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Clinical Impact and Safety of Anticoagulants for Portal Vein Thrombosis in Cirrhosis

Pettinari, I., MD, PhD1; Vukotic, R., MD, PhD1; Stefanescu, H., MD, PhD2; Pecorelli, A., MD, PhD1; Morelli, Mc, MD3; Grigoras, C.2; Sparchez, Z., MD, PhD2; Andreone, P., MD1; Piscaglia, F., MD, PhD1 the BO-LIVES (BOlogna LIVEr vascular Studies)

American Journal of Gastroenterology: February 2019 - Volume 114 - Issue 2 - p 258–266
doi: 10.1038/s41395-018-0421-0
ARTICLES

Objectives: Portal vein thrombosis (PVT) is a frequent complication of cirrhosis. Benefit, safety, and duration of anticoagulant treatment in this setting are controversial issues. The aim of this study was to analyze the course of PVT in a large cohort of cirrhotic patients undergoing or not anticoagulation therapy.

Methods: The data of 182 patients who presented between January 2008 and March 2016 with cirrhosis and PVT with at least 3 months of follow-up after the first PVT detection were analyzed. Eighty-one patients received anticoagulants and 101 were untreated per physician discretion.

Results: The extension of the thrombosis decreased by >50% in 46 (56.8%, with complete recanalization in 31/46) patients under anticoagulation and in 26 (25.7%) untreated patients. Of the 46 patients who underwent recanalization, 17 (36%) suffered recurrent thrombosis after stopping anticoagulation therapy. Kaplan–Meier analysis showed a higher survival rate in the treated group (p = 0.010). At multivariate analysis, anticoagulation was an independent factor associated with longer survival (HR:0.30, CI:0.10–0.91, p = 0.014). The Child–Turcotte–Pugh classes B/C negatively influenced survival (hazard ratio, (HR):3.09, confidence interval (CI):1.14–8.36, p = 0.027 for Child–Turcotte–Pugh B and HR:9.27, CI:2.67–32.23, p < 0.001 for Child–Turcotte–Pugh C). Bleeding complications occurred in 22 (21.8%) untreated and 16 (19.7%) treated patients, but in only four cases was it judged to be related to the anticoagulant treatment. No death was reported as a consequence of the bleeding events.

Conclusions: Anticoagulant treatment is a safe and effective treatment leading to partial or complete recanalization of the portal venous system in 56.8% of cases, improving the survival of patients with cirrhosis and PVT. Discontinuation of the therapy is associated with a high rate of PVT recurrence.

1Department of Medical and Surgical Sciences, University of Bologna, Azienda Ospedaliero Universitaria S.Orsola Malpighi, Bologna, Italy;

2Gastroenterology Department, University of Medicine and Pharmacy “Iuliu Hatieganu", Cluj-Napoca, Romania;

3Unit of Internal Medicine, Azienda Ospedaliero Universitaria S.Orsola Malpighi, Bologna, Italy.

Correspondence: F. Piscaglia, MD, PhD. E-mail: fabio.piscaglia@unibo.it.

SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/A51

These authors contributed equally and share first authorship: Pettinari I, Vukotic R. The members of the group are listed above references.

Received February 27, 2018

Accepted September 27, 2018

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INTRODUCTION

Portal vein thrombosis (PVT) is a frequent complication in patients with cirrhosis, although it may often remain asymptomatic, at least early after onset (1). The prevalence of PVT ranges from 0.6 to 26% in patients with cirrhosis (1-13). The effects of PVT on the course of cirrhosis and its overall prognostic significance are still not clear. Some studies have suggested that PVT in cirrhosis could increase the rate of decompensation and worsen survival whereas others report an insignificant impact of PVT (14,15). However, PVT is usually associated with some major clinical complications, including worsening of portal hypertension and liver function, and an increased risk of suffering from varices and gastrointestinal bleeding (1,16).

Currently, the optimal management of PVT in cirrhosis remains unclear and no definitive recommendations have been reported in clinical guidelines or consensus conferences. The therapeutic strategies available are anticoagulation therapy and, in some technically suitable patients, transjugular intrahepatic portosystemic shunt (TIPS). Although anticoagulation therapy is associated with a high rate of recanalization, the indications for treating PVT in cirrhotic patients are still not strictly defined and neither is the optimal treatment duration.

Accordingly, not all PVT patients have been treated with anticoagulants in the past decade (1). In fact, patients with cirrhosis are considered at risk of bleeding events due to the common findings of a low platelet count and prolonged prothrombin time, although the quantification of this risk does not appear to be well defined. The safety of anticoagulation in cirrhosis is still a matter of debate. At the same time, the pro-thrombotic potential of cirrhotic patients is often underestimated and, in the clinical practice, it is difficult to assess where on the bleed/clot spectrum a patient is at any time (17). The authors took advantage of this gray area of clinical management to collect a large series of cirrhotic patients with non-tumoral PVT and to compare those who were treated with anticoagulants to those who were left untreated based on the decision of the physician.

The aim of this study was to retrospectively analyze the course of PVT in cirrhotic patients, and the occurrence and pattern of bleeding events in a large cohort of patients, either untreated or treated with anticoagulation therapy in order to assess its safety and efficacy.

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PATIENTS AND METHODS

Patients

All adult patients with cirrhosis of any etiology and PVT definitively characterized as non-neoplastic (i.e., no tumor vein invasion) according to validated criteria (18) at the General and University Hospital Sant’Orsola-Malpighi, Bologna (Italy) and the Regional Institute of Gastroenterology and Hepatology of Cluj-Napoca (Romania), between January 2008 and March 2016 were retrospectively evaluated for this study.

The exclusion criteria were: a lack of clinical and demographic variables, insufficient follow up (<3 months), active tumors apart from hepatocellular carcinoma (HCC) at the time of the diagnosis of the PVT, and anticoagulation use at the time of the first observation at the study center.

Patients presenting a cavernomatous transformation of the portal vein were not excluded. Patients were followed until death, liver transplantation (LT) or the end of the study (July 2016). Clinical, epidemiologic, laboratory and radiologic data were collected at the time of the diagnosis of the PVT, and at intervals of 3, 6, and/or 12 months ± 2 months.

The study was approved by the Ethics Committees of the General and University Hospital SantOrsola-Malpighi, Bologna, Italy and of the University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca, Romania (111/2015/O/OssN).

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Definition

Portal vein thrombosis was defined as the absence of flow in part of or in the entire lumen of any site among portal vein trunk, portal vein branches, superior mesenteric vein (SMV) or splenic vein (SV) caused by the presence of solid material within the vein, as documented by an imaging technique (Doppler ultrasound [US], contrast enhanced ultrasound [CEUS] computed tomography [CT], or magnetic resonance imaging [MRI]). With the concurrent presence of the following findings, the PVT was considered to be non-neoplastic: the lack of vascularization of the thrombus at contrast imaging, the absence of mass-forming features of PVT and the absence of evidence of disruption of vessel walls. If uncertainty persisted after these three criteria had been applied, a bioptic sampling of the thrombus was performed whenever possible (18). Spontaneous cavernomatous transformation of the PVT was also considered to be suggestive of a non-neoplastic nature (18).

Thrombosis was considered complete when the blood flow was absent or the thrombus involved more than 90% of the vessel diameter. Recanalization was considered complete when the portal vein trunk, portal vein branches, SMV, and SV were all completely patent. Recanalization was considered partial when some parts of the thrombus persisted but there was at least a 50% reduction in the thickness or length of the thrombus, or when complete patency was achieved in the portal vein trunk and in at least one of the following segments if previously thrombosed: main intrahepatic branches, SV or SMV. Lack of recanalization according to the definition above was considered to be a non-response to treatment. Thrombosis progression was considered to occur when thrombus thickness increased > 50% or when the thrombosis extended to previously unaffected segments of the spleno-porto-mesenteric axis. All patients were consecutively enrolled from the time of the first detection of PVT, including either complete or partial PVT, and regardless of the presence of symptoms at presentation.

Splenomegaly was considered when the maximal spleen diameter was greater than 12 cm.

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Statistical Analysis

Continuous variables are expressed as mean ± standard deviation (SD) and categorical variables as numbers and frequencies. Variable distribution was assessed by the Kolmogorov–Smirnov test, and continuous variables were compared using analysis of variance (ANOVA). Categorical variables were compared using the χ 2 test with a Yates’ correction.

Survival was calculated as the time from the PVT diagnosis to death/LT or the last follow-up visit (censoring events) and was expressed as medians and 95% confidence intervals (95% CIs). Survival curves were generated by using the Kaplan–Meier method and were compared with the log rank test.

Cox univariate analysis was carried out to assess the degree of association between survival and the above-mentioned variables. Variables associated (p ≤ 0.10) with survival at the univariate analysis were tested using the Cox multivariate regression model. Before entering into the multivariate analysis model, the variance inflation factor (VIF) was calculated to check multicolinearity among the variables; a VIF value < 5 was considered indicative of no colinearity. The hazard ratio (HR) and 95% CI were calculated for independent predictors of survival.

A two-tailed p < 0.05 was considered statistically significant. All statistical analyses were performed using the ®SPSS 21.0 statistical package (SPSS Inc., Chicago, Illinois, USA).

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Endpoints

The primary endpoints of this study were to explore the safety of anticoagulant treatment of PVT in terms of the rate and pattern of the bleeding events, and its efficacy, in terms of rate of PVT recanalization, in a retrospective cohort of cirrhotic patients. The secondary endpoints were to explore the rate of PVT recurrence after recanalization and to identify the clinical factors significantly influencing survival.

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RESULTS

Of the 208 patients retrospectively identified during the predefined enrollment period, 23 were excluded due to the lack of clinical demographic variables or sufficient follow up and 3 due to the presence of non-HCC active cancer at the time of diagnosis. Thus, 182 cirrhotic patients with PVT were finally included in the analysis.

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Patient baseline characteristics and extent of the PVT

The median follow-up was 19 months (range 3–94) after PVT detection. The main characteristics of the study population at baseline are shown in Table 1. Hepatitis C virus (HCV) was the leading cause of liver disease occurring in 55/182 patients (30.2%), followed by alcohol-related cirrhosis (47/182, 26.4%). HCC was present in 30/182 patients (16.5%).

Table 1

Table 1

The Child–Turcotte–Pugh (CTP) class was significantly better in the treated than in the untreated group (CTP-A 53.1 vs. 36.6%, p = 0.035; CTP-C 5 vs 19% p = 0.015). The Model for End-Stage Liver Disease (MELD) score was also lower in the treated group (MELD < 9 35.8 vs. 13.9%, p = 0.001).

No significant difference was found in the platelet count between groups.

The diagnosis and the extension of PVT at baseline were obtained by Doppler examination in 127 patients (69.8%), CT in 46 patients (25.2%), and MR in 9 patients (4.9%) (Table 2). The extent of the portal vein thrombosis is shown in Table 2.

Table 2

Table 2

One hundred and thirty-two patients (72.5%) had involvement of the portal trunk (partial in 122 cases and complete in 10 cases). The presence of thrombosis in the portal vein branches was significantly more frequent in the treated group (52/82 [64%] vs 44/101 [43.6%]; p = 0.007). Portal cavernoma was more frequent in the untreated patients (p = 0.030).

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Anticoagulant Therapy

Anticoagulant therapy was administered to 81 patients (44.5%) while 101 patients (55.5%) received no anticoagulation (Table 3). Sixty-six out of 81 (81.5%) started treatment within 6 months from diagnosis, 7/81 (8.6%) between 6 and 12 months, and 8/81 (9.9%) after 12 months. The mean treatment duration was 13.4 ± 14.0 months. Prior to anticoagulation, all patients had received an esophagogastroduodenoscopy for variceal screening. All 66 patients with high-risk varices underwent either variceal prophylactic eradication by endoscopic ligation prior to starting anticoagulation (12/81, 14.8%) and/or were treated with beta blockers (54/81, 66.6%).

Table 3

Table 3

Fifty-six patients (69.1%) were treated with low-molecular-weight heparin (LMWH), 15 patients (18.5%) with fondaparinux and 10 patients (12.3%) with oral anticoagulants (vitamin K antagonists, VKAs). Of the 56 patients treated with LMWH, 32 (57%) received ≤ 50% of the full dose of LMWH, administered once a day whereas the remainder received 51 to 100% of the expected full dose, administered in two injections per day.

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Course of Portal Vein Thrombosis

Recanalization was observed in 46 of the 81 treated patients (56.8%, after a median of 5 months (range 1–13) whereas no response to anticoagulation was observed in 35 patients. In 31/46 (67.4%) of the treated patients who responded to anticoagulant treatment, the PVT recanalization was complete while it was partial in the remaining 15/46 (32.6%).

Twenty-eight patients (60.9%) achieved recanalization at 3 months after the start of the anticoagulant therapy, 13 patients (28.3%) after 6 months and 5 patients (10.8%) after 12 months.

Of the untreated patients, 26/101 (25.7%) had spontaneous recanalization, complete in 13 (50%) cases and partial in 13 (50%). Recanalization occurred after a median of 5 months.

The recanalization rate was significantly higher in the anticoagulation group than in the untreated group (56.8 vs. 25.7% p < 0.0001) (Table 2). After excluding patients with cavernoma, the recanalization rate was 59.7 and 30.6%, respectively (p = 0.0235). The rates of partial and complete recanalization were both higher in treated than in untreated patients (Table 2).

Multivariate analysis revealed no predictive factors of recanalization in treated patients (data not shown).

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Follow-up After Discontinuation of The Anticoagulant Therapy

Seventeen of the 46 recanalized patients (36%) had recurrence of PVT after stopping the anticoagulant therapy.

Seven of the 35 patients (20%) who did not achieve recanalization at the time of anticoagulation discontinuation showed additional progression of the PVT after treatment discontinuation.

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Safety

Bleeding events in patients not treated with anticoagulants

During the follow-up, 22 untreated patients (22/101, 21.8%) presented with events of bleeding. In all cases, the bleeding events were related to portal hypertension, supposedly aggravated by PVT. In particular, 16 patients presented variceal bleeding, 1 hemorrhoidal bleeding and 5 bleeding due to gastric antral vascular ectasia (GAVE). Three patients had > 2 events of bleeding requiring hospitalization; two of the latter 3 patients had a concurrent progression of the thrombosis.

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Bleeding events in patients treated with anticoagulants

Bleeding events were reported in 16 treated patients (16/81, 19.7%): 12 related to portal hypertension (4 variceal bleeding, 6 hemorrhoidal bleeding and 2 due to GAVE), and 4 probably favored by anticoagulant treatment (following trauma or accidental falls). There were no significant differences in the rate of bleeding complications between the two groups (p = 0.855).

No death was reported within 30 days of the bleeding events in either group.

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Outcomes

The median overall survival (Fig. 1) for the treated group was 70 months and for the untreated group 59 months. Kaplan–Meier curve analysis revealed higher cumulative survival in the treated group than in the untreated group (p = 0.010). Twenty-four patients underwent LT (18 [17.8%] untreated and 6 [7.4%] treated patients, p = 0.0476). Univariate analysis showed that anticoagulant treatment, liver function (expressed in CTP classes) and infection at the diagnosis of PVT were associated with survival (Table 4). Anticoagulant treatment and CTP B and C classes were the only independent factors related to, respectively, longer and shorter survival at multivariate analysis (Table 4).

Fig. 1

Fig. 1

Table 4

Table 4

Multivariate analyses carried out to identify factors predictive of survival in treated patients and in the subgroup of the treated patients who experienced progression or relapse of PVT after stopping anticoagulant treatment did not identify any significant factor (Supplementary Tables 1 and 2, see http://links.lww.com/AJG/A51). Finally, a subgroup analysis of the treatment outcomes according to the CTP class revealed significantly shorter survival and higher rates of bleeding along with the progression of the CTP class with the worst outcomes in CTP-C patients, as expected according to the natural history of the disease (Supplementary Table 3, see http://links.lww.com/AJG/A51). However, no relevant difference in recanalization rates was observed between CPT-A and -B patients. No case of recanalization was observed in the in CPT-C class, which was, however, made of only 5 patients. The rate of recurrence after treatment discontinuation was lower in CPT-B than CPT-A class, although without reaching the statistical significance.

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DISCUSSION

Portal vein thrombosis is a frequent complication in liver cirrhosis but its natural history as well as therapeutic management have not yet been clearly addressed by either international guidelines or consensus conferences. The present study confirmed that recanalization of PVT may occur spontaneously, but it is significantly favored by anticoagulant treatment. Of note, limited to the study observation timeframe, anticoagulation was not associated with an increased risk in major bleeding complications and it positively influenced survival.

It is worth mentioning that the present study population was by far the largest regarding cirrhotic patients with PVT, reporting not only long-term observation of the course of PVT, but also a survival analysis of both patients who underwent anticoagulant treatment and those who did not.

The rate of spontaneous partial or complete recanalization of PVT rates ranged from 5 to 48% in the literature (14,19), the wide range due to heterogeneity in terms of thrombus extension, study populations and imaging methods. In a study by Luca et al. involving 42 patients with cirrhotic PVT, a spontaneous reduction in thrombosis occurred in 47.6% of those with partial thrombosis (14) while Senzolo et al. reported a spontaneous rate of improvement in thrombosis in 5% (19). In the present study, 25.7% of untreated subjects showed spontaneous recanalization.

The rates of recanalization under anticoagulant therapy in the present study (56.8%) were in keeping with those reported to date (37–93%) (20) and in particular with a recent metanalysis by Loffredo et al. (21). It should be pointed out that the population in the present study alone was bigger than approximately half of that of all the studies taken together in this recent metanalysis (21).

The rates of complete recanalization were reported to be 42–45% in patients treated with VKAs (6,22) and similarly, it ranged from 33 to 50% in patients treated with LMWH (19,23). In keeping with these data, no statistically significant differences were found in the present study in terms of rates of recanalization according to different anticoagulant therapies. To date, no answer can be provided to the question as to whether certain anticoagulants work better than others. Both the decision to treat and the choice of the type of anticoagulant are influenced by both drug-related and patient-related factors. In fact, LMWH has a shorter time duration of effects, and its dose can be easily and precisely modulated. However, its pharmacokinetics are more influenced by a reduced glomerular filtration rate, it requires daily subcutaneous injection(s) and, notably, heparin resistance due to low levels of antithrombin III may occur in cirrhosis. Conversely, VKAs can require up to a few days to spontaneously restore normal clotting function. Moreover, their daily dose is titrated based on the International Normalized Ratio (INR) value, which unfortunately is an imperfect measure in cirrhotics and indeed the anticoagulant effect may oscillate, additionally increasing the risk of bleeding. On the other hand, they are not significantly affected by the renal impairment and are taken orally. Direct oral anticoagulants (DOACs) have not yet been studied in cirrhotic patients with severely impaired liver function and their dosage cannot easily be modulated, but the recent data are promising when it comes to their safety profile compared to the traditional anticoagulants (24).

Some relevant considerations were prompted by our findings in anticoagulated subjects. Not all patients displayed recanalization within the first 3 or 6 months, suggesting that prolongation of the therapy should be attempted even after apparent initial inefficacy. This is further confirmed by the finding that, after the discontinuation of therapy, 36% of our patients who had a partial or a complete recanalization subsequently reported a recurrence/progression of PVT. These results are in line with those reported in the literature (22,23) and to those of Delgado et al (22). who showed recurrence or progression of PVT in approximately one third of patients who discontinued treatment. Complete recanalization was achieved by 31 (38.3%) patients after a median of 6 months after starting anticoagulant therapy. Partial recanalization was achieved in 15 (18.5%) patients after a median of 3 months of therapy. As described in an observational study (23), where full recanalization was reached in 33% and partial in 50% of patients after 6 months of anticoagulant therapy, continued treatment might perhaps subsequently allow complete recanalization. Therefore, the continuation of anticoagulant therapy for at least 6 months could have a role in the secondary prophylaxis of PVT recurrence after having achieved recanalization. Whether similar results of secondary prophylaxis could be achieved with lower doses of anticoagulants remains to be explored.

Nevertheless, 8 (9.9%) of our patients had progression of the thrombosis during treatment, which is again in line with the recent metanalysis of Loffredo et al. (21) which reported a 9% rate of progression during therapy (vs. 33% of untreated patients). Whether these are truly refractory patients or simply sub-maximally treated patients has still not been clarified and requires prospective studies with focused dedicated laboratory testing.

Currently, concerns regarding the use of anticoagulant therapy in patients with liver disease are mainly related to the fear of an increased risk of bleeding due to the compromised coagulation function and to the risk of acute variceal hemorrhage due to portal hypertension. In agreement with the current literature, the present study has shown that individualized anticoagulant therapy in cirrhotic patients with PVT is safe as bleeding events do not occur at higher rates than in untreated patients, and the hemorrhagic complications are seldom ascribed to the anticoagulant therapy itself. In the present study, 16 (19.7%) treated patients had hemorrhagic complications, but only four were likely related to the anticoagulant treatment. It is important to point out that all patients with high-risk varices at the time of the diagnosis of PVT underwent prophylactic therapy (variceal band ligation and/or beta-blockers) prior to initiating anticoagulant therapy. The rate of hemorrhagic complications associated with therapy for PVT reaches 18% in the literature (21,22). The bleeding rate seems to correlate with severe thrombocytopenia and the use of VKAs (22). No such correlation emerged from our data whereas nearly all bleeding events were related to portal hypertension and the incidence rates were similar in both the treated (19.7%) and the untreated (21.8%) groups, hence without any additional hazard related to anticoagulation. Unfortunately, data about the number of hospitalizations, length of intensive care unit admissions and number of transfusions associated with bleeding episodes were not sufficient for statistical reporting, since this was a retrospective real-life study and such information could not be systematically retrieved.

Our data also show no significant difference in the rates of recanalization between CPT-A and -B patients. Conversely, recanalization occurred less in CPT-C class (Supplementary Table 3, see http://links.lww.com/AJG/A51) but only 5 CPT-C patients were treated which also showed longer survival despite 40% rates of bleeding (making it difficult to dissect the beneficial contribution of anticoagulation from the possibility that only the less severe CPT-C patients were treated). Surely, this more severe patient category deserves targeted investigation. Apparently CPT-B patients were the category benefitting most of the anticoagulation, showing a lower rate of recurrence after stopping treatment and longer survival than the untreated subjects (Supplementary Table 3, see http://links.lww.com/AJG/A51), in keeping with a previous prospective study which showed survival benefit with enoxaparin in such patients (25).

In the present study population, not all the treated patients received full-dose anticoagulation. Since this was a retrospective study, the reasons for individual treatment schedules were not reported but, most likely, the reduced doses were prescribed to avoid exposing fragile patients to an increased bleeding risk while maintaining beneficial anticoagulant effect. The individually tailored approach was probably relevant in optimizing the risk/benefit ratio by producing significant recanalization rates without having an additional bleeding risk. Another limitation is that the reasons for deciding whether or not to start anticoagulation cannot be clearly determined. However, the untreated patients in this study displayed higher baseline INR values as well as higher baseline CTP and MELD scores, suggesting that decompensated cirrhosis and/or an impaired coagulative state were conditions which tended to deter physicians from prescribing anticoagulation therapy, even following PVT occurrence. However, the present data indicated a good safety profile for anticoagulation. Future prospective trials should also investigate attenuated anticoagulation schedules in comparison to those adopted in systemic anticoagulation in non-cirrhotic patients. This hypothesis should also be considered for DOACs as they have not yet been approved for PVT, and very limited data exist regarding their use in cirrhotic patients (24,26). However, their utilization is very tempting due to the ease of use. Accordingly, prospective data exploring safety and efficacy of DOACs compared to the traditional anticoagulants specifically in PVT are warranted in the next future.

Limitations of the present study are mainly related to its retrospective nature. One is the lack of a standardized anticoagulation protocol, which translates into the impossibility of making clear cut recommendations regarding anticoagulation drug choice and doses. Moreover, the assessment of PVT extension and evaluation of the degree of response were provided using different imaging techniques. Ultrasound is accurate in investigating the presence and extension of intrahepatic thrombosis; however, it is not as accurate as CT and MRI in the case of extrahepatic involvement. Computed tomography and MRI are expensive and require the injection of potentially harmful contrast agents while US is less costly and easily complemented by color/duplex Doppler and by safe contrast agents. Computed tomography also implies exposure to ionizing radiation. Therefore, CT and MRI are much less feasible for the short-/mid-term follow-up of PVT to monitor progression or regression. For this reason, the US was the technique adopted in the majority of the patients in the present study. In the authors’ view, the different imaging techniques have complementary rather than competing roles in this setting.

Another point to highlight is that it is often impossible to correctly date the thrombus. In the present study, all patients were consecutively enrolled at the time of the first observation of PVT, regardless of the presence or absence of PVT-related symptoms. Partial PVT is commonly asymptomatic and, furthermore, symptoms may develop only later when partial PVT progresses to complete PVT. Finally, only the detection of a cavernomatous transformation of the portal veins excludes acute PVT. Hence, the presence/absence of symptoms is not a reliable index for dating the first occurrence of PVT when imaging cannot provide this information.

Our study included similar rates of patients with viral hepatitis B or C and alcoholic cirrhosis, but a limited number of cirrhosis due to non-alcoholic liver disease. Whether the present results fully apply also to the latter etiology remains to be elucidated.

Importantly, unlike previous studies which concentrated only on the rates of recanalization, the present study also reported survival information and showed that patients who received anticoagulation therapy following PVT diagnosis had greater survival rates than the untreated patients, independently of liver dysfunction severity. This result appeared to confirm the data of a prospective, randomized controlled trial regarding the primary prophylaxis of PVT (25).

In conclusion, anticoagulant therapy appeared to be effective in cirrhotic patients with PVT, reaching recanalization rates of 56.8%, more than doubling the spontaneous recanalization rates. Recanalization was commonly obtained in the first 6 months after the start of treatment. Prior to initiating treatment, either beta-blocker therapy was started or prophylactic endoscopic band ligation of high-risk varices was carried out to protect from the risk of variceal bleeding during treatment. Finally, anticoagulant treatment significantly improved the survival of cirrhotic patients with PVT.

However, although the treatment response occurred mainly within 6 months, precocious discontinuation for the presumed lack of treatment response should be avoided.

In patients who responded to anticoagulation treatment, its discontinuation was associated with a high risk of PVT recurrence. For this reason, it could be speculated that some patients might benefit from a secondary prophylactic strategy which should be maintained after recanalization.

Finally, anticoagulant treatment in cirrhotic patients with PVT was shown to be safe in the short/mid-term. These findings highlighted the need for randomized prospective trials to test the safety and efficacy of a long-term secondary prophylaxis with anticoagulants for PVT in cirrhosis.

Members of the BOlogna LIVEr vascular Studies (BO-LIVES). L Badia, S Berardi, A Cappelli, M Cescon, F Conti, A Cucchetti, C Galaverni, R Golfieri, A Granito, C Mosconi, M Renzulli, Mr Tamè, G Verucchi, G Vitale, L Bolondi.

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CONFLICTS OF INTEREST

Guarantor of the article: Fabio Piscaglia, MD, PhD.

Specific author contributions: Pettinari I: conducted the study and drafted the manuscript . Vukotic R: conducted the study, analyzed and intrepreted the data, and drafted the manuscript. Stefanescu H: conducted the study, analyzed and intrepreted the data, and drafted the manuscript. Pecorelli A: analyzed and intepreted the data. Morelli MC, Grigoras C, and Sparchez Z: collected data. Andreone P: interpreted the data and revised the manuscript. Piscaglia F: planned the study, interpreted data, and drafted and revised the manuscript. All authors approved the final draft submitted. All members of the study group helped collecting minor data.

Financial support: None.

Potential competing interests: None.

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Study Highlights

WHAT IS KNOWN

  • ✓ There are no cutting-edge indications for the treatment of non-neoplastic PVT in cirrhosis and its clinical management is still variable and inhomogeneous.
  • ✓ Few data exist regarding the impact of anticoagulation on PVT improvement, but hardly anything is known regarding the impact of therapeutic anticoagulation on overall survival in cirrhotic patients with PVT.

WHAT IS NEW HERE

  • ✓ Our data highlighted the satisfactory safety and efficacy profile of anticoagulant treatment for PVT in cirrhosis and showed an independent beneficial effect on survival.
  • ✓ A non-negligible rate of recurrence of thrombosis occurred after treatment discontinuation.
  • ✓ These real-life, large cohort data support the use of anticoagulation in non-neoplastic PVT in cirrhosis and produce evidence warranting prospective studies to standardize the doses and duration of anticoagulation in this setting.
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