EASL Clinical Practice Guidelines

Cirrhosis as a prothrombotic condition. Portal vein obstruction

Introduction

Venous thromboembolism (VTE), once considered unlikely in cirrhosis, has recently been documented to occur [[180], [181]] not only in the portal system, but also in the lower limbs and in the lung. Recently, a procoagulant imbalance was demonstrated in cirrhotic patients probably due to increased levels of factor VIII (procoagulant driver) combined with decreased levels of protein C (anticoagulant driver) [182]. These features are common in patients with cirrhosis and may explain the increased risk of VTE. This new concept makes the treatment with anticoagulants such as heparins or VKA, once regarded as contraindicative, possible in patients with cirrhosis who present with thrombosis.

Incidence and prevalence of PVT in cirrhosis

PVT is the most common of thrombotic events occurring in cirrhotic patients, with a reported prevalence ranging from 2.1% to 23.3% in a published series of transplant candidates without HCC [183]. Incidence at 1 year has been described to be 7.4% and 11% in two cohort studies, respectively [[184], [185]]. In the general population, the presence of cirrhosis is associated with a relative risk of 7.3 of developing non-neoplastic PVT [186].

Manifestations

PVT in cirrhotic patients is often asymptomatic and detected at follow-up ultrasound evaluation. In other instances, PVT is diagnosed in coincidence with a liver decompensation. PVT has been shown to be independently associated with a higher risk of variceal bleeding, failure of endoscopic control of bleeding and rebleeding, leading to an increased 6 week mortality (36% in PVT vs. 16% in non-PVT patients) [[187], [188], [189]]. In those patients with extension of the thrombus into the superior mesenteric vein the risk of intestinal infarction and associated mortality is higher [190]. Englesbe et al. showed an increased mortality in cirrhotic patients with occlusive PVT listed for liver transplantation, independently from transplant (HR 1.99) [191]. Moreover, among all the published studies, the presence of PVT was associated with a significant increase in 30-day and 1-year mortality post-LT when compared to patients without PVT [183]. However, only complete PVT accounted for this increased mortality, also confirmed in a study from the registry data [191].

Risk factors

The occurrence of pathological thrombosis is determined by an alteration in the physiological equilibrium that regulates coagulation and anticoagulation dynamics as one of the components of Virchow’s triad. In cirrhotic patients the pathogenesis of PVT is likely to be multifactorial. Reduced portal flow velocity was associated with higher risk of developing PVT in one study [185]. The possible role of thrombophilic genetic defects has been investigated in several cohorts and G20210A prothrombin gene variant has been the most common abnormality associated with PVT [[192], [193]]. Moreover the occurrence of PVT has been associated with more advanced liver disease (Child-Pugh C), presence of portal hypertensive complications and previous endoscopic sclerotherapy of oesophageal varices [183].

Diagnosis

The diagnosis of PVT is often made during routine ultrasound in asymptomatic patients, or once a new event of hepatic decompensation occurs. Doppler ultrasound is the first line method used, with sensitivity of about 90% for complete PVT which decreases to about 50% for partial PVT [183]. CT scan or MR imaging can better define the extension of PVT into the other splanchnic vessels. The presence of neoplastic infiltration of the portal vein has been shown to be associated in patients with underlying HCC, high serum alpha-fetoprotein levels, enlarged portal vein diameter, enhancement of the thrombus in the arterial phase of contrast injection at CT scan or contrast ultrasound [194], or an arterial-like flow observed on Doppler ultrasound [195].

Treatment

A recent randomized controlled trial has shown that enoxaparin 4000 IU daily for 1 year is able to completely prevent the occurrence of PVT, without increasing bleeding complications [196].

Spontaneous complete recanalisation of the portal vein may occur, mainly when thrombosis is partial [[197], [198]]. Progression of thrombosis has also been reported in 48% up to 70% of patients at 2 years follow-up [[197], [199]]. Data on the efficacy of medical anticoagulation to treat PVT come from five cohort studies [[184], [199], [200], [201], [202]] which included 163 anticoagulated patients, most with partial PVT, with different regimens (LMWH or VKA). Repermeation rate ranged from 55% to 75% with a mean interval time of about 6 months. Time interval between diagnosis of PVT and start of anticoagulation treatment less than 6 months, seems to be the most important factor able to predict the chance of response to anticoagulation [199]. When anticoagulation has been stopped soon after repermeation of the PV recurrence of thrombosis has been reported in up to 38% of cases after a few months [201]. This observation suggests that the prolongation of anticoagulation treatment after repermeation of the PV may prevent rethrombosis. Overall, bleeding complications were seen in 9/163 (5%) patients and correlated with PH in three cases. A multicentre study showed a correlation between platelet count less than 50 × 109/L and risk of bleeding [201].

Either beta blockers or band ligation can be used to prevent variceal bleeding before anticoagulation. TIPS has been shown to be feasible in the presence of PVT, even in some cases with cavernous transformation [[117], [199], [203], [204]]. However, in most cases the indication for TIPS was not PVT per se, but complications of PH. Therefore, the applicability of TIPS to treat PVT is unknown. The thrombotic occlusion of the intrahepatic portal vein branches compels the use of transcutaneous approach with associated increased risk of complications [[205], [206]]. While waiting for the results of randomized controlled trials, each institution/liver unit should define its own algorithm of treatment of PVT in cirrhosis, based on its experience, pattern of referral, etc. Candidacy to liver transplantation, degree and extent of occlusion, underlying conditions, past history and presence of PH complications among others need to be taken into account when designing such an algorithm.