Portal vein thrombosis, revisited

Digestive and Liver Disease 42 (2010) 163–170

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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld

Review Article

Portal vein thrombosis, revisited Massimo Primignani ∗ Gastroenterology 3 Unit, IRCCS Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena Foundation, Via Francesco Sforza, 35, 20122 Milano, Italy

a r t i c l e

i n f o

Article history: Received 6 July 2009 Accepted 16 August 2009 Available online 18 September 2009 Keywords: Portal vein thrombosis Cirrhosis Thrombophilia Anticoagulation

a b s t r a c t This review article aims to discuss the aetiology, pathophysiology, clinical presentation, diagnostic workup and management of portal vein thrombosis, either as a primary vascular liver disease in adults and children, or as a complication of liver cirrhosis. In addition, indications and limits of anticoagulant therapy are discussed in detail. © 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

1. Introduction The term “portal vein thrombosis” (PVT) refers to an obstruction in the trunk of the portal vein. It can, however extend downstream to the portal branches, or upstream to the splenic and/or the mesenteric veins, with different clinical features according to the site and extension of the obstruction in the portal venous system. Although “portal vein thrombosis” rather than “obstruction” is the term generally adopted, it should be noted that thrombosis is only one, although the most frequent, of the three possible causes for this condition. Invasion by abdominal malignancy (most often hepatocellular carcinoma) and constriction within a malignant tumour (mainly pancreatic cancer or cholangiocarcinoma) are the other two causes, with thrombosis often superimposed as a secondary event. PVT is frequent in advanced liver cirrhosis, often associated with hepatocellular carcinoma; it is less frequent in compensated cirrhosis, and is a relatively rare condition in patients with a previously healthy liver, at least in developed countries. Like venous thromboembolism of the lower extremities, PVT is a multifactorial process, in which local inflammatory foci and systemic prothrombotic factors concur. Its pathogenetic factors are the same as those long recognized for venous thromboembolism: damage to the vessel wall, slowing of blood flow, and hypercoagulability. The last of these three factors can be defined as a procoagulant imbalance due to increased plasma levels of coagulation factors caused by acquired disorders, such as cancer and inflammation, or inherited thrombophilia. For clarity as well as for the clinical implications, it is appropriate to distinguish PVT occurring in a previously healthy

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liver (primary venous disease), from PVT complicating the course of parenchymal liver diseases or abdominal cancer. In addition, PVT in infancy and childhood, given its different aetiology, clinical presentation and possible management, deserves a separate discussion. This review article aims to discuss the aetiology, pathophysiology, clinical presentation and general management of portal vein thrombosis, either as a primary vascular liver disease or as a complication of liver cirrhosis, and to consider the indications and limits of anticoagulant therapy in these two conditions. 2. Portal vein thrombosis as a primary venous disease PVT is common in developing countries, accounting for as many as 20% of all cases of portal hypertension [1], whereas in the West its prevalence is lower, no more than 5% of cases of portal hypertension [2]. Poor standard of living and of medical care, and the different impact of infectious and inflammatory causes are the alleged factors explaining such a difference. In developed countries, a thorough investigation can actually identify one or more systemic prothrombotic factors in approximately 60% of patients, and further local triggering factors in as many as 40% of cases [3–8]. The frequent finding of several prothrombotic disorders in the same individual justifies the need for a comprehensive thrombophilia screening, even in the presence of known underlying predisposing factors or of obvious precipitating abdominal causes; conversely, a local factor should be looked for, even when one or more systemic prothrombotic factors have been identified. This is relevant, since it implies important decisions regarding long-term anticoagulation. On the other hand, currently available investigations fail to identify a causal factor in about 20% of patients. This suggests the existence of other, still unidentified, prothrombotic risk factors.

1590-8658/$36.00 © 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2009.08.003

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The role played by thrombophilia in PVT occurring in developing countries or in children, even in the West, has not been extensively investigated. In children or infants PVT represents the most frequent cause of severe upper gastrointestinal bleeding worldwide. 3. Portal vein thrombosis aetiology in adults Hypercoagulability, due to inherited or acquired conditions, and clonal disorders of haemopoiesis such as the chromosome Philadelphia-negative chronic myeloproliferative disorders (MPD) are the principal causes of PVT in individuals with a previously healthy liver. Prevalence of risk factors for PVT and suggested diagnostic procedures are reported in Table 1. 3.1. Local risk factors The occurrence of abdominal inflammatory foci, through the added hypercoagulability due to the systemic inflammatory response, explains the abrupt onset of PVT in the setting of latent thrombophilia. Local factors commonly triggering PVT include: acute or chronic pancreatitis, diverticulitis, appendicitis, inflammatory bowel diseases and liver abscess. Abdominal surgery, especially when injury to the portal venous system is involved, is another common precipitating factor. 3.2. Inherited risk factors Among the “gain of procoagulant function” mutations, the prothrombin gene mutation G20210A is a more frequent cause for PVT than the factor V G1691A mutation (factor V Leiden) or the “loss of anticoagulant function” mutations leading to antithrombin, protein C or protein S deficiency [3–7]. Indeed, in most instances, decreased plasma levels of these naturally occurring anticoagulant proteins should be regarded as the consequence of defective liver synthesis caused by PVT rather than its cause, unless a confirmatory familial study is available [7,9–10]. Further inherited causes may be high levels of factors VIII [11], IX, and XI or hyperhomocysteinemia. As for naturally occurring anticoagulant deficiency, hyperhomocysteinemia is also difficult to define as the cause rather than the effect of PVT once liver disease, even if mild, has ensued. The same difficulty applies to the finding of high factor VIII levels, which are consistently observed in chronic liver disease. 3.3. Acquired risk factors Among the acquired prothrombotic disorders responsible for PVT are the anti-phospholipid syndrome and, more rarely, paroxysmal nocturnal haemoglobinuria (PNH). A diagnosis of antiphospholipid syndrome should be established by the detection of lupus anticoagulant or anti-beta-2 glycoprotein antibodies, since low levels of anti-cardiolipin antibodies are a non-specific finding in as many as 20% of patients with chronic liver disease [12]. Thus, it appears that the onset of PVT acts as a confounder in the diagnosis of several prothrombotic disorders, either inherited (i.e., naturally occurring anticoagulant deficiency), possibly inherited (i.e., hyperhomocysteinemia and high factor VIII levels), or acquired (i.e., anti-phospholipid syndrome). Paroxysmal nocturnal haemoglobinuria is a rare acquired disorder of haemopoietic stem cells, characterized by intravascular haemolysis and venous thrombosis, mainly of the cerebral and abdominal veins. It is more strongly associated with Budd-Chiari syndrome than with PVT, but the latter may occur as a further thrombotic progression of this severe disease. Philadelphia-chromosome negative chronic myeloproliferative disorders (MPD), namely polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis or unclassifiable MPD, are by

far the main causes of splanchnic vein thrombosis, at least in Western countries, accounting for at least 30% of PVT cases [7,13–14]. Only few of these patients meet the conventional haematological diagnostic criteria, because in most cases blood cell counts are normal due to haemodilution and hypersplenism ensued as a consequence of PVT and portal hypertension [7,13–14]. Given the frequent absence of conventional diagnostic criteria, the diagnosis of MPD in these patients required, until recently, additional tests such as the endogenous erythroid colony assessment [14–17], or the search for specific morphological changes in bone marrow biopsy [14,18–20] as well as of molecular markers of clonality. Currently, the discovery of a remarkable association between MPD and a somatic point mutation of the JAK2 tyrosine kinase (JAK2 V617F) has simplified the diagnostic approach to the diagnosis of MPD in PVT or other splanchnic vein thromboses [21–26]. This mutation confers erythropoietin hypersensitivity and growth factor independence leading to constitutive kinase activity causing enhanced haematopoiesis. The prevalence of this mutation is estimated at 90–95% for polycythemia vera, and at approximately 50–60% for both essential thrombocythemia and idiopathic myelofibrosis. As a consequence of these developments, WHO guidelines for MPD diagnosis have been revised and JAK2 mutation screening has been added as a major diagnostic criteria for polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis [27]. In the diagnostic workup of splanchnic vein thrombosis, the search for the JAK2 mutation has led to an increase in the diagnosis of underlying myeloprolipherative disorders by approximately 20% [28]. However, it should be emphasized that the JAK2 mutation, if present, confirms the existence of a MPD, but, if absent, does not exclude it. Therefore, a bone marrow biopsy is still often needed, either for an accurate diagnosis of MPD in JAK2-positive patients, or to rule out MPD in JAK2-negative individuals [29]. The JAK2 mutation has been demonstrated in approximately 40% of patients with PVT, mostly not fulfilling the conventional diagnostic criteria for MPD [29]. The recognition of other MPD-associated JAK2 mutations (in exon 12) [30] and of two gain-of-function mutations in the gene encoding the thrombopoietin receptor (MPL) [31,32] has further clarified the molecular mechanisms of Philadelphia-negative MPD. JAK2 exon 12 mutations have been identified in the few JAK2 V617F negative patients with polycthemia vera [30], MPL mutations in 5–10% of patients with primary myelofibrosis and 1–2% of those with essential thrombocythemia [31,32]. JAK2 exon 12 mutations have been identified in two patients with splanchnic vein thrombosis and polycythemia vera [33], but not in two other large studies [28,34] that were also investigating MPL mutations; these mutations were not detected in the former [28], but were found in approximately 3% of the patients in the latter [34]. Overall, these results suggest that the search for JAK2 and MPL mutations is useful in the diagnostic workup of PVT and other splanchnic vein thromboses. Finally, among factors that cause acquired thrombophilia and may cause PVT, physiological conditions such as pregnancy and the post-partum period must also be included; these conditions are characterized by a physiological hypercoagulable state, particularly during the third trimester of pregnancy and up to 8 weeks after delivery, and may trigger venous thromboembolism, most often in the setting of a latent thrombophilia. The same holds true for oral contraception and hormone replacement therapy.

4. Portal vein thrombosis aetiology in children The aetiology of PVT in children has not been as comprehensively studied as in adults. Several hypotheses call for developmental anomalies of the portal vein, omphalitis, neonatal umbilical sepsis and possibly endothelial injury due to prolonged umbilical vein catheterization [1]. Although the available studies

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Table 1 Prevalence of risk factors (often more than one factor coexists) and suggested diagnostic procedures in non-malignant, non-cirrhotic portal vein thrombosis in adults. Risk factors

Prevalence (%)

Comments and references

Suggested procedures

Acquired thrombophilia Philadelphia-negative myeloproliferative disorders (MPD)

17–53

More often young females. Peripheral blood cell count frequently normal due to plasma volume expansion and hypersplenism caused by portal hypertension Refs. [3,4,7,8,28,29,34,44,78] Usually primary APS Refs. [3,7,8,44,78]

JAK2 V617F mutation; JAK2exon 12 mutations. MPL mutations Bone marrow biopsy

Anti-phospholipid syndrome (APS)

1–11

Paroxysmal nocturnal haemoglobinuria (PNH)

0–9

Hyperhomocysteinemia

11–15

Inherited thrombophilia Factor V Leiden

3–9

Prothrombin gene mutation G20210A

2–22

Increased factor VIII levels

Protein C deficiency

1–9

Protein S deficiency Antithrombin deficiency

0–7 1–4

Hormonal risk factors Oral contraceptives Pregnancy and post-partum state

0–4 7–44

Local factors Abdominal inflammatory lesions

7–34

Abdominal surgery, surgical injury of the portal vein axis

3–45

are limited and small-sized, the prevalence of inherited or acquired thrombophilia in children with PVT is probably lower than in adults. 5. Portal vein thrombosis aetiology in liver cirrhosis In stable cirrhotic patients, despite the decreased synthesis of most coagulation and fibrinolytic factors and of possible platelet dysfunctions, the balance stemming from pro- and anticoagulants is normal, if assessed as thrombin generation in the presence of thrombomodulin, provided that the platelet count is adequate (i.e., not lower than 60 × 109 /L) [35,36]. In fact, increased levels of Von Willebrand Factor compensate for primary haemostasis defects, while increased factor VIII levels and decreased levels of proteins C and S and antithrombin compensate for other procoagulant factors whose synthesis is decreased. Clinical evidence from a nationwide population-based case-control study [37] has recently demonstrated that cirrhotic patients have an increased risk of venous thromboembolism, thus supporting the hypothesis of liver cirrhosis as an acquired prothrombotic condition. The prevalence of PVT increases with the severity of cirrhosis, being approximately 1% in patients with compensated cirrhosis [38], and rising to 8–25% in candidates for liver transplantation [39]. Slowing of portal vein flow and unbalanced haemostasis are probably both involved in advanced disease. However, in compensated cirrhotic patients, the coexistence of an underlying thrombophilia could be considered. Indeed, cirrhotic patients with PVT have an increased prevalence of factor V Leiden and prothrombin gene mutations than those

More often in the Budd-Chiari syndrome than in PVT Refs. [3,29,44,78] Doubtful whether inherited or acquired as a consequence of PVT Refs. [3,7,8,29,44]

Anti-cardiolipin antibodies, lupus-like anticoagulant, anti-beta-2 glycoprotein antibodies Flow cytometry

Basal plasma homocysteine levels

Relative risk ≈ 3 Refs. [3,4,7,8,29,44,78] Relative risk ≈ 8 Refs. [3,4,7,8,29,44,78] Doubtful whether inherited or acquired as a consequence of PVT odds ratios ≈ 8 Refs. [11] Relative risk ≈ 6. Natural occurring anticoagulant deficiency more likely acquired than inherited. Familial studies needed to confirm inherited defect Refs. [4,8,29,44,78] Usually in the setting of a pre-existent thrombophilia Refs. [7,8,29,44,78]

DNA analysis for G1691A substitution in factor V gene DNA analysis for G20210A substitution in factor II gene

Often in the setting of a pre-existent thrombophilia Refs. [7,8,44] Usually in the setting of a pre-existent thrombophilia Refs. [4,8,29,44,78]

Thrombophilia screening

Thrombophilia screening

Thrombophilia screening

without PVT [40,41]. Although the link between hepatocellular carcinoma and PVT is strong, and a differential diagnosis of malignant obstruction should always be considered in cirrhotic patients with PVT, the coexistence of PVT and hepatocellular carcinoma does not always signify a malignant obstruction. 6. Clinical presentation Acute and chronic portal vein thrombosis are different stages of the same disease. In the past, the disease was more frequently recognized at the chronic stage because of complications of portal hypertension, such as variceal bleeding, thrombocytopenia or symptomatic splenomegaly. Currently, due to an easier access to imaging techniques, the diagnosis at the acute stage, at least in adults, is more frequent. By contrast, in infants the acute stage is still most often undetected and the most frequent presentation is at the late stage of portal cavernoma, with gastrointestinal bleeding, splenomegaly and thrombocytopenia, in the presence of normal or almost normal liver function tests. 6.1. Acute portal vein thrombosis The extent of the obstruction in the portal venous system and the speed of its development explain the heterogeneity of the clinical presentation. The acute episode may in fact be asymptomatic or characterized by transient abdominal pain, fever, even in the absence of an identifiable inflammatory focus, and unspecific dys-

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peptic symptoms [8]. In other cases symptoms overlap with those of the precipitating cause, such as acute pancreatitis or diverticulitis. In septic portal vein thrombosis, also called pylephlebitis, usually due to an intra-abdominal abscess, symptoms are more pronounced and include spiking fever, chills, and a painful liver; multiple liver abscesses due to the intra-hepatic spread from the septic thrombus are frequently detected. Blood culture typically grows Bacteroides species. Indeed the link between Bacteroides bacteremia and PVT is so strong to justify the search for portal or mesenteric vein thrombosis in every case of Bacteroides bacteremia. In partial PVT symptoms are fewer or absent. On the other hand, if the superior mesenteric vein is involved, symptoms are more severe with colicky abdominal pain and diarrhea [42]. When the extension of the thrombosis reaches the proximal mesenteric venous arches, severe abdominal pain, often radiating to the back, and ileus, due to intestinal ischemia, ensue. Signs of progression to intestinal infarction include hematochezia, ascites, metabolic acidosis and renal or respiratory failure. Intestinal infarction carries a high mortality and a severe morbidity rate in surviving patients, even if surgical resection of the affected bowel is promptly accomplished. 6.2. Chronic portal vein thrombosis Portal cavernoma is a hepatopetal network of collaterals around the obstructed portal tract which can be detected at its early stage within few days from the acute episode and enlarges thereafter if recanalization of the portal vein is not achieved. Although a relevant amount of portal flow may reach the liver through this compensatory mechanism, portal hypertension often develops and its complications are the main clinical manifestations of chronic PVT. Gastro-oesophageal varices may be detectable as early as 1 month after acute PVT. Thus, an endoscopic screening for gastrooesophageal varices must be performed within few months and, if varices are not identified, repeated 6 months later (if portal vein recanalization has not been achieved). No available data dictate a timetable for further endoscopies if varices are still absent at 9–12 months from acute PVT, but a re-assessment after 2–3 years may be advisable [43]. Bleeding from oesophageal or gastric varices and hypersplenism are the most common complications of chronic PVT. The mortality rate from oesophageal bleeding is consistently lower than in patients with cirrhosis [44–45]. If acute PVT was asymptomatic or unrecognized, the detection of chronic portal vein thrombosis may be fortuitous, in the diagnostic workup of thrombocytopenia or an enlarged spleen. Gastric, duodenal or anorectal varices are much more frequent in chronic PVT than in cirrhotic patients. Ascites, usually transient and easily treatable, is rarely observed, mainly after a bleeding episode or a surgical procedure. Mild cholestasis or more severe biliary complications in patients with long-standing disease are increasingly recognized and are related to “portal biliopathy” [46–48]. This term refers to anatomical changes of the extra- and intra-hepatic bile ducts observed in many patients with chronic PVT. These include compression, strictures or displacements of the bile ducts, and stones as a late complication. Compression by paracholedochal and paracholecystic veins, which are the major component of portal cavernoma, or ischemic bile duct damage, due to thrombosis of the veins draining the bile ducts, are the alleged causes for these abnormalities. The left hepatic duct is typically more severely involved, because of the development of major collaterals at the confluence of the umbilical vein with the left portal vein branch. Portal biliopathy may be either asymptomatic or associated with jaundice, pruritus, fever or abdominal pain. It appears to be a slowly progressive disease, since symptomatic patients are most frequently adults with

long-standing chronic PVT. Biliary changes can be identified by MRI cholangiography in the vast majority of patients with long-standing chronic PVT [49,50], but have also been described in children [51]. Apart from mild cholestasis, which is very common, more severe biliary complications such as cholecystitis, cholangitis or obstructive jaundice may occur in up to one third of patients [46–51]. Overt hepatic encephalopathy is uncommon, except in patients with large spontaneous shunts, but may be observed after shunt surgery or TIPS in approximately 30% of patients. However, subclinical cognitive changes can be frequently detected [52]. Growth retardation has been reported in up to 50% of children with chronic PVT. Resistance to growth hormone function [53] and decreased insulin-like growth factor related to the reduced portal blood supply are the alleged causes for growth retardation. However, the occurrence of growth impairment has not been demonstrated in a subsequent study [54]. Other frequent unspecific dyspeptic symptoms such as early satiety and abdominal discomfort are commonly related to a massively enlarged spleen [55,56]. 6.3. Portal vein thrombosis in patients with cirrhosis PVT in cirrhotic patients is often asymptomatic and detected at follow-up ultrasound evaluation. In other instances gastrointestinal bleeding, development or abrupt worsening of ascites or hepatic encephalopathy are associated with the onset of PVT. Neoplastic infiltration of the portal vein should be excluded: suggestive features include high serum alpha-fetoprotein levels, a portal vein diameter larger than 23 mm at imaging, enhancement of the thrombus in the arterial phase of contrast injection [57] or an arterial-like flow observed on Doppler ultrasound [58]. As for previously healthy subjects, if the thrombus proximally involves the superior mesenteric vein, abdominal pain and signs of intestinal ischemia ensue, and the risk of intestinal infarction is high. 7. Diagnosis In most patients, US pulsed-Doppler allows non-invasive diagnosis of acute PVT by demonstrating hyperechoic material within the portal vein, distension of the portal vein and its tributaries, and total or partial absence of flow [59]. Accuracy is high, but sensitivity and specificity may be affected by patient variability, expertise of the operator and awareness of the clinical suspicion. Contrast enhanced US could be more sensitive than conventional US. CT scanning and MRI angiography may provide further information, particularly on the extension of thrombosis within the mesenteric veins, which may be hardly assessed on ultrasound, and the presence of signs of bowel infarction, such as thinning or thickening of the intestinal wall, lack of mucosal enhancement after contrast injection or the presence of intramural gas [60]. These suggestive signs of intestinal infarction warrant consideration for surgical exploration. 8. Treatment of acute portal vein thrombosis Acute PVT in previously healthy subjects must be treated as early as possible with anticoagulants [43,61]. Despite the lack of randomized studies, the rationale for early anticoagulation is based on the exceedingly rare spontaneous recanalization [8,61] as compared to an approximately 40% recanalization rate achieved in patients receiving early anticoagulation, which, in addition, appears to prevent progression to intestinal infarction [11,44,62]. Since recanalization has been shown to occur within 4–6 months and has never been observed after 6 months of treatment, antico-

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agulation should be of at least 3 and preferably 6 months’ duration [11,44,63]. Although no data from clinical studies exist, current expert opinion is in favour of lifelong anticoagulation in patients with a recognized prothrombotic disorder, a personal or familial history of venous thromboembolism, or with presenting features of intestinal ischemia or infarction [63]. This recommendation should be probably maintained even in the presence of a theoretical contraindication such as thrombocytopenia. Indeed, adverse events due to anticoagulation in acute PVT are rare, while benefits on recanalization, prevention of the extension, or thrombosis recurrence are relevant [64]. Anticoagulation should be initiated with subcutaneous low molecular weight heparin (LMWH), which is as effective as intravenous unfractionated heparin, does not require laboratory monitoring, and has a more predictable dose response relationship and a lower risk of adverse events (i.e., heparin-induced thrombocytopenia). After 2–3 weeks, or when invasive procedures are no longer indicated, LMWH can be shifted to vitamin K antagonists, targeting the INR at a range of 2–3. Abdominal pain, in the absence of relevant ischemic intestinal damage, decreases within 1–2 weeks, whereas the inflammatory syndrome declines earlier. If ischemic bowel damage is suspected, monitoring is best achieved by CT scan. Otherwise, if clinical signs and symptoms have improved, Doppler ultrasound examination at 3- and 6-month follow-up is adequate to check for recanalization. Late abdominal pain recurrence may suggest the development of short bowel stenosis. Since extensive thrombosis and ascites are predictive factors of poor recanalization on anticoagulants, patients carrying these features at diagnosis could be treated with other, more aggressive therapies, such as local or systemic thrombolysis [65,66], TIPS (to sustain a high velocity flow in the portal vein), or both treatments sequentially. However, no data exist on the risk-benefit ratio of these invasive procedures compared to simple early anticoagulation. Given the not negligible risk of severe complications due to thrombolysis, such a treatment should be undertaken only in patients with severe disease unresponsive to anticoagulation [67]. Studies are needed to assess whether these more invasive treatments are more effective than early anticoagulation in selected patients with extensive thrombosis of the portal venous system. Surgical thrombectomy is generally not indicated, unless laparotomy is needed because bowel infarction is suspected. Indeed, the recurrence rate of surgical thrombectomy is exceedingly high, unless anticoagulation is concurrently administered. On the opposite spectrum of severity are those patients without further identified prothrombotic risk factors and with a non-extensive thrombosis triggered by inflammatory abdominal causes which can be successfully cured. In these patients lifelong anticoagulation treatment is probably avoidable. Concerns on long-term anticoagulation also apply to patients in whom advanced age or co morbidities entail an increased bleeding risk. Hence, in many instances, a decision on lifelong anticoagulation must be made on a case by case basis. 8.1. Long-term prognosis of acute portal vein thrombosis In the last decade the mortality rate for acute PVT has decreased from 30% to about 10%. Early diagnosis and anticoagulation are probably the main determinants of the improved survival, through the prevention or the rapid relief of superior mesenteric vein thrombosis. The development of portal hypertension can be prevented if the portal vein trunk and at least one of its two branches obtain patency, and this goal can be achieved in up to 40% of patients treated with anticoagulants within the first weeks from the onset of acute symptoms. Currently, 5-year survival in patients without previous liver disease is around 85% and mortality is mostly related to postoperative complications or underlying disease [68].

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9. Treatment of chronic portal vein thrombosis When the disease is discovered at the late stage of portal cavernoma, bleeding from oesophageal, gastric or even ectopic varices may occur. Although clinical studies are lacking, it is reasonable to manage the acute bleeding episode as in cirrhotic patients, with vasoconstrictors, endoscopic treatments (preferably banding for oesophageal varices and glue injection for fundal varices), and antibiotic pharmacotherapy [43]. There is some concern on the use of vasoconstrictors since the decreased portal venous inflow induced by these drugs could cause thrombosis progression, however very few data support this criticism. Prophylaxis of bleeding should be performed with beta-blockers and/or banding of oesophageal varices. Both treatments have been shown, in retrospective studies, to decrease the risk of first or recurrent bleeding [64] or to improve survival [69]. TIPS may be attempted in patients with portal cavernoma [70], but its technical feasibility is limited. Shunt surgery should be considered in endoscopic therapy failures or in severe portal hypertensive biliopathy [71,72]. However, extensive thrombosis involving the mesenteric and the splenic veins may preclude the mesocaval or the Warren shunts in more than one third of patients. Other non-shunting surgical procedures such as oesophageal transection with or without splenectomy, and variceal ligation are less indicated because portal hypertension is not relieved and the risk of late rebleeding is relevant. The Rex shunt (mesenteric-left portal vein bypass) is currently widely used in children, but its technical feasibility needs evaluation in adults [73]. Other procedures, such as percutaneous stenting of the portal cavernoma may be occasionally successful. According to the few available data from retrospective studies, anticoagulation is not contraindicated in patients with portal cavernoma and oesophageal or gastric varices: it can prevent recurrent thrombosis without increasing the risk or the severity of gastrointestinal bleeding [64], provided that prophylaxis of bleeding is instituted beforehand, and optimal therapeutic compliance is assured. However, the strength of this recommendation depends on the clinical setting: it is high in the presence of one or more identified prothrombotic factors, a personal or familial history of venous thromboembolism, or recurrent abdominal pain due to extensive thrombosis in the portal venous system. A low bleeding risk (i.e., no history of previous bleeding, no co morbidities that increase the risk of anticoagulation-related bleeding) reinforces the indication. In other cases the decision should be made on a case by case basis, taking into account the risk of bleeding and the risk of recurrent thrombosis [43]. Although clinical evidence is lacking, symptomatic portal biliopathy can be treated with ursodeoxycholic acid. Jaundice due to bile duct stenosis should be firstly approached by ERCP and biliary stent placement. A persistent relief of biliary symptoms after stent removal can be achieved in approximately 50% of patients [74,75], and recurrences require restenting. Sphincterotomy is dangerous and contraindicated if stones are not demonstrated. Persistent severe biliary symptoms need porto-systemic shunting as a first step, followed by a hepaticojejunostomy if the biliary obstruction is not sufficiently relieved [76]. Liver transplantation may be the last option for severe biliary complications due to portal vein cavernoma [77]. 9.1. Long-term prognosis of chronic portal vein thrombosis Morbidity is mainly related to variceal bleeding, recurrent thrombosis, symptomatic portal biliopathy and hypersplenism [14]. Mortality among patients with chronic PVT is low (5–10% at 5 years) and is mainly related to age, aetiology of PVT or unrelated disease, rather than to complications of portal hypertension [78].

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10. Treatment of portal vein thrombosis in patients with cirrhosis Although no longer considered an absolute contraindication to liver transplantation (LT), extensive PVT still precludes LT in many centres. Overall, PVT increases the complexity of LT, the operative time, rate of reoperation or postoperative complications, transfusion requirement, and length of hospital stay; survival rates, related to the extent of thrombosis, are decreased [79–81]. For the purpose of liver transplantation PVT is classified, according to its severity, into four grades, ranging from less than 50% obstruction of the vessel lumen, with or without minimal obstruction of the superior mesenteric vein (grade 1), more extensive portal vein occlusion (grade 2), complete thrombosis of both portal vein and proximal superior mesenteric vein (grade 3) and complete thrombosis of the two vessels involving also the distal part of the superior mesenteric vein (grade 4) [80]. Whereas terminal to terminal portal vein anastomosis, with or without thrombectomy, is appropriate for grades 1–2 PVT, more complex vascular reconstruction techniques are required for grades 3–4 PVT. Survival rates are similar to those of non-PVT transplanted controls only in grade 1 PVT patients, but are considerably lower in grades 2–4 PVT patients [81]. Hence, aims of the management of PVT in cirrhotic patients listed for LT are the achievement of complete or partial recanalization and the prevention of thrombosis progression. These goals can be pursued either through the placement of a transjugular intra-hepatic porto-systemic shunt (TIPS), with or without local thrombolysis or thrombectomy [82,83], or through anticoagulation [39]. Experience is limited and large studies are needed to establish limits and indications of each therapy. Several reports [82,83] indicate that TIPS, through the attainment of an increased portal inflow, is effective in preserving or restoring vessel patency in patients with newly diagnosed PVT. Thus, TIPS can be considered a suitable treatment, particularly when anticoagulation is contraindicated because of risk of bleeding. As far as anticoagulation is concerned, the very few data available in the literature refer to patients who develop PVT while awaiting liver transplantation: in 10 out of 19 patients given anticoagulation patency of the portal vein was restored, as compared to none of 10 historical controls [39]. Since extensive PVT precludes transplantation in many centres and certainly worsens the post-transplantation prognosis, these data argue in favour of anticoagulation in this clinical setting until LT is performed. At the present time, expert opinion favours anticoagulation in patients with advanced cirrhosis and PVT if at least one the following features is present: (1) patients are candidates for liver transplantation; (2) thrombosis involves the superior mesenteric vein and causes abdominal pain, or (3) a prothrombotic disorder coexists. On the other hand, PVT in compensated cirrhosis not awaiting LT should be investigated for an underlying thrombophilia and treated with anticoagulants (similarly to PVT occurring without cirrhosis), in order to prevent thrombosis progression and worsening of liver function. Adequate prophylaxis of bleeding in patients with oesophageal varices should be accomplished before starting anticoagulation. A combination treatment with propranolol and prophylactic banding of large oesophageal varices is currently the approach in our centre. No data exist to dictate how long anticoagulation treatment should be maintained. Overall, no recommendation can be provided on this issue and further data, stemming from large clinical studies, are needed to substantiate the effectiveness and safety of this therapeutic approach. 11. Treatment of chronic portal vein thrombosis in children Until recently, portal hypertension surgery in children was reserved for those with refractory variceal bleeding or severe

hypersplenism. This was justified by the assumption that bleeding is usually well tolerated and symptoms would decrease over time, yielding an acceptable quality of life in adulthood. Moreover, the high rate of complications of vascular reconstructions and of thrombosis of surgical venous anastomoses in children discouraged an extensive indication for shunt surgery in children with chronic PVT. However, evidence suggests that chronic PVT in children is not a benign disorder. Indeed these children require frequent medical care and hospitalizations, may have neurological and cognitive defects, poor somatic growth, progressive portal biliopathy, possibly evolving in advanced liver disease in the adult life [84], and poor quality of life. Currently, remarkable advances in vascular surgery and the introduction of the meso-Rex bypass have challenged the traditional conservative approach. The Rex shunt (mesenteric-left portal vein bypass) is an innovative surgical intervention that, unlike porto-systemic shunts which divert portal blood flow into the systemic circulation, restores portal flow to the liver by bringing mesenteric and splenic venous blood around the obstructed portal tract, through the interposition of an autologous jugular vein into a patent left portal vein in the Rex recessus [73]. This operation require the patency of the left intra-hepatic portal vein in the Rex recessus, of the superior mesenteric vein and of both internal jugular veins. It has been shown to correct the deficiency of several haemostatic factors synthesized by the liver [85], to reverse the neuro-cognitive defects indicative of hepatic encephalopathy [86], and to promote height and weight gain. In addition the meso-Rex bypass is believed to relieve portal biliopathy. Hence the meso-Rex bypass is probably the best currently available treatment in children with chronic PVT and its feasibility should be evaluated in referral hospitals. In children unsuitable for the Rex shunt because of intra-hepatic cavernoma, or with poor quality splanchnic veins, surgical options are limited. Since portal cavernoma is no longer a contraindication to LT in referral centres, children with severe recurrent bleeding or signs of liver decompensation should be evaluated for LT. In this context, in cases of organ shortage, living donor LT may be considered [87]. Band ligation of oesophageal varices remains the best non-surgical option [88].

12. Concluding remarks There is little doubt that thrombophilia plays an important role as a risk factor for portal vein thrombosis. However, due to the multifactorial nature of venous thromboembolism, the coexistence of abdominal inflammatory or neoplastic diseases should be actively investigated in patients with acute or chronic PVT, even in the presence of known prothrombotic risk factors. Chronic myeloproliferative disorders, often occult, are the leading cause for PVT or other splanchnic vein thromboses in developed countries, and should be investigated even in the presence of normal blood cell counts. Given the frequent occurrence of several prothrombotic risk factors in the same individual, far more than expected by chance, a thorough evaluation is advisable in all patients. This should include, besides the routine thrombophilia screening, the search for JAK2 mutation and, in most instances, bone marrow biopsy. Early anticoagulation treatment is highly recommended in acute PVT, due to its favourable risk-benefit ratio, and its lifelong maintenance should be considered for those patients with one or more prothrombotic disorders. The same recommendations apply for chronic portal vein thrombosis, at least in patients with persistent thrombophilia and low risk of anticoagulation-related bleeding, provided that adequate prophylaxis of portal hypertensive-related bleeding is assured. Inherited thrombophilia may also cause PVT in patients with liver cirrhosis. However, increasing evidence suggests that cirrho-

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sis per se is a prothrombotic disorder. Slowing of portal flow and procoagulant imbalance are the alleged causes of PVT in advanced cirrhosis. Despite little available data, current opinion favours anticoagulation for patients with PVT listed for liver transplantation, or with extensive symptomatic thrombosis of the portal venous system. On the other hand, PVT in compensated cirrhotic patients should not be considered a mere consequence of cirrhosis and should warrant aetiologic investigation and anticoagulation treatment. However, the risk-benefit ratio of long-term anticoagulation in cirrhotic patients not listed for liver transplantation is unknown. Hence, whether anticoagulation should be extensively recommended in unselected cirrhotic patients with PVT requires further data from large studies. In children, the aetiology of PVT may be different than in adults, and the clinical presentation, most often at the chronic stage of portal cavernoma, is mainly characterized by recurrent variceal bleeding. For this reason, anticoagulation has rarely been considered in this age group. Also, large studies are needed to assess the role of thrombophilia in this population. The meso-Rex bypass, if technically feasible, is likely the most effective one step treatment able to achieve resolution of portal hypertension and prevention of bleeding, restoration of portal inflow, preservation of hepatic function, and improvement in cognitive function, hence assuring a good quality of life in children with chronic PVT. However, studies are needed to assess the long-term results of this new surgical approach and its feasibility in selected adult, non-cirrhotic patients with chronic PVT.

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