If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, FranceService d'Hépatologie, AP-HP, Hôpital Beaujon, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France
Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, FranceService d'Hépatologie, AP-HP, Hôpital Beaujon, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France
Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, FranceService de radiologie, Hôpital Beaujon APHP.Nord, Clichy, France
Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, FranceService d’anatomie et cytologie pathologique, Hôpital Beaujon APHP.Nord, Clichy, France
Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, FranceService d'Hépatologie, AP-HP, Hôpital Beaujon, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France
Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, FranceService d'Hépatologie, AP-HP, Hôpital Beaujon, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France
Splanchnic vein thromboses include Budd-Chiari syndrome and portal vein thrombosis. These disorders have common characteristics: (i) they are rare diseases; and (ii) they can cause portal hypertension and its complications. Budd-Chiari syndrome and portal vein thrombosis in the absence of underlying liver disease share many risk factors, among which myeloproliferative neoplasms represent the most common; a rapid comprehensive workup for risk factors for thrombosis is needed in these patients. Long-term anticoagulation is indicated in most patients. Portal vein thrombosis can also develop in patients with cirrhosis and in patients with portosinusoidal vascular liver disease. The presence and nature of underlying liver disease impact the management of portal vein thrombosis. Indications for anticoagulation in patients with cirrhosis are growing, while transjugular intrahepatic portosystemic shunt (TIPSS) appears as a second-line option. Due to the rarity of these diseases, studies yielding high grade of evidence are scarce. However, collaborative studies have provided new insight into the management of these patients. This article focuses on the causes, diagnosis, and management of patients with Budd-Chiari syndrome, patients with portal vein thrombosis without underlying liver disease, patients with cirrhosis and nonmalignant portal vein thrombosis.
Patients with Budd-Chiari syndrome or portal vein thrombosis in the absence of underlying liver disease should be systematically screened for myeloproliferative neoplasm by testing the presence of V617F mutation of the JAK2 gene. Molecular profiling using next-generation sequencing is a promising tool for diagnosis and prognosis purposes.
2.
The diagnosis of Budd-Chiari syndrome or portal vein thrombosis is suspected using abdominal Doppler ultrasonography, and confirmed using contrast-enhanced computed tomography or magnetic resonance imaging. Liver biopsy is generally not necessary for a diagnosis of Budd-Chiari syndrome. In patients with portal vein thrombosis, liver stiffness measurement using transient elastography < 10 kPa rules out underlying cirrhosis.
3.
In patients with Budd-Chiari syndrome, long-term anticoagulation is recommended; prompt identification and treatment of the causal factor have a beneficial impact on patient’s outcomes.
4.
Spontaneous recanalization is exceptional in patients with portal vein thrombosis in the absence of underlying liver disease. By contrast, in patients with cirrhosis and PVT, spontaneous recanalization occurs in ≈40% of the patients, especially in those with nonocclusive PVT.
5.
In patients with portal vein thrombosis in the absence of underlying liver disease, long-term anticoagulation is generally recommended. In patients without a strong risk factor for thrombosis, a lower dose (e.g. rivaroxaban 15 mg once daily) may be sufficient to prevent recurrence of thrombosis
6.
In patients with portal vein thrombosis in the absence of underlying liver disease, preliminary data suggest that portal vein recanalization with or without TIPSS is a safe option when performed in expert centers in patients with refractory complications of portal hypertension or portal cavernoma cholangiopathy
7.
In patients with cirrhosis and portal vein thrombosis, anticoagulation is recommended in all potential candidates for liver transplantation regardless of age and the thrombus extension. In non-candidates for liver transplantation, anticoagulation is recommended in case of recent (<6 months) thrombosis, occluding > 50% of the lumen of the main portal vein
8.
In patients with cirrhosis, TIPSS can be considered as the 2nd-line option for the treatment of portal vein thrombosis, especially in case of significant concomitant complications of portal hypertension
9.
Anticoagulation of patients with splanchnic vein thrombosis used to be based on low molecular weight heparin and vitamin K antagonists. There is now growing evidence demonstrating that DOACs are as safe and effective an option. However, high-grade of evidence is still needed before making strong recommendations on the use of DOACs in patients with splanchnic vein thrombosis.
Introduction
Splanchnic vein thromboses (SVT) include Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT). PVT can develop in patients without underlying liver disease or affect patients with cirrhosis. Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT) in the absence of underlying liver disease share several similarities. First, they belong to rare disorders since they affect fewer than 1 in 2000 people in the general population
. Second, they are commonly associated with risk factors for thrombosis. Third, they have portal hypertension as a common consequence. PVT can also occur in patients with cirrhosis, where it is usually non-occlusive and found in the absence of symptoms. Risk factors for thrombosis in patients PVT and cirrhosis are uncommon. However, PVT in cirrhosis carries specific challenges, especially in liver transplant candidates.
The present review focuses on the recent findings on the management of BCS and PVT without underlying liver disease or with underlying cirrhosis. PVT occurring in patients with PSVD will not be discussed here, since it has been recently reviewed elsewhere
. Management of BCS and PVT is multidisciplinary, with a growing place for interventional radiology. Importantly, besides treating portal-hypertension-related complications, managing patients with splanchnic vein thrombosis largely depends on associated risk factors for thrombosis or extra-hepatic conditions. Indeed, the outcome and prognosis of patients with vascular liver diseases differ according to the causal factors.
Causes of splanchnic vein thrombosis in the absence of underlying liver diseases
Causes for SVT include general risk factors for thrombosis, namely systemic acquired prothrombotic diseases and inherited thrombophilia, and local factors. General risk factors for thrombosis are found in approximately 70% of the patients with SVT, while local factors are identified in 20% and 5% of the patients with PVT and BCS, respectively.
A combination of two or more genetic or acquired risk factors is found in 26%-46% and 10-23% of patients with BCS or PVT, respectively
. These results justify comprehensive investigations, even when predisposing or precipitating factors have already been shown (Table 1). This workup should be performed at diagnosis of SVT since control of some conditions (e.g., myeloproliferative neoplasms (MPN), Behcet’s disease, paroxysmal nocturnal hemoglobinuria (PNH)) influences patients’ outcomes
Table 1Prevalence of risk factors for Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT) in the absence of underlying liver disease and proposed diagnostic work-up and specific management (see
Systematic genetic testing of the V617F mutation of the JAK2 gene in all patients If negative
-
genetic testing of the calreticulin gene if platelet count ≥ 200 x109/L and/or spleen height ≥ 16 cm
-
discuss next-generation sequencing
-
discuss bone marrow biopsy
JAK2 V617F
28-45%
15-21%
CALR mutation
1-3%
1-2%
Inherited thrombophilic disorders
Genetic testing
-
Prothrombin G20210A gene mutation
-
Factor V Leiden
Protein S activity Protein C activity Antithrombin activity Dosage should be performed in the absence of VKA. Cautious interpretation of impaired liver function
Prothrombin G20210A gene mutation
12%
5%
Factor V Leiden mutation
4%
8%
Antithrombin deficiency
3%
5%
Protein C deficiency
2%
1%
Protein S deficiency
2%
2%
Acquired thrombophilic disorders
Antiphospholipid antibody syndrome
5%
5%
Lupus anticoagulant, Anti-cardiolipin, and Anti-beta2 glycoprotein 1 antibodies testing Repeat testing after 12 weeks in case of positive testing
Paroxysmal nocturnal hemoglobinuria
10%
0-0.5%
Flow cytometry analysis
Behcet’s disease
1-2%
uncommon
No specific testing, clinical diagnosis Suspect Behcet's disease if: male gender, Mediterranean origin IVC stenosis, genital/oral ulcers, deep vein thrombosis in other sites, arterial thrombosis
MPNs represent the most common risk factor for BCS and PVT in Europe and Asia. In Europe, the reported prevalence of MPNs in patients with BCS and PVT is 30-57% and 21-25%, respectively
Prevalence of prothrombotic factors in patients with Budd-Chiari syndrome or non-cirrhotic nonmalignant portal vein thrombosis: A hospital-based observational study.
. In over 90% of the patients with SVT and MPN, Janus kinase 2 gene (JAK2) V617F mutation can be detected. Thus, routine screening for JAK2 V617F mutation should be performed in all patients with SVT. Somatic mutations of the gene encoding calreticulin (CALR) are identified in about 2% of SVT patients without JAK2 V617F mutation. CALR mutations should be searched particularly in patients with spleen height ≥16 cm, and a platelet count ≥200 x 109/L since 33-56% of the patients with this association have CALR mutations
. Next-generation sequencing (NGS) has recently been shown to be an interesting tool for diagnosing an underlying MPN in patients without JAK2 V617F or CALR mutations
Benefits of molecular profiling with next-generation sequencing for the diagnosis and prognosis of myeloproliferative neoplasms in splanchnic vein thrombosis.
. Moreover, in patients with SVT, NGS molecular profiling carries prognosis information since some molecular risk factors predict the risk of thrombosis recurrence in patients without MPN
. Portal hypertension, by causing hypersplenism and hemodilution, often masks the increased blood cell counts and makes the diagnosis of MPN challenging
. Therefore, given the frequency of MPN in patients with SVT and the consequences of its diagnosis, referral to a hematologist should be systematically considered to discuss NGS and/or bone marrow biopsy (Table 1).
Other acquired pro-thrombotic disorders
The frequency of antiphospholipid antibodies in patients with SVT has been reported to be between 5% and 30%
. Therefore, in the case of antiphospholipid antibodies at diagnosis of SVT, it is recommended to perform second testing for antiphospholipid antibodies 12 weeks after the diagnosis.
The association between Behcet’s disease and SVT mainly concerns BCS and is especially relevant in the Mediterranean population
. Diagnosis of Behcet’s disease should be suspected in case of inferior vena cava obstruction, oral and/or genital ulcers, male gender, deep venous thrombosis in other territories, and systemic inflammatory syndrome
. Early medical therapy, including anticoagulation and immunosuppressive agents, may improve symptoms of BCS (including requirement of invasive treatments) in patients with BCS and Behcet’s disease
. Still, systematic screening for PNH is recommended in all patients with SVT since specific therapies, especially eculizumab, have been shown to decrease the recurrence of thrombosis and mortality in this setting
Cytomegalovirus disease is another recently highlighted rare (<5%) risk factor for PVT. This association should be suspected in patients with recent PVT displaying features of mononucleosis syndrome. CMV disease should not deter a complete workup since a general risk factor for thrombosis (especially G20210A prothrombin gene mutation) was found in 50% of the patients
. CMV disease does not influence thrombosis extension or recanalization. In addition, acute SVT has been reported in patients with Sars-Cov-2 infection. Although rare, SVT may be severe in this setting, suggesting that patients with Sars-Cov-2 infection and severe gastrointestinal symptoms should be screened for SVT
. Although rare cases of SVT occurring after Covid-19 vaccination were reported, the risk of thrombosis is higher after Sars-Cov-2 infection than after Covid-19 vaccination
, a history of SVT should not contraindicate Covid-19 vaccination.
Inherited thrombophilia
Factor V Leiden and G21020 prothrombin gene mutations have been reported in 12% and 4% of the patients with BCS, respectively. In patients with PVT, the prevalence of Factor V Leiden and G21020 prothrombin gene mutations are 5% and 8%, respectively
. Compared to healthy individuals, Factor V Leiden mutation is associated with an increased risk of both BCS and PVT, whereas G21020 prothrombin gene is associated with PVT but not with BCS
Associations of coagulation factor V Leiden and prothrombin G20210A mutations with Budd-Chiari syndrome and portal vein thrombosis: a systematic review and meta-analysis.
. Diagnosis of inherited deficiencies in antithrombin, protein C, and protein S may be difficult to establish because liver dysfunction can induce a nonspecific decrease in those natural anticoagulants, as recently highlighted with antithrombin deficiency
. Although not widely available, genetic testing might be considered in cases of rethrombosis, family history of deep vein thrombosis or doubtful interpretation of antithrombin, protein C, and protein S concentrations.
Hyperhomocysteinemia and/or homozygous C677T methylene-tetrahydrofolate reductase (MTHFR) gene polymorphism has been found in 22% of the patients with BCS
. However, the role of hyperhomocysteinemia as a risk factor for SVT is difficult to assess because homocysteine levels are highly influenced by diet and by vitamin B6, B12, or B9 deficiencies. The role of homozygous C677T MTHFR mutation as a risk factor for BCS seems more relevant in Asia than in Europe
Methylenetetrahydrofolate reductase C677T gene mutation and hyperhomocysteinemia in Budd-Chiari syndrome and portal vein thrombosis: A systematic review and meta-analysis of observational studies.
Methylenetetrahydrofolate reductase C677T gene mutation and hyperhomocysteinemia in Budd-Chiari syndrome and portal vein thrombosis: A systematic review and meta-analysis of observational studies.
Pregnancy and oral contraceptives have been associated with BCS. Up to 74% of western women with BCS have been using oral contraceptive agents and a temporal link between pregnancy and BCS has been described
. Local or other general pro-thrombotic factors are commonly associated with pregnancy or oral contraceptives in women with BCS. Regarding PVT, exposure to female hormones does not appear to cause PVT, as illustrated by the absence of female predominance among patients with PVT contrary to BCS
Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study.
Local risk factors for SVT include abdominal surgery and infectious or inflammatory conditions involving splanchnic organs, such as cancer or inflammatory bowel disease
(Table 1). Certain local factors can be identified on the CT scan performed at SVT diagnosis. In PVT, colonoscopy is recommended to screen for colon cancer or inflammatory bowel disease, although level of evidence is low
Risk factors for vascular liver diseases: Vascular liver diseases: position papers from the francophone network for vascular liver diseases, the French Association for the Study of the Liver (AFEF), and ERN-rare liver.
. PVT associated with alcoholic pancreatitis has some specificity since it does not seem to be favored by general risk factors for thrombosis, so the interest in a comprehensive workup for risk factors for thrombosis is questionable in this setting
Extrahepatic portal venous system thrombosis in recurrent acute and chronic alcoholic pancreatitis is caused by local inflammation and not thrombophilia.
. Visceral adipose tissue might also promote PVT. Indeed, in a retrospective case control study gathering 79 patients with PVT and 79 healthy individuals, features of the metabolic syndrome were more frequent in patients with “idiopathic PVT” (i.e. no risk factor for PVT identified) than in those with either secondary PVT (i.e. risk factor for PVT identified) or healthy individuals. Especially, increased waist circumference was found in ≈75% of the patients with “idiopathic PVT” versus ≈30% of the patients with either secondary PVT or healthy individuals, pointing to visceral adipose tissue as a potential risk factor for PVT.
. Confirmatory studies addressing the link between visceral obesity and PVT are needed.
In patients with BCS, local factor appears to be rare. However, in countries with a high prevalence of Echinococcus granulosus, liver hydatid cysts have been associated with BCS in up to 4% of the patients
BCS is caused by hepatic venous outflow tract obstruction, from the small hepatic veins to the entrance of the inferior vena cava into the right atrium. BCS is usually caused by thrombosis. Heart failure, constrictive pericarditis, and sinusoidal obstruction syndrome/veno-occlusive disease are differential diagnoses of BCS.
Diagnosis
BCS should be considered in patients with any acute or chronic liver disease. Clinical presentation of BCS varies from asymptomatic (3% of the cases) to severe portal hypertension or liver insufficiency. In most patients, clinical manifestations include abdominal pain and ascites
The diagnosis of BCS is based on radiological findings on Doppler ultrasonography and contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). Because BCS diagnosis can be difficult, radiologists should be experienced and aware of the clinical suspicion of BCS. Radiological features of BCS include (i) direct arguments of obstruction, including solid non-enhancing endoluminal material or transformation of the veins into a cord devoid of flow signal, and (ii) indirect arguments of outflow obstruction, including dilatation of the vein upstream to the obstruction, inter-hepatic venous collateral or inverted venous flow, atrophy/hypertrophy of affected/unaffected segments
. “Classical” forms of BCS do not require liver biopsy for diagnosis, whereas it can be helpful in the rare form of small hepatic veins BCS where large hepatic veins are patent. Location of obstruction varies according to geographic areas: 62% of BCS in Western countries are pure hepatic vein obstruction, whereas membranous obstruction of the inferior vena cava is more common in Asia
. The difficulty of BCS diagnosis is illustrated by a French epidemiological study where the duration between first clinical manifestations and diagnosis of primary BCS exceeded 6 months in 15% of the patients and one year in 6% of the patients
BCS requires referral to centers with expertise in managing patients with vascular liver diseases and having access to interventional radiology and liver transplantation. The approach should be multidisciplinary, including specialists in hemostasis, hematology, diagnostic and interventional radiology, and liver transplantation. For more than 15 years, a stepwise treatment strategy, according to response to previous therapy (from less to more invasiveness), has been proposed and is now largely used worldwide
Vascular Liver Disorders, Portal Vein Thrombosis, and Procedural Bleeding in Patients With Liver Disease: 2020 Practice Guidance by the American Association for the Study of Liver Diseases.
. Among patients alive at 5 year, around 30% are controlled with medical therapy alone, 35% with interventional radiology and 10% with liver transplantation
. The exact timing for further intervention is not stated. Improvement with no need of further intervention is considered in the presence of the combination of several of the following features: decreasing rate of ascites formation, decreasing serum bilirubin, decreasing serum creatinine and decreasing INR (or increasing factor V in patients receiving vitamin K antagonists)
. Several prognostic indices have been proposed for all patients with BCS (Child-Pugh score, MELD, Clichy prognostic index, Rotterdam BCS index, New Clichy prognostic index) and one for BCS patients in whom TIPS is considered as a therapeutic option (BCS-TIPS). These prognostic indices are accurate to assess transplant-free survival and invasive therapy-free survival. However, because i) they derived from retrospective cohorts constituted over several decades with drastically different therapeutic options and outcomes, and ii) they had low prognostic accuracy in most recent studies, they are considered insufficiently accurate to base the management of individual BCS patients
Prompt identification of MPN, PNH, or Behcet’s disease associated with BCS is essential since targeting the underlying condition positively influences patients’ outcomes
. Anticoagulation should be started at BCS diagnosis, even in absence of identified prothrombotic disorder. Despite the absence of randomized study comparing anticoagulation vs. no treatment, long-term anticoagulation therapy is currently recommended for all BCS patients. This recommendation is based on the comparison of survival between historical studies not using anticoagulation and studies after using anticoagulation
. However, there is no clear or sufficient argument currently to stop anticoagulation once BCS is stabilized and causal factor adequately treated. Because of a high rate of heparin-induced thrombocytopenia, mainly observed with unfractionated heparin (15%), low-molecular-weight heparin (LMWH) is currently recommended
Heparin-induced thrombocytopenia in patients with Philadelphia-negative myeloproliferative disorders and unusual splanchnic or cerebral vein thrombosis.
. LMWH is usually substituted with VKA in patients with stable disease, targeting an INR between 2 and 3. Although the experience is limited, direct oral anticoagulants (DOACs) seem safe and effective in BCS patients, but larger prospective studies are needed
(Table 2). A recent retrospective case-control study found that dabigatran was associated with similar stent patency and complications rates after endovascular intervention as VKAs
. DOACs are currently not recommended in patients with antiphospholipid syndrome as they have been associated with an increased risk of recurrent arterial thrombosis
. Ascites, gastrointestinal bleeding, infections, renal failure, and encephalopathy should be treated as recommended for patients with cirrhosis, due to absence of specific data in the BCS population. Severe bleeding related to paracentesis have been reported in these patients receiving anticoagulation. A brief interruption of anticoagulation could be considered before paracentesis
2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation.
Short-length hepatic vein stenosis should be systematically searched for to re-establish the physiological drainage of the portal and sinusoidal blood. When identified, i.e., in ≈15% of the patients, percutaneous transluminal angioplasty (PTA) of accessible stenosis should be performed since this procedure has good efficacy and low morbidity
. In a recent Chinese randomized controlled trial including 88 patients with BCS and short-length stenosis, stent placement improved hepatic vein patency and reduced symptom recurrence over PTA alone
Transjugular intrahepatic portosystemic shunt (TIPSS) has become the standard of care for patients with BCS and incomplete response to medical therapy and/or angioplasty
. The technical success rate exceeds 90% in expert centers and the 10-year liver transplantation-free survival reaches 76%. Long term anticoagulation therapy should be maintained after TIPSS placement
. TIPSS dysfunction occurs in 42% and was mostly due to re-thrombosis of the stent which can be managed with TIPSS revision leading to a secondary patency rate close to 100%. The incidence of late hepatic encephalopathy is 25% in these patients, mostly transient encephalopathy, easily medically controlled with no reappearance
Despite medical therapy and interventional radiology, liver transplantation is necessary for ≈10% of BCS patients. Previous TIPSS does not compromise the results of liver transplantation
Pregnancy is not contra-indicated in BCS women with controlled disease. Three retrospectives studies, including 55 pregnancies carried out between 1985 and 2015, reported no maternal death
. Liver-related complications were rare in women with BCS known and treated before pregnancy. Bleeding events occurred in women receiving anticoagulation and were unrelated to portal hypertension. The reported rate of miscarriages or ectopic pregnancies before the 20th week of pregnancy was about 30%, higher than in healthy women of similar age. On the other hand, after 20 weeks of pregnancy, 93% of children were healthy, but the prematurity rate was high. Practical management of pregnancy in women with vascular liver diseases is described in Table 3. All VKAs must be switched to LMWH before the 6th weeks of gestation as VKAs cross placenta and can cause fetal hemorrhage and fetal vitamin K antagonist syndrome, especially between 6 to 12 weeks of gestation
VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
Table 3Practical management of pregnancy in patients with vascular liver diseases.
Before conception
Early counseling should always be proposed before conception. Pregnancy should be planned when the liver disease and the prothrombotic condition are well-controlled. Cytoreductive therapy for myeloproliferative neoplasm should be stopped before conception as they are teratogenic.
Anticoagulation
VKA must be switched to LMWH before the 6th week of amenorrhea, as they cross placenta and can cause fetal warfarin syndrome or warfarin embryopathy. LMWH are then continued during the whole pregnancy. DOACs are contraindicated during the whole pregnancy.
Portal hypertension
Gastroesophageal varices should ideally be investigated in the year before conception or during the second trimester of pregnancy. Variceal hemorrhage occurring during pregnancy should be prevented and managed as in non-pregnant patients
Delivery
Vaginal delivery should be preferred even in case of portal hypertension. Caesarian section reserved only for obstetrical indications. Platelet count > 20 x109/L and > 50 x109/L considered as safe for vaginal delivery and caesarean section respectively. Platelet counts > 75 x109/L are considered safe for epidural anesthesia and over 50 x109/L for spinal anesthesia. Stop anticoagulation therapy 24h before epidural analgesia
Post-partum
Estrogen-derived oral contraceptives are contraindicated. Breastfeeding is possible with beta-blockers therapy and warfarin but not with other VKA molecules or DOACs.
Abbreviations: VKA, vitamin K antagonists; DOACs, direct oral anticoagulants, LMWH, low molecular weight heparin
Early decrease in portal perfusion associated with a compensatory increase in hepatic arterial perfusion is thought to contribute to the development of liver nodules in chronic BCS. Most liver nodules are benign regenerative nodules, also called focal nodular hyperplasia-like (FNH-like) nodules, but hepatocellular adenomas or hepatocellular carcinoma (HCC) can also arise
Hepatocellular carcinoma associated with membranous obstruction of the inferior vena cava: incidence, characteristics, and risk factors and clinical efficacy of TACE.
. When liver nodules are detected, MRI is the imaging procedure of choice, ideally with the injection of hepatobiliary contrast agent, to distinguish malignant from benign nodules. The vast majority of nodules show arterial phase hyper-enhancement
. Washout is observed in 75% of HCC vs. 29% of benign lesions and is thus not specific for HCC. Additional features are helpful to differentiate benign nodules from HCC, including serum alpha-fetoprotein (AFP) > 15 ng/ml, fat content, capsule, hypointensity on T1-weighted sequence, hyper-intensity on T2-weighted sequence, hyper-intensity on high b value diffusion-weighted imaging, or hypo-intensity on hepatobiliary phase
. A liver biopsy is required in case of suspicion of HCC (Figure 1). Management of hepatocellular adenoma and HCC should be discussed case by case in specialized centers. Ablation, transarterial chemoembolization, and liver transplantation can be considered
Hepatocellular carcinoma associated with membranous obstruction of the inferior vena cava: incidence, characteristics, and risk factors and clinical efficacy of TACE.
Portal vein thrombosis in patients without underlying cirrhosis
Diagnosis
Recent PVT refers to the recent formation (<6 months) of a thrombus within the portal vein and/or its branches and/or radicles. Abdominal pain is the most frequent clinical feature (91%); high leukocyte count and C-reactive protein levels are common
. Conversely, signs of peritoneal irritation, organ failure, clinical ascites, and/or high lactate levels are rare and should raise suspicion of PVT complicated with intestinal necrosis, i.e., a complication requiring emergency surgery (see below)
Diagnosis of recent PVT is based on imaging. Ultrasound coupled with Doppler is usually the first-line approach, allowing the direct detection of the thrombus in the portal vein and the absence of flow in case of complete PVT. Contrast-enhanced CT or MRI is recommended to (i) confirm the diagnosis of PVT, showing a hyperattenuating (hyperintense) thrombus on unenhanced CT (MRI) and a lack of enhancement of the lumen in contrast-enhanced portal venous phase; enlargement of the portal vein can be observed when PVT is complete; (ii) determine the extension of the thrombus to splenic and mesenteric veins; (iii) identify potential local factors and (iv) search for complications including signs of acute mesenteric ischemia and intestinal necrosis
. Bowel wall thickening, mesenteric fat stranding, and ascites are common both in patients without acute mesenteric ischemia, with acute mesenteric ischemia and with intestinal necrosis
Chronic extrahepatic portal vein obstruction (EHPVO) in the absence of underlying liver disease refers to incomplete resolution of the portal vein obstruction 6 months after recent PVT or to portal cavernoma (Figure 2). Portal cavernoma is a network of porto-portal collaterals that develop following portal vein obstruction. Obstruction leading to cavernoma is mainly related to thrombosis in adults but less likely so in children and young adults
. Diagnosis of EHPVO is based on contrast-enhanced CT or MRI, showing a lack of visualization of the portal vein, usually associated with a cavernoma enhancing after contrast injection
. A liver biopsy is needed when an underlying chronic liver disease (cirrhosis or porto-sinusoïdal vascular liver disorder (PSVD)) is suspected based on abnormal liver morphology and/or increased liver stiffness measurement. Liver stiffness measurement <10 kPa can rule-out underlying cirrhosis in this setting
A female patient presented with abdominal pain. Contrast-enhanced CT (all portal venous phase, axial view) showed a complete occlusion of an enlarged portal trunk and intrahepatic portal branches by nonenhancing and hypoattenuating material (arrow) consistent with an acute portal vein thrombosis. Note the heterogeneous enhancement of the hepatic parenchyma with central hypoenhancement relative to the liver periphery (zonal perfusion, *). Over time, CT shows the progressive development of numerous tortuous veins in the hepatic pedicle and the hepatic hilum corresponding to a cavernous transformation of the portal vein (dashed arrows). Note the absence of recanalization of the portal veins and the progressive enlargement of the cavernoma, with progressive extension to the pancreas. No bile duct dilatation was noted.
In patients with recent PVT, immediate initiation of anticoagulation therapy is recommended because it has been associated with the prevention of thrombus extension and a decreased incidence of intestinal infarction to only 2%, compared with 30% in patients not receiving anticoagulant
. In a study gathering 67 patients with acute mesenteric ischemia (arterial and venous), administration of oral antibiotics (gentamicin 80 mg/day + metronidazole 1.5 g/day) was associated with a decreased incidence of intestinal necrosis
Recanalization of the thrombosed veins is achieved in ≈30% of the patients treated with anticoagulation and takes place within the first six months of therapy
. Factors associated with recanalization include the site of thrombosis (splenic or superior mesenteric veins having a higher rate of recanalization than main portal vein) and early anticoagulation (<15 days after first symptoms)
. By contrast, in patients with recent PVT, ascites, an occluded splenic vein, and underlying prothrombotic disorders have been associated with failure to recanalize the portal vein
. In most studies, anticoagulation therapy was based on unfractionated heparin or low molecular weight heparin within the first weeks and then substituted for VKAs targeting an INR between 2 and 3
Heparin-induced thrombocytopenia in patients with Philadelphia-negative myeloproliferative disorders and unusual splanchnic or cerebral vein thrombosis.
. Although mostly derived from small retrospective unselected cohort studies, DOACs are now part of the therapeutic arsenal in patients with recent PVT. Despite the absence of direct comparison between LMWH or VKA and DOACs, the rates of PVT recanalization seem similar, without a higher risk of bleeding. Dedicated studies are still needed to assess the efficacy and safety of each DOAC in patients with PVT in the absence of underlying liver disease. The choice of anticoagulant therapy in PVT should be individualized, considering comorbidities and risk factors for PVT (table 2).
In patients with past PVT (i.e. who achieved recanalization after 6 months of anticoagulation) or in patients with chronic EHPVO, long-term anticoagulation is indicated in most cases since it decreases the incidence of recurrent thrombosis
GS-613 Prophylaxis of recurrent thrombosis by rivaroxaban in patients with non-cirrhotic chronic portal vein thrombosis (PVT): a multicentre randomized controlled study testing rivaroxaban vs no anticoagulation.
. Recent Baveno VII consensus conference recommended adapting the dosage of anticoagulant therapy according to the etiologic workup (grade B recommendation). In patients with a permanent and strong risk factor for thrombosis (MPN, PNH, Behcet’s diseases, antiphospholipid syndrome, personal or 1st-degree familial history of spontaneous venous thrombosis or a history of intestinal necrosis due to mesenteric ischemia), full-dose long-term oral anticoagulation should be maintained
Vascular Liver Disorders, Portal Vein Thrombosis, and Procedural Bleeding in Patients With Liver Disease: 2020 Practice Guidance by the American Association for the Study of Liver Diseases.
. Although solid data are still lacking, DOACs at therapeutic dosage (e.g., Rivaroxaban 20 mg once a day or apixaban 5 mg twice a day) appear an attractive alternative in patients without antiphospholipid syndrome
. In patients without underlying permanent and strong risk factors for thrombosis, the recent RIPORT randomized controlled trial found that rivaroxaban at the dose of 15 mg per day decreased the incidence of recurrent thrombosis from 19/100 patients-years to 0 patients-years. Of note, in this trial, plasma D-dimers concentration <500 ng/mL 1 month after interruption of anticoagulation was predictive of a low risk of recurrence
GS-613 Prophylaxis of recurrent thrombosis by rivaroxaban in patients with non-cirrhotic chronic portal vein thrombosis (PVT): a multicentre randomized controlled study testing rivaroxaban vs no anticoagulation.
. Furthermore, recurrence of thrombosis was uncommon in patients with an isolated transient local factor for PVT. Therefore, in patients with no general risk factor for thrombosis and a transient local factor, anticoagulation might be discontinued, with D-dimer monitoring one month later to determine whether or not to resume anticoagulation
In patients with recent PVT or chronic EHPVO, endoscopy should be performed within the first months after diagnosis to screen for gastroesophageal varices. In patients with recent PVT, varices develop mainly during the first year of follow-up
. In patients with chronic EHPVO, a study gathering 178 patients showed that the course of gastroesophageal varices is similar to that in patients with cirrhosis. Therefore, primary prophylaxis is usually based on nonselective beta-blockers or endoscopic band ligation, and secondary prophylaxis on the association of both
. This suggests that oral anticoagulation can be maintained in patients undergoing scheduled endoscopic variceal band ligation.
Radiology
In patients with recent PVT, invasive strategy including transjugular or transhepatic thrombus-aspiration, local fibrinolysis, and/or TIPSS has been proposed in the first weeks after PVT diagnosis in highly selected patients, namely those with PVT and extension to the superior mesenteric vein, particularly when features predicting intestinal necrosis are present
. However, further studies are needed to clarify indications and patients’ outcomes.
In patients with chronic EHPVO, portal vein recanalization with or without TIPSS can be considered in patients with portal-hypertensive related bleeding not controlled with endoscopic treatment or in patients with symptomatic portal cavernoma cholangiopathy. Various approaches have been reported, including transjugular, transhepatic and transsplenic route. This procedure is technically successful in more than 80% of the cases when performed in expert centers if intrahepatic portal branches are patent
. The usefulness of long-term anticoagulation after portal vein recanalization is unknown. Maintaining anticoagulation seem reasonable, especially in patients with risk factors for thrombosis. The clinical outcome seems favorable. Recent data suggest successful portal vein recanalization is associated with increased muscle mass and decreased spleen volume
. However, these results are mainly based on small, retrospective mostly single-center unselected cohort studies. Dedicated comparative studies are needed to evaluate the impact of portal vein recanalization on long-term outcome and to determine the best technical approach.
Surgery
In patients with acute mesenteric ischemia, emergency surgery is indicated in case of signs suggesting intestinal necrosis to assess bowel viability. Patients should be transfer to a referral center, enabling a multidisciplinary approach
. Shunt surgery to treat portal-hypertension related complications has lost ground to radiological portal vein recanalization.
Specific issues
Pregnancy
Pregnancy is not contraindicated in women with stable chronic EHPVO. The best information stems from three series of patients, two Indian and one European, including 104 pregnancies
. Anticoagulation was administered on a case-by-case basis. Rates of miscarriage and preterm birth were 14% and 14%, respectively. Fetal and maternal outcomes were favorable for most pregnancies. Only five episodes of variceal hemorrhage happened, including three among patients without adequate prophylaxis for portal hypertension-related bleeding. This highlights the importance of upper gastrointestinal endoscopy before conception or during the second trimester of pregnancy in women not receiving beta-blockers (Table 2). Thrombotic events occurred in two patients.
Portal cavernoma cholangiopathy
‘‘Portal cavernoma cholangiopathy’’ refers to abnormalities of the biliary tract in patients with chronic EHPVO
. MR cholangiography shows bile duct changes, including stenoses, upstream dilatation, and irregularities in the caliber of bile ducts; MR angiography shows cavernomatous veins in the vicinity of stenoses
Treatment of portal cavernoma cholangiopathy should be discussed on individual basis at referral centers. Specific treatments of portal cavernoma cholangiopathy include endoscopic retrograde cholangiopancreatography (ERCP) and portal vein recanalization. These treatments should be considered only in patients with cholangitis, pancreatitis, jaundice, or pruritus. ERCP allows bile stones extraction and temporary stenting of biliary strictures
. The risk of bleeding from bile duct varices should be kept in mind. Treatment with ursodesoxycholic acid following endoscopic therapy was associated with a reduction of symptoms in ≈ 50% of the patients
. The prevalence of PVT increases in parallel with the severity of cirrhosis: 10% in patients with compensated cirrhosis, 17% in patients with decompensated cirrhosis, and up to 26% in liver transplants (LT) candidates
In patients with cirrhosis and PVT, systematic screening for factor V Leiden and G20210A prothrombin gene mutation is not systematically recommended because their prevalence is low in this setting
Associations of coagulation factor V Leiden and prothrombin G20210A mutations with Budd-Chiari syndrome and portal vein thrombosis: a systematic review and meta-analysis.
have been associated with the occurrence of PVT, although the impact of these features on PVT development might be limited. Local risk factors, such as abdominal surgery, have also been reported
. The only study evaluating the association between beta-blockers and PVT occurrence by time-dependent analysis did not find any association between beta-blockers and with PVT occurrence
In patients with cirrhosis, PVT is usually found in the absence of symptoms on the occasion of imaging performed as part of the screening for HCC or when a decompensation of cirrhosis occurs
. Although PVT is generally recognized in US, CT or MR angiography are recommended to assess the degree and extent of obstruction. Contrasting with the findings in patients without cirrhosis, non-occlusive PVT is the predominant form in patients with cirrhosis, accounting for around 70% of cases
. Recent recommendations concur for considering that the following characteristics need to be provided as part of the description of PVT: time course (recent, i.e., < 6 months or chronic, i.e., ≥ 6 months), degree of occlusion (minimally occlusive, i.e., <50% of the lumen obstructed, partially occlusive, i.e., ≥ 50% of the lumen obstructed or completely occlusive, i.e., no persistent lumen), and response to treatment or interval change (progression, stability or regression)
Vascular Liver Disorders, Portal Vein Thrombosis, and Procedural Bleeding in Patients With Liver Disease: 2020 Practice Guidance by the American Association for the Study of Liver Diseases.
. Patients with HCC are at risk of tumoral invasion of the portal vein but also at higher risk of nontumoral PVT since HCC may tilt the hemostatic balance towards hypercoagulability
The presence of three or more features among serum AFP concentrations >1,000 μg/L, venous expansion, thrombus enhancement at arterial phase, neovascularity, and PVT adjacent to HCC have a 100% sensitivity and 94% specificity for the diagnosis of tumoral invasion of the portal vein
. In the absence of these specific features, fine needle ultrasound-guided biopsy of the thrombi may be safe and useful to obtain a definitive diagnosis
Natural history of PVT and impact on patients’ outcome
Spontaneous regression or even recanalization of PVT may occur in ≈ 40 % of the patients, mainly in those with non-occlusive PVT and compensated cirrhosis
. In patients with cirrhosis with recent PVT and extension to the superior mesenteric vein, acute mesenteric ischemia or intestinal necrosis can occur but remains uncommon
, including a large prospective study gathering over 1,200 patients with compensated cirrhosis: occurrence of PVT was not associated with subsequent decompensation of cirrhosis
, suggesting that PVT is a marker but not a direct cause of the progression of liver disease. By contrast, the impact of PVT in the context of liver transplantation is significant. Pre-transplantation PVT has been associated with an increased post-transplant short-term mortality and graft failure in large databases
. However, in the latter studies, the link between the size and extent of PVT and post-transplant outcomes was not evaluated. The impact of PVT appears to depend on the possibility of restoring physiologic portal perfusion to the graft using anatomical (physiological) procedures. Good results are obtained when the superior mesenteric vein is patent. By contrast, an irremovable thrombus occluding the superior mesenteric vein requires left renal to portal vein anastomosis, or portocaval hemi-transposition. These interventions that do not relieve portal hypertension and do not restore graft perfusion with portal blood are associated with a high rate of failure or complications
. Thus, in patients awaiting liver transplantation, persistent complete extensive thrombosis may preclude liver transplantation.
Management
Medical therapy
In patients with cirrhosis and PVT, potential candidates for liver transplantation - meaning those without definitive contraindication to liver transplantation - the main objective of anticoagulation therapy is to maintain or obtain a patent portal vein trunk to allow liver transplantation. The efficacy of anticoagulation therapy in this setting has been evaluated in several cohort studies, mostly retrospective
. In a meta-analysis of eight studies involving 353 patients, PVT progression was observed in 9% of treated patients compared to 33% of untreated patients. Portal vein recanalization was achieved in 71% of treated patients compared to 42% of untreated patients
. A detailed analysis of the structure and composition of portal vein thrombi showed that portal vein obstruction consists of intimal fibrosis with an additional fibrin-rich thrombus in only one-third of cases, which may account for the unsystematic recanalization observed after anticoagulation
(Figure 4). Likewise, factors associated with recanalization in patients receiving anticoagulant therapy include recent PVT and duration between PVT diagnosis and treatment initiation shorter than 6 months
A. Recent portal vein thrombosis in a 59 years old man with viral cirrhosis. Contrast-enhanced CT (coronal view, portal venous phase) shows partially occlusive non-enhancing material corresponding to the clot in the lumen of the portal trunk (arrows). The downstream venous branches are patent.B. HES staining. Low magnification. Recent portal vein partial thrombosis
C. HES staining. Higher magnification. Recent portal vein thrombi composed of fibrinous deposits associated with red blood cells
D. Chronic portal vein thrombosis in a 52 years old man with alcohol-related cirrhosis. Contrast-enhanced CT (coronal view, portal venous phase) shows minimally occlusive non-enhancing material corresponding to the incorporation of the clot in the wall of the portal trunk and the superior mesenteric vein (arrows)
E. HES staining. Low magnification. Non-malignant chronic portal vein thrombi
F. HES staining. Higher magnification. Chronic portal vein thrombi with fibro-oedematous intimal thickening with numerous siderophagous and neovessels partially repermeabilizing the luminen
In patients with cirrhosis and PVT not candidates for liver transplantation, the beneficial effect of anticoagulation might go beyond its impact on PVT. A landmark prospective randomized controlled trial gathering 70 patients with cirrhosis without PVT showed that treatment with 4000 IU/day enoxaparin for 48 weeks effectively prevented PVT occurrence and, more importantly, decreased decompensation of cirrhosis and death
. In a large individual patient data meta-analysis gathering 5 studies and 500 patients with cirrhosis and PVT, anticoagulation increased overall survival, and the beneficial effect was independent of portal vein recanalization
OS-1544 Anticoagulation improves overall survival through portal vein recanalization in patients with cirrhosis and portal vein thrombosis: Individual patient data meta-analysis (IMPORTAL study).
. Based on those data, the recent Baveno VII consensus conference recommended initiating anticoagulation (i) in all patients with cirrhosis and PVT potentially candidates for liver transplantation, independently of the degree of occlusion and extension and (ii) in patients with cirrhosis and recent (<6 months) completely or partially occlusive (>50%) thrombosis of the portal vein trunk even if not a candidate to liver transplantation
. After that, the decision for maintaining anticoagulation depends on the response to therapy and the project or not of liver transplantation. Anticoagulation is generally maintained until liver transplantation, except if a TIPSS is performed in potential candidates for liver transplantation. In other patients, the continuation of anticoagulation should be considered in patients without complete PVT with a regular evaluation balancing the benefits and risks of anticoagulation (Figure 3B).
Bleeding events not related to portal hypertension occur in ≈10% of the patients with cirrhosis receiving anticoagulation
. This rate does not seem to be higher than that observed in patients with cirrhosis and PVT not receiving anticoagulation nor in patients without cirrhosis receiving anticoagulation
. Data obtained in the setting of atrial fibrillation suggest that VKAs are associated with a higher risk of major bleeding events than DOACs in patients with cirrhosis
. Bleeding events related to portal hypertension are less frequent in patients receiving anticoagulation than in those without anticoagulation, possibly due to a beneficial effect of anticoagulation on intrahepatic vascular resistance
00239-7&id=gr1.jpg){kind=link}
00239-7&id=gr2.jpg){kind=link}
00239-7&id=gr3.jpg){kind=link}
00239-7&id=gr4.jpg){kind=link}