the CALR gene mutations are apparently associated with lower risk for PVT/SPVT relative to the JAK2 V617 mutation.48

Protein S, protein C, antithrombin antigen, and antiphospholipid antibodies levels are frequently drawn initially to screen for suspected thrombophilia. However, these tests have been shown to be inadequate, and should be replaced by their corresponding functional assays to define thrombophilia phenotypes or by selected genetic testing, such as for factor V Leiden.49,50

Interventions

Intervention for PVT depends on defining the patient-specific goals for the intervention, while also weighing the risks and benefits in achieving treatment objectives. Given the delicate balance between thrombosis and bleeding in all PVT patients, interventions may disrupt this equilibrium and affect clinical outcome. The range of treatment for PVT includes close monitoring without intervention, anticoagulation, thrombolysis, thrombectomy, and transjugular intrahepatic portosystemic shunt (TIPS). A clinician’s role is, therefore, to understand the range of options and to recommend the most appropriate treatment based on these considerations.

Traditional anticoagulants: Systemic anticoagulation has been the mainstay of VTE treatment. For many decades, standard care was to start with unfractionated heparin51 or low molecular weight heparin (LMWH), then bridging to oral vitamin K antagonist (VKA) for long-term anticoagulation.52 Unfractionated heparin has been largely replaced by LMWH in most clinical situations due to the ease of outpatient administration, given subcutaneously once or twice a day, without the need for laboratory monitoring. LMWH has also been used as an alternative for chronic anticoagulation. The recommended dose for enoxaparin is 1 mg/kg every 12 hours (maximum dose 150 mg) and for dalteparin is 10,000 to 18,000 IU once a day (depending on weight).53 Of note, a previous randomized trial comparing enoxaparin at the standard doses of 1 mg/kg twice a day and 1.5 mg/kg once a day showed that the latter was associated with nearly 4-fold greater risk for nonvariceal bleeding.54

Anti-Xa level may be useful in patients with bleeding complications, extreme body weight, renal insufficiency (creatinine clearance <10 mL/min), pregnancy, acute burns, and recurrent thrombosis despite LMWH treatment.5558 However, insufficient evidence currently supports routine monitoring of anti-Xa, even in cancer patients, who are known to have 3-fold higher recurrent thrombosis and 2-fold higher major hemorrhage rate.59 VKA (warfarin) has been in use in patients with VTE for several decades. In treatment and prevention of VTE and PE, the daily oral VKA dose targets to individualized therapeutic international normalized ratio value of 2.5 (range 2-3).53

Direct-acting oral anticoagulants (DOACs): DOACs have been in increasing use for treatment of VTE, in a variety of clinical settings. This group of agents includes orally available direct factor Xa inhibitors (rivoraxaban, apixaban, edoxaban, betrixaban) and the direct thrombin inhibitor dabigatran.60 DOACs avert daily subcutaneous injections of LWMHs and the frequent monitoring of VKA. In patients with heparin-induced thrombocytopenia, DOACs represent effective options for anticoagulation.61 There is no validated clinical monitoring approach for these agents.60 Dose adjustment for renal impairment should be considered for the direct factor Xa inhibitors at creatinine clearance of <30 mL/min and avoidance at creatinine clearance <15 mL/min. Dabigatran depends on renal clearance and should be avoided at creatinine clearance <30 mL/min.

A comparison of commercially available DOACs is presented in Table 3. In 2015, idarucizumab, a monoclonal antibody fragment that binds dabigatran, was approved by the USA Federal Drug Administration to reverse dabigatran anticoagulation.62,63 Most recently, based on the results of the ANNEXA4-A clinical trial, the USA Federal Drug Administration also approved andexanet-alfa, a recombinant modified human factor Xa fragment that binds factor Xa inhibitors without thrombin cleavage activity, as a reversal agent for direct factor Xa inhibitors.64 Dabigatran, apixaban, and rivoraxaban have been examined in published PVT clinical trials and case reports (see Supplemental Table 1); edoxaban and betrixaban have not. It should be noted that betrixaban was recently approved in the USA for use in medically frail adults.65 The discussion of DOACs in management of PVT will be reserved for the section on Management of PVT in Selective Populations (below).

Table 3.

Comparison of available DOACs65,104,105

Dabigatran
(Pradaxa®)
Rivoraxaban
(Xarelto®)
Apixaban
(Eliquis®)
Edoxaban
(Savaysa®)
Betrixaban
(BevyxXa®)
FrequencyTwice a dayDailyTwice a dayDailyDaily
Dosing150 mg BID
220 mg QDay
15 mg BID for 21 days then 20 mg QDay10 mg BID for 7 days then 5 mg BID60 mg (or 30 mg) QDay160 mg initially then 80 mg Qday
MetabolismHeavy renal clearance
Contraindicated at ClCr<30
Avoid at CrCl < 15mL/minAvoid at CrCl < 15mL/minAvoid at CrCl < 15 mL/minAvoid at CrCl < 15 mL/min. 50% dose for CrCl between 15 and 30 mL/min
AntidoteIdarucizumabAndexanet-alfaAndexanet-alfaAndexanet-alfa
InteractionP-gp inducers/inhibitors*CYP3A4>>P-gp inducers/inhibitors*CYP3A4>>P-gp
inducers/inhibitors
Anticoagulants;
P-gp inducers
P-gp inducers
Adverse EffectsDyspepsia; bleedingBleedingBleedingRash, abnormal liver function, anemia, bleedingDiarrhea, abnormal liver function
ContraindicationsElderlyBreast feeding; hepatic impairedBreast feeding; hepatic impairedBreast feeding; hepatic impairedPregnancy; hepatic impairment; hypersensitivity

Pharmacological methods: Thrombolytic therapy for acute PVT and SPVT has been reported in the literature, as used by the transhepatic, transjugular and retrograde approach through omental veins.6668 These approaches appear to be safe and effective, and have been used primarily in selected nonmalignant, noncirrhotic patients with acute symptomatic thrombosis. The TIPS procedure has been investigated for therapy in the decompression of portal congestion and in the management of portal hypertension due to PVT.69 The TIPS is placed, with minimal invasiveness, under fluoroscopy into the hepatic vein, through the liver, or into the portal vein via the transjugular approach. TIPS placement has been accepted for the prevention of variceal bleeding and management of refractory ascites. Transplenic access into the portal system for placement of intrahepatic portosystemic shunt has been increasingly used to recanalize the portal vein, and has a high success rate.70,71 Kallini et al.70 reported the placement of TIPS through the transplenic approach in five symptomatic, noncirrhotic patients with complete occlusive chronic PVT, having durable patency rate and providing symptom alleviation. TIPS, therefore, has been used routinely in the management of symptomatic PVT; however, limited formal trials have been performed to define its precise role in specific clinical settings.7274

Existing clinical guidelines: Clinical guidelines for management of PVT have been published by at least two liver associations,75,76 several hematology societies,53,77,78 and others (Table 4).37,79 The guidelines vary depending on expert opinions and stringency by which the existing clinical trial data have been evaluated. After comparing the different guidelines, it is essential to note the following:

  • All guidelines agree on the recommendation of anticoagulation for acute symptomatic, nonmalignant PVT or SPVT after carefully mitigating risk of gastrointestinal bleeding, especially in patients with mesenteric vein extension associated with evidence of small bowel ischemia.

  • Guidelines differ in the length of anticoagulation: for 3-months, 6-months, or indefinitely. In patients with chronic VTE, a strong recommendation could not be made to routinely institute anticoagulation unless an underlying risk factor of neoplasm or thrombophilia could be identified.75,76

  • In cirrhotics, anticoagulation should be considered on a case-by-case basis, factoring in risk of bleeding and history of symptomatic intestinal ischemia.

  • In liver transplant candidates, the European Association for the Study of Liver76 and the Thrombosis Canada and 7th International Coagulation in Liver Disease Conference37 recommend the consideration of anticoagulation for 6 months or until transplantation.53,76 The American Association for the Study of Liver Diseases offers no recommendation,75 although it is accepted in practice to anticoagulate patients prior to liver transplantation.

Table 4.

Summary of existing guidelines for management of PVT

American Association for the Study of Liver Diseases75European Association for the Study of Liver76Thrombosis Canada53“ACCP”77; British Society of Hematology78
Acute PVT/SPVT noncirrhotic• Anticoagulate all patients with acute PVT for three-months (IB)
• Continue long-term therapy in patient with uncorrectable permanent thrombotic risk factors (IB)
• Consider long-term anticoagulation for patients with thrombus extension into mesenteric veins (IIa-C)
• Initiate antibiotic promptly in patients with any evidence of infection (IC)
• Initiate immediate anticoagulation with LMWH in the absence of major contraindication (A1)
• Monitor anti-Xa activity in overweight patients, pregnant or with poor kidney function (A1)
• Oral VKA are used for long-term anticoagulation targeting INR 2-3 (B1)
• Anticoagulation therapy should be given for at least 6 month. (A1)
• Anticoagulation is recommended for patients with symptomatic or extensive PVT and in those with extension of the PVT into the superior mesenteric vein
• The role of anticoagulation in patients with asymptomatic PVT is controversial
• The duration of anticoagulation in patients with PVT is uncertain
“ACCP”
• In patients with symptomatic “SVT”, anticoagulation is recommended over no anticoagulation (1B)
• In patients with incidentally detected SPVT, no anticoagulation is recommended over anticoagulation (2C)
British Society of Hematology
• In acute PVT without cirrhosis anticoagulation is recommended (1C)
• Patients with acute mesenteric vein thrombosis without peritonitis can be managed conservatively with anticoagulation (1B)
• There is no evidence as to whether it should be given for 3–6 months or long-term for above
Chronic PVT noncirrhotic• Consider long-term anticoagulation therapy in patients with uncorrectable permanent risk factors (IIa-C)• Consider permanent anticoagulation in patients with a strong prothrombotic condition, or past history suggesting intestinal ischemia, or recurrent thrombosis on follow-up (B2) Long-term anticoagulation in case of underlying MPN• The role of anticoagulation in patients with portal vein thrombosis and cavernous transformation is very unclear
PVT in cirrhotics• No generalized recommendation
• Anticoagulation to be considered on case-by-case basis
• Consider anticoagulation at therapeutic dose for atleast 6 months (B1)
• In patients with superior mesenteric vein thrombosis, with a past history suggestive of intestinal ischemia, consider lifelong anticoagulation (C2)
British Society of Hematology
• In PVT with cirrhosis the risk of anticoagulation will usually outweigh the benefit but an individual decision is needed for each patient. (2C)
PVT awaiting liver transplant• No generalized recommendation• Consider anticoagulation until transplant in liver transplant candidates (B2)
• In liver transplant candidates, who have progressive PVT not responding to anticoagulation, consider referring the patients for TIPS (B2)
• Patients with PVT who are potential transplant candidates should be considered for anticoagulation

Given that 70-75% of PVTs occur in the setting of known malignancy (HCC, solid tumors, lymphomas, MPNs), it is worthwhile to revisit the clinical guidelines for the management of cancer and VTE. The National Comprehensive Cancer Network80 and American Society of Clinical Oncology have published guidelines for venous thromboembolic diseases in cancer patients.81,82 In the 2018 National Comprehensive Cancer Network guideline,80 anticoagulation for at least 6 months is recommended in the setting of acute SPVT (defined as symptom and signs ≤8 weeks and no cavernous transformation/collaterals) without contraindication to anticoagulation. Pharmacomechanical thrombectomy can also be considered in this setting. The American Society of Clinical Oncology’s recommendation only addresses incidentally found VTE, where treatment should be considered on a case-by-case basis.81 For cancer patients with newly diagnosed VTE and relatively preserved renal function (creatinine clearance <30 mL/min), treatment with LMWH is preferred over “UHF” for the initial 5 to 10 days. Anticoagulation should be continued for at least 6 months with LMWH, being preferred over VKAs. Long-term anticoagulation with either LMWH or VKA beyond the initial 6 months may be considered for patients with active cancer, such as those with metastatic disease or those receiving chemotherapy.81

Management of PVT in selected clinical populations

The following sections offer a discussion of selective management considerations, paired with specific discussion on the use of DOACs. A summary table of the trials discussed may be found in Supplemental Table 1.

Cirrhotic patients without underlying malignancies

Prognosis: Acute PVT occurring in cirrhotic patients without evidence of underlying malignancies constitutes 20-25% of all PVT cases. PVTs in this setting can result in both immediate and delayed complications. The impact of PVT on survival of nontransplant patients with liver cirrhosis is conflicting.83 In a series of 185 patients with advanced cirrhosis and bleeding esophageal varices, Amitrano et al.84 found that the presence of PVT was associated with nonstatistically significant predictors of 5-day mortality rate (odds ratio: 2.94; p-value of 0.079). Only Child-Pugh staging and white blood cell count demonstrated statistical significance as independent variables. It was reported that 16.8% of patients failed the protocol control of variceal bleeding and 87.1% of these cases resulted in death. In the majority (70%) of these cases, death was due to an irreversible worsening of liver function.

In an older multicenter, prospective cohort study consisting of 465 bleeding cirrhotic patients, D’Amico and colleagues85 found PVT to be significant predictor of 5-day failure rate but not 6-week mortality rate. Both these series contained patients with underlying HCC and neither series specifically identified acute PVT or related symptoms. These two studies show that in patients with severe cirrhosis, the finding of PVT, especially if asymptomatic, is associated with high mortality risk. The risk of death may be as high as 15%, related either to uncontrollable bleeding or to irreversible deterioration of underlying liver disease.

Outcomes of treated versus untreated PVT in cirrhotic patients: Senzolo et al.86 reported the only prospective matched cohort study, in which 35 consecutive cirrhotic patients with PVT were treated with anticoagulation and TIPS, and 21 untreated cirrhotic patients with PVT were followed for a mean of 22.5 months. The LMWH nadroparin was started at therapeutic doses for patients found to have acute PVT and continued after complete recanalization at prophylactic doses or for 1 year if recanalization could not be achieved. TIPS was placed in 7 patients, 5 for thrombosis extension. The study included patients with Child-Pugh classes A, B and C patients and having an average model for end-stage liver disease score of 12.6 for the intervention group and 13.7 for the untreated cohort. The following findings were reported:

  • Recanalization was achieved in 94% (33/35) of the treatment group with 54% within 6 months of intervention, while spontaneous recanalization was observed in 5% (1/21) of the untreated group.

  • Shorter interval between PVT diagnosis and study enrollment (<6 months) and between diagnosis of thrombosis and anticoagulation (<6 months) correlated with partial or total recanalization.

  • Five variceal bleeding episodes, unrelated to endoscopic variceal ligation, occurred in the nontreatment group, while only one occurred in the treatment group (p = 0.09).

  • Intestinal ischemia was described in two cases of the control arm and zero in the interventional arm.

  • One major bleeding event occurring in the central nervous system was reported in the anticoagulation arm.

Scheiner and colleagues87 recently reported a retrospective study of 51 patients with nonmalignant cirrhosis. Twelve of these patients were given early short-term anticoagulation (LWMH, VKA or DOACs) and thirty-nine were observed initially and then given long-term anticoagulation. The long-term anticoagulation was given for at least 9 months. The length of early anticoagulation administration was not specified and the decision to start early anticoagulation was started at the discretion of the providers. The 51-patient cohort comprised all CP stages and had a mean MELD of 13.6. The findings are:

  • The PVT regression and PVT reprogression rates between the early anticoagulation patients were not statistically different from patients who did not receive early anticoagulation.

  • Only 12 patients were kept on long-term therapy. Of these, a trend to higher PVT regression rate was observed in the long-term anticoagulation patients in comparison with patients without long-term anticoagulation. Long-term anticoagulation also resulted in a significantly higher rate of PVT regression in patients who experienced liver decompensation (70% vs. 24%, p = 0.031).

  • However, anticoagulation did not alter liver enzymes, synthetic function, or control of ascites.

Two other retrospective cohort studies88,89 (Table 3) studied LMWH or VKA in cirrhotic patients with PVT. These two studies showed efficacy of anticoagulation on the recanalization of patients; however, they could not demonstrate statistically significant clinical outcome differences. Bleeding complication rates were low in both studies.

Role of DOACS: The experience of using DOACs in cirrhotic patients with PVT is limited to three retrospective case series9092 (also see Supplemental Table 1 for summary) and several case reports.9395 These have been recently reviewed by Priyanka et al.96 The patients are generally asymptomatic with Child-Pugh class B and model for end-stage liver disease score of 10. Bleeding events for DOACs within the observational period (16-22 months) were low, being <5% for major bleeding and 10-12% for minor bleeding. Hum et al.91 compared DOAC anticoagulated patients with VKA-treated patients and concluded that bleeding was less frequent with DOACs. Recanalization of the portal vein was reported in several cases and DOACs did not produce hepatotoxicity. These studies demonstrate safety of DOACs in cirrhotic patients, leading the consensus statements of the 7th International Coagulation in Liver Disease Conference to include DOACs as a therapeutic option for patients with compensated cirrhosis.37

Summary: The existing clinical evidence does not support routine anticoagulating cirrhotic patients with PVT but without underlying cancers. Even when anticoagulation results in significantly higher recanalization rates and reduced thrombosis recurrence/progression rates, these objectives have not been associated with improvement of clinical outcomes such as mortality rate, portal hypertensive complications, or stabilization/improvement of liver decompensation. Since acute liver decompensation in these patients has been shown to be associated with extreme mortality risk, emergent anticoagulation should only be reasonably considered in patients with evidence of acute liver decompensation after active bleeding has been managed through endoscopic or pharmacomechanical intervention. Anticoagulation appears to be associated with low risk for bleeding, even in very high-risk patients. However, until more definitive evidence emerges, cirrhotics without evidence of liver decompensation should not be routinely treated. In emergent cases, LMWH should be the initial choice due to the availability of effective reversal agent protamine sulfate97 and should be continued until liver decompensation stabilizes before switching to long-term anticoagulation or discontinued if rapid decompensation persists. If a clinician chooses to place a cirrhotic without clinical deterioration on long-term anticoagulation, DOACs can be considered as a safe, if not preferable, alternative given their safety over LMWH.

Patients with PVT and underlying malignancy (with or without cirrhosis)

Prognosis: In 60-70% of cases, PVT occurs in patients with known malignancy, such as hepatobiliary advanced solid tumors or lymphomas. In a small subset, occult malignancy or MPNs may be found on investigation. In HCC patients, PVT has been reported in 23% of an untreated HCC population14 and in 35-40% in an autopsy series.15 PVT occurs more often in patients with metastatic disease, limits cancer therapeutic options, and is associated with significantly shorter overall survival.14,22 Similarly, SPVT has been shown by Sogaard and colleagues19 to be an adverse prognostic indicator for cancer survival.

Outcomes of treated versus untreated PVT in patients with underlying malignancy: The primary objectives of anticoagulation treatment for cancer patients with VTE are to prevent recurrence, extension, or embolism without incurring unacceptable risk for bleeding. LMWH has been established as the preferred treatment option historically, based on the Comparison of Low-molecular-weight heparin versus Oral anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (known as CLOT) trial,98 which compared LMWH to VKA in patients with active cancer and acute symptomatic proximal deep venous thrombosis or pulmonary embolism. The CLOT trial randomized 672 patients to receive dalteparin or a VKA as treatment and secondary prevention, and demonstrated significantly less recurrent VTE risk (9% vs. 17%) in favor of LMWH with comparable bleeding risk. In a post-hoc analysis, the CLOT investigators also found dalteparin to be associated with survival benefit over VKA in patients with nonmetastatic cancer (the probability of death at 12 months was 20% vs. 36%, p = 0.03); this survival benefit was not found in patients with metastatic cancer.

Role of DOACs: Recently, two DOACs, edoxaban and rivoraxaban, were separately compared to LMWH.2,99 These two trials each demonstrated noninferiority of DOAC in comparison with LMWH for recurrent VTE and bleeding risk in cancer patients. It is worthwhile to note that in a series reported by Janczak et al.,100 in which 36 patients with VTE of atypical location were treated with DOACs, recurrence rates and bleeding rates were not different between these patients and other patients who received either LMWH. Of the 36 patients, 26 had SPVT and 54% of these patients had underlying malignancy. All recurrence occurred in patients with underlying cancers.

Summary: In patients with PVT and underlying malignancy, it is reasonable to adhere to existing clinical guidelines for cancer-related VTE with the goals of treating symptoms and preventing recurrence. Even though PVT is often found incidentally, cancer-related hypercoagulability leads to thrombotic progression and related complications, possibly limiting treatment options. LMWH should be considered as the preferred anticoagulant over VKA, although DOACs are reasonable alternatives given the comparable safety. Anticoagulation should be administered for 6 months and could be discontinued if remission is attained following treatment.

Conclusions

Extrapolation of existing clinical trial evidence in PVT research to guide evidence-based practice is difficult, primarily due to heterogeneity of trial population, design, and lack of more meaningful end-points such as mortality, liver decompensation, and bleeding. It underscores the need for more organized nomenclature, classification, and internationally agreed upon trial designs. In this era of genomic medicine, novel predictive and prognostic markers should also be sought to define clinical indications for treatment. Currently, LMWH remains the standard treatment for noncancer patients with severe liver cirrhosis and evidence of acute liver decompensation. In all other situations, the use of DOACs appears to be safe and likely noninferior to LMWH.

Supplementary information

Supplemental Table 1.

Clinical trials in PVT

(DOCX)

Abbreviations

CLOT trial: 

Comparison of Low-molecular-weight heparin versus Oral anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer

CT: 

computed tomography

DOAC: 

direct-acting oral anticoagulant

HCC: 

hepatocellular carcinoma

LMWH: 

low molecular weight heparin

MPN: 

myeloproliferative neoplasms

MRI: 

magnetic resonance imaging

PVT: 

portal vein thrombosis

SPVT: 

splanchnic vein thrombosis

TIPS: 

transjugular intrahepatic portosystemic shunt

VKA: 

vitamin K antagonist

VTE: 

venous thromboembolism

Declarations

Conflict of interest

The author has no conflict of interests related to this publication.

Authors’ contributions

Drafting of the manuscript (MW), revision of the manuscript for important intellectual content (MW and MT), and contribution of images for figures (MS).

References

  1. Balfour GW, Stewart TG. Case of enlarged spleen complicated with ascites, both depending upon varicose dilatation and thrombosis of the portal vein. Edinb Med J 1869;14:589-598
  2. Young K, Wong R. Evaluation and management of acute and chronic portal vein thrombosis in patients with cirrhosis. Clin Liver Dis (Hoboken) 2018;10:152-156 View Article
  3. Lang SA, Loss M, Wohlgemuth WA, Schlitt HJ. Clinical management of acute portal/mesenteric vein thrombosis. Viszeralmedizin 2014;30:394-400 View Article
  4. Ageno W, Dentali F, Squizzato A. How I treat splanchnic vein thrombosis. Blood 2014;124:3685-3691 View Article
  5. Donadini MP, Dentali F, Ageno W. Splanchnic vein thrombosis: new risk factors and management. Thromb Res 2012;129:S93-S96 View Article
  6. Ogren M, Bergqvist D, Björck 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;12:2115-2119 View Article
  7. Amitrano L, Guardascione MA, Brancaccio V, Margaglione M, Manguso F, Iannaccone L. Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol 2004;40:736-741 View Article
  8. Okuda K, Ohnishi K, Kimura K, Matsutani S, Sumida M, Goto N. Incidence of portal vein thrombosis in liver cirrhosis. An angiographic study in 708 patients. Gastroenterology 1985;89:279-286 View Article
  9. Belli L, Romani F, Sansalone CV, Aseni P, Rondinara G. Portal thrombosis in cirrhotics. A retrospective analysis. Ann Surg 1986;203:286-291 View Article
  10. Francoz C, Valla D, Durand F. Portal vein thrombosis, cirrhosis, and liver transplantation. J Hepatol 2012;57:203-212 View Article
  11. Zocco MA, Di Stasio E, De Cristofaro R, Novi M, Ainora ME, Ponziani F. Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development. J Hepatol 2009;51:682-689 View Article
  12. Trebicka J, Strassburg CP. Etiology and complications of portal vein thrombosis. Viszeralmedizin 2014;30:375-380 View Article
  13. Quirk M, Kim YH, Saab S, Lee EW. Management of hepatocellular carcinoma with portal vein thrombosis. World J Gastroenterol 2015;21:3462-3471 View Article
  14. Llovet JM, Bustamante J, Castells A, Vilana R, Ayuso Mdel C, Sala M. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology 1999;29:62-67 View Article
  15. Pirisi M, Avellini C, Fabris C, Scott C, Bardus P, Soardo G. Portal vein thrombosis in hepatocellular carcinoma: age and sex distribution in an autopsy study. J Cancer Res Clin Oncol 1998;124:397-400 View Article
  16. Smalberg JH, Arends LR, Valla DC, Kiladjian JJ, Janssen HL, Leebeek FW. Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis. Blood 2012;120:4921-4928 View Article
  17. Anderson FA, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003;107:I9-I16 View Article
  18. Ogren M, Bergqvist D, Björck M, Acosta S, Sternby NH. High incidence of concomitant venous thromboembolism in patients with portal vein thrombosis: a population study based on 23 796 consecutive autopsies. J Thromb Haemost 2007;5:198-200 View Article
  19. Søgaard KK, Farkas DK, Pedersen L, Sørensen HT. Splanchnic venous thrombosis is a marker of cancer and a prognostic factor for cancer survival. Blood 2015;126:957-963 View Article
  20. Kreuziger LB, Ageno W, Lee A. Management of incidental splanchnic vein thrombosis in cancer patients. Hematology Am Soc Hematol Educ Program 2014;2014:318-320 View Article
  21. Nery F, Chevret S, Condat B, de Raucourt E, Boudaoud L, Rautou PE. Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study. Hepatology 2015;61:660-667 View Article
  22. Schöniger-Hekele M, Müller C, Kutilek M, Oesterreicher C, Ferenci P, Gangl A. Hepatocellular carcinoma in Central Europe: prognostic features and survival. Gut 2001;48:103-109 View Article
  23. 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:e112501 View Article
  24. Sarin SK, Philips CA, Kamath PS, Choudhury A, Maruyama H, Nery FG. Toward a comprehensive new classification of portal vein thrombosis in patients with cirrhosis. Gastroenterology 2016;151:574-577.e3 View Article
  25. Plessier A, Rautou PE, Valla DC. Management of hepatic vascular diseases. J Hepatol 2012;56:S25-S38 View Article
  26. Plessier A, Darwish-Murad S, Hernandez-Guerra M, Consigny Y, Fabris F, Trebicka J. Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study. Hepatology 2010;51:210-218 View Article
  27. Amitrano L, Guardascione MA, Scaglione M, Pezzullo L, Sangiuliano N, Armellino MF. Prognostic factors in noncirrhotic patients with splanchnic vein thromboses. Am J Gastroenterol 2007;102:2464-2470 View Article
  28. Condat B, Pessione F, Helene Denninger M, Hillaire S, Valla D. Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy. Hepatology 2000;32:466-470 View Article
  29. Sheen CL, Lamparelli H, Milne A, Green I, Ramage JK. Clinical features, diagnosis and outcome of acute portal vein thrombosis. QJM 2000;93:531-534 View Article
  30. Acosta S, Alhadad A, Svensson P, Ekberg O. Epidemiology, risk and prognostic factors in mesenteric venous thrombosis. Br J Surg 2008;95:1245-1251 View Article
  31. Sogaard KK, Astrup LB, Vilstrup H, Gronbaek H. Portal vein thrombosis; risk factors, clinical presentation and treatment. BMC Gastroenterol 2007;7:34 View Article
  32. Luca A, Caruso S, Milazzo M, Marrone G, Mamone G, Crinò F. Natural course of extrahepatic nonmalignant partial portal vein thrombosis in patients with cirrhosis. Radiology 2012;265:124-132 View Article
  33. Afifi AF, Basha OM, Wadea FM, Samack AE, Hafez RA. Portal vein thrombosis in patients with liver cirrhosis: insights to risk factors, clinical presentation and outcome. Int J of Adv Res 2015;3:1539-1548
  34. Cagin YF, Atayan Y, Erdogan MA, Dagtekin F, Colak C. Incidence and clinical presentation of portal vein thrombosis in cirrhotic patients. Hepatobiliary Pancreat Dis Int 2016;15:499-503 View Article
  35. De Gaetano AM, Lafortune M, Patriquin H, De Franco A, Aubin B, Paradis K. Cavernous transformation of the portal vein: patterns of intrahepatic and splanchnic collateral circulation detected with Doppler sonography. AJR Am J Roentgenol 1995;165:1151-1155 View Article
  36. Condat B, Vilgrain V, Asselah T, O’Toole D, Rufat P, Zappa M. Portal cavernoma-associated cholangiopathy: a clinical and MR cholangiography coupled with MR portography imaging study. Hepatology 2003;37:1302-1308 View Article
  37. Intagliata NM, Argo CK, Stine JG, Lisman T, Caldwell SH, Violi F. Concepts and controversies in haemostasis and thrombosis associated with liver disease: Proceedings of the 7th International Coagulation in Liver Disease Conference. Thromb Haemost 2018;118:1491-1506 View Article
  38. Margini C, Berzigotti A. Portal vein thrombosis: The role of imaging in the clinical setting. Dig Liver Dis 2017;49:113-120 View Article
  39. Rossi S, Rosa L, Ravetta V, Cascina A, Quaretti P, Azzaretti A. Contrast-enhanced versus conventional and color Doppler sonography for the detection of thrombosis of the portal and hepatic venous systems. AJR Am J Roentgenol 2006;186:763-773 View Article
  40. Tarantino L, Francica G, Sordelli I, Esposito F, Giorgio A, Sorrentino P. Diagnosis of benign and malignant portal vein thrombosis in cirrhotic patients with hepatocellular carcinoma: color Doppler US, contrast-enhanced US, and fine-needle biopsy. Abdom Imaging 2006;31:537-544 View Article
  41. Tarantino L, Ambrosino P, Di Minno MN. Contrast-enhanced ultrasound in differentiating malignant from benign portal vein thrombosis in hepatocellular carcinoma. World J Gastroenterol 2015;21:9457-9460 View Article
  42. Groszmann RJ, Wongcharatrawee S. The hepatic venous pressure gradient: anything worth doing should be done right. Hepatology 2004;39:280-282 View Article
  43. Merkel C, Bolognesi M, Sacerdoti D, Bombonato G, Bellini B, Bighin R. The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal bleeding in cirrhosis. Hepatology 2000;32:930-934 View Article
  44. Kiladjian JJ, Cervantes F, Leebeek FW, Marzac C, Cassinat B, Chevret S. The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. Blood 2008;111:4922-4929 View Article
  45. Shetty S, Kulkarni B, Pai N, Mukundan P, Kasatkar P, Ghosh K. JAK2 mutations across a spectrum of venous thrombosis cases. Am J Clin Pathol 2010;134:82-85 View Article
  46. How J, Zhou A, Oh ST. Splanchnic vein thrombosis in myeloproliferative neoplasms: pathophysiology and molecular mechanisms of disease. Ther Adv Hematol 2017;8:107-118 View Article
  47. Kim BH, Cho YU, Bae MH, Jang S, Seo EJ, Chi HS. JAK2 V617F, MPL, and CALR mutations in Korean patients with essential thrombocythemia and primary myelofibrosis. J Korean Med Sci 2015;30:882-888 View Article
  48. Langabeer SE. CALR mutation analysis is not indicated in patients with splanchnic vein thrombosis without evidence of a myeloproliferative neoplasm: a micro-review. Ann Gastroenterol 2016;29:557-558 View Article
  49. Tripodi A, Mannucci PM. Laboratory investigation of thrombophilia. Clin Chem 2001;47:1597-1606
  50. Nakashima MO, Rogers HJ. Hypercoagulable states: an algorithmic approach to laboratory testing and update on monitoring of direct oral anticoagulants. Blood Res 2014;49:85-94 View Article
  51. Englesbe MJ, Kubus J, Muhammad W, Sonnenday CJ, Welling T, Punch JD. Portal vein thrombosis and survival in patients with cirrhosis. Liver Transpl 2010;16:83-90 View Article
  52. Buller HR, Sohne M, Middeldorp S. Treatment of venous thromboembolism. J Thromb Haemost 2005;3:1554-1560 View Article
  53. 2018;Available from: http://thrombosiscanada.ca/wp-content/uploads/2018/02/Portal-Vein-Thrombosis-2018Jan30.pdf
  54. Cui SB, Shu RH, Yan SP, Wu H, Chen Y, Wang L. 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;27:914-919 View Article
  55. Vega JA, Lee YR, McMahan D, Duong HQ. Monitoring enoxaparin with antifactor Xa levels in severe renal impairment. J Pharma Care Health Sys 2016;3:161 View Article
  56. Levine L, Pallme N, Angelotti E, Shiltz D. Analysis of anti-xa concentrations in patients on treatment dose enoxaparin: A retrospective chart review. Advances in Pharmacology and Pharmacy 2013;1:37-41 View Article
  57. Yentz S, Onwuemene OA, Stein BL, Cull EH, McMahon B. Clinical use of anti-Xa monitoring in malignancy-associated thrombosis. Thrombosis 2015;2015:126975 View Article
  58. Egan G, Ensom MH. Measuring anti-factor Xa activity to monitor low-molecular-weight heparin in obesity: a critical review. Can J Hosp Pharm 2015;68:33-47 View Article
  59. Kreuziger LB, Streiff M. Anti-Xa monitoring of low-molecular-weight heparin in adult patients with cancer. Hematology Am Soc Hematol Educ Program 2016;2016:206-207 View Article
  60. Joppa SA, Salciccioli J, Adamski J, Patel S, Wysokinski W, McBane R. A practical review of the emerging direct anticoagulants, laboratory monitoring, and reversal agents. J Clin Med 2018;7:E29 View Article
  61. Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood 2017;130:1104-1113 View Article
  62. Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-520 View Article
  63. Pollack CV, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017;377:431-441 View Article
  64. Connolly SJ, Milling TJ, Eikelboom JW, Gibson CM, Curnutte JT, Gold A. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016;375:1131-1141 View Article
  65. Available from: http://www.crtonline.org/news-detail/fda-approved-betrixaban-bevyxxa-portola-prophylaxi
  66. Hollingshead M, Burke CT, Mauro MA, Weeks SM, Dixon RG, Jaques PF. Transcatheter thrombolytic therapy for acute mesenteric and portal vein thrombosis. J Vasc Interv Radiol 2005;16:651-661 View Article
  67. Chen C. Direct thrombolytic therapy in portal and mesenteric vein thrombosis. J Vasc Surg 2012;56:1124-1126 View Article
  68. Klinger C, Riecken B, Schmidt A, De Gottardi A, Meier B, Bosch J. Transjugular local thrombolysis with/without TIPS in patients with acute non-cirrhotic, non-malignant portal vein thrombosis. Dig Liver Dis 2017;49:1345-1352 View Article
  69. Copelan A, Kapoor B, Sands M. Transjugular intrahepatic portosystemic shunt: indications, contraindications, and patient work-up. Semin Intervent Radiol 2014;31:235-242 View Article
  70. Kallini JR, Gabr A, Kulik L, Ganger D, Lewandowski R, Thornburg B. Noncirrhotic complete obliterative portal vein thrombosis: Novel management using trans-splenic transjugular intrahepatic portosystemic shunt with portal vein recanalization. Hepatology 2016;63:1387-1390 View Article
  71. Pimpalwar S, Chinnadurai P, Hernandez A, Kukreja K, Siddiqui S, Justino H. Trans-splenic access for portal venous interventions in children: Do benefits outweigh risks?. Cardiovasc Intervent Radiol 2018;41:87-95 View Article
  72. Blum U, Haag K, Rössle M, Ochs A, Gabelmann A, Boos S. Noncavernomatous portal vein thrombosis in hepatic cirrhosis: treatment with transjugular intrahepatic portosystemic shunt and local thrombolysis. Radiology 1995;195:153-157 View Article
  73. Han G, Qi X, Guo W, Niu J, Bai M, Fan D. Transjugular intrahepatic portosystemic shunt for portal vein thrombosis in cirrhosis. Gut 2012;61:326-327 View Article
  74. Qi X, Han G. Transjugular intrahepatic portosystemic shunt in the treatment of portal vein thrombosis: a critical review of literature. Hepatol Int 2012;6:576-590 View Article
  75. DeLeve LD, Valla DC, Garcia-Tsao G. Vascular disorders of the liver. Hepatology 2009;49:1729-1764 View Article
  76. Clinical Practice Guidelines: Vascular diseases of the liver.. J. Hepatol 2016;64:179-202 View Article
  77. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e419S-e496S View Article
  78. Tait C, Baglin T, Watson H, Laffan M, Makris M, Perry D. Guidelines on the investigation and management of venous thrombosis at unusual sites. Br J Haematol 2012;159:28-38 View Article
  79. Ageno W, Beyer-Westendorf J, Garcia DA, Lazo-Langner A, McBane RD, Paciaroni M. Guidance for the management of venous thrombosis in unusual sites. J Thromb Thrombolysis 2016;41:129-143 View Article
  80. Available from: https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf
  81. Lyman GH, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013;31:2189-2204 View Article
  82. Streiff MB, Bockenstedt PL, Cataland SR, Chesney C, Eby C, Fanikos J. Venous thromboembolic disease. J Natl Compr Canc Netw 2013;11:1402-1429
  83. Qi X, Dai J, Yang M, Ren W, Jia J, Guo X. Association between portal vein thrombosis and survival in non-liver-transplant patients with liver cirrhosis: A systematic review of the literature. Gastroenterol Res Pract 2015;2015:480842 View Article
  84. Amitrano L, Guardascione MA, Manguso F, Bennato R, Bove A, DeNucci C. The effectiveness of current acute variceal bleed treatments in unselected cirrhotic patients: refining short-term prognosis and risk factors. Am J Gastroenterol 2012;107:1872-1878 View Article
  85. D’Amico G, De Franchis R. Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators. Hepatology 2003;38:599-612 View Article
  86. Senzolo M, M Sartori T, Rossetto V, Burra P, Cillo U, Boccagni P. Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis. Liver Int 2012;32:919-927 View Article
  87. Scheiner B, Stammet PR, Pokorny S, Bucsics T, Schwabl P, Brichta A. Anticoagulation in non-malignant portal vein thrombosis is safe and improves hepatic function. Wien Klin Wochenschr 2018;130:446-455 View Article
  88. Amitrano L, Guardascione MA, Menchise A, Martino R, Scaglione M, Giovine S. Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis. J Clin Gastroenterol 2010;44:448-451 View Article
  89. Delgado MG, Seijo S, Yepes I, Achécar L, Catalina MV, García-Criado A. Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis. Clin Gastroenterol Hepatol 2012;10:776-783 View Article
  90. De Gottardi A, Trebicka J, Klinger C, Plessier A, Seijo S, Terziroli B. Antithrombotic treatment with direct-acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis. Liver Int 2017;37:694-699 View Article
  91. Hum J, Shatzel JJ, Jou JH, Deloughery TG. The efficacy and safety of direct oral anticoagulants vs traditional anticoagulants in cirrhosis. Eur J Haematol 2017;98:393-397 View Article
  92. Intagliata NM, Henry ZH, Maitland H, Shah NL, Argo CK, Northup PG. Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when compared to traditional anticoagulation. Dig Dis Sci 2016;61:1721-1727 View Article
  93. Yang H, Kim SR, Song MJ. Recurrent acute portal vein thrombosis in liver cirrhosis treated by rivaroxaban. Clin Mol Hepatol 2016;22:499-502 View Article
  94. Martinez M, Tandra A, Vuppalanchi R. Treatment of acute portal vein thrombosis by nontraditional anticoagulation. Hepatology 2014;60:425-426 View Article
  95. Lenz K, Dieplinger B, Buder R, Piringer P, Rauch M, Voglmayr M. Successful treatment of partial portal vein thrombosis (PVT) with low dose rivaroxaban. Z Gastroenterol 2014;52:1175-1177 View Article
  96. Priyanka P, Kupec JT, Krafft M, Shah NA, Reynolds GJ. Newer oral anticoagulants in the treatment of acute portal vein thrombosis in patients with and without cirrhosis. Int J Hepatol 2018;2018:8432781 View Article
  97. Christos S, Naples R. Anticoagulation reversal and treatment strategies in major bleeding: Update 2016. West J Emerg Med 2016;17:264-270 View Article
  98. Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-153 View Article
  99. Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378:615-624 View Article
  100. Janczak DT, Mimier MK, McBane RD, Kamath PS, Simmons BS, Bott-Kitslaar DM. Rivaroxaban and apixaban for initial treatment of acute venous thromboembolism of atypical location. Mayo Clin Proc 2018;93:40-47 View Article
  101. Fujiyama S, Saitoh S, Kawamura Y, Sezaki H, Hosaka T, Akuta N. Portal vein thrombosis in liver cirrhosis: incidence, management, and outcome. BMC Gastroenterol 2017;17:112 View Article
  102. Al-Azzawi Y, Al-Abboodi Y, Fasullo M, Kheder J. Risk factors stratifications for portal venous thrombosis (PVT). J Liver 2017;6:208 View Article
  103. Dentali F, Galli M, Gianni M, Ageno W. Inherited thrombophilic abnormalities and risk of portal vein thrombosis. a meta-analysis. Thromb Haemost 2008;99:675-682 View Article
  104. Coulis AA, Mackey WC. A review of the efficacy and safety profiles of the novel oral anticoagulants in the treatment and prevention of venous thromboembolism. Clin Ther 2018;40:2140-2167 View Article
  105. Djulbegovic M, Lee AI. An update on the “novel” and direct oral anticoagulants, and long-term anticoagulant therapy. Clin Chest Med 2018;39:583-593 View Article
  106. Villa E, Cammà C, Marietta M, Luongo M, Critelli R, Colopi S. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012;143:1253-1260.e4 View Article
  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819