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Address for correspondence. Dr. Akash Shukla, Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Ward 32A, 9th floor, New OPD Building, Acharya Donde Marg, Parel, Mumbai, 400012, India. Tel.: +91 9137009394.
Patients with cirrhosis of the liver are at high risk of developing portal vein thrombosis (PVT), which has a complex, multifactorial cause. The condition may present with a myriad of symptoms and can occasionally cause severe complications. Contrast-enhanced computed tomography (CT) is the gold standard for the diagnosis of PVT. There are uncertainties regarding the effect on PVT and its treatment outcome in patients with cirrhosis. The main challenge for managing PVT in cirrhosis is analyzing the risk of hemorrhage compared to the risk of thrombus extension leading to complications. All current knowledge regarding non-tumor PVT in cirrhosis, including epidemiology, risk factors, classification, clinical presentation, diagnosis, impact on natural history, and treatment, is discussed in the present article.
Portal vein thrombosis (PVT) is defined as thrombus formation within the main portal vein (PV) or its branches, with or without extension into the splenic and superior mesenteric vein (SMV).
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.
PVT is a well-known complication of cirrhosis associated with the rebalanced coagulation system and alteration in the portal venous flow in these patients. PVT can be acute, leading to intestinal ischemia or hepatic decompensation, or chronic, when the hepatopetal collaterals bypass the obstructed portion with the development of portal hypertension. The majority of cirrhotics with PVT are asymptomatic, and if symptomatic, the symptoms are usually non-specific. To avoid complications resulting from acute PVT, it is imperative to diagnose patients with high suspicion and initiate early therapy. However, coagulation abnormality associated with cirrhosis and increased risk of bleeding poses a challenge for patient selection and determination of optimal treatment for the patient. Transjugular intrahepatic portosystemic shunt (TIPS) has emerged as a therapeutic option for cirrhotics with PVT, but the ideal candidates for TIPS need to be defined. Another matter of debate is the effect of PVT on the natural course of liver cirrhosis and its outcome. This review article summarizes the current evidence on non-tumoral PVT in cirrhosis with a focus on controversial topics.
Epidemiology
The prevalence of PVT in cirrhosis varies with age, underlying liver disease, hepatic function status, and the patient's procoagulant status. The relative risk of development of PVT in cirrhotics is seven-fold higher compared to the general population.
As assessed by the Child–Pugh score, the severity of liver dysfunction in a cirrhotic is a major determinant of PVT. The reported cumulative incidence of PVT in Child–Pugh A and B patients is 4.6% and 10.7% at 1 and 5 years, respectively.
Similarly, the prevalence of PVT in compensated cirrhosis is around 1%, increasing to 8–25% in liver transplant (LT) candidates and 40% in patients with hepatocellular carcinoma (HCC), including tumoral PVT.
Faculty of the 7th international coagulation in liver disease. Concepts and controversies in haemostasis and thrombosis associated with liver disease: proceedings of the 7th international coagulation in liver disease conference.
Among the patients undergoing LT, the prevalence of PVT was higher with non-alcoholic steatohepatitis (NASH)-related cirrhosis, independent of other risk factors.
The pathogenesis of PVT in cirrhosis is multifactorial (Figure 1), among which Virchow's triad (venous stasis, hypercoagulability, and endothelial dysfunction) is the main predisposing factor.
Hemodynamic alteration in the portal venous system is critical to the pathogenesis of PVT in cirrhosis. Fibrous tissue proliferation and hepatic sinusoidal destruction in cirrhosis lead to increased intrahepatic resistance causing reduced portal venous blood flow. Studies have shown that reduction of PV velocity on Doppler-ultrasound (US) to less than 15 cm/s is associated with a 10–20 fold increased risk of PVT.
Two other factors that can reduce PV blood flow include portosystemic shunt causing a “steal” syndrome and non-selective beta-blockers (NSBBs). Maruyama et al. reported that collateral vessels with a flow volume >400 mL/min and a flow velocity >10 cm/s predicted the development of PVT in patients with cirrhosis.
Results have been conflicting with regard to the contribution of NSBB to PVT, with few studies reporting the use of NSBBs as a risk factor for the development of PVT,
A recent meta-analysis of nine studies showed that NSBBs increased the risk of PVT in cirrhotic patients by 4.62-fold. However, heterogeneity was significant because most studies were retrospective, including abstracts in the analysis.
It can be assumed that severe portal hypertension associated with an advanced liver disease requiring NSBB is the main contributor to PVT, rather than the use of NSBB per se. Patients with Budd–Chiari syndrome (BCS) have stagnant blood flow in the PV and an underlying prothrombotic state, which predisposes them to the development of PVT. Concomitant splanchnic vein thrombosis (SVT) and BCS have been described in epidemiological studies, with incidence varying from 3.8 to 21%.
Patients with cirrhosis have a fragile but rebalanced coagulation system due to changes in the level of various procoagulant and anticoagulant factors (Figure 2). Contrary to the traditional belief of increased risk of hemorrhage associated with cirrhosis, newer evidence suggests a hypercoagulable state in cirrhosis that is not assessed by conventional tests for coagulation.
Faculty of the 7th international coagulation in liver disease. Concepts and controversies in haemostasis and thrombosis associated with liver disease: proceedings of the 7th international coagulation in liver disease conference.
leading to a hypercoagulable ratio. In a study, patients with PVT had higher von Willebrand factor (vWF) levels compared to those without PVT, and ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was independently and inversely associated with PVT.
PVT can occur in the absence of cirrhosis as a result of inherited and acquired thrombophilic disorders. But, the role of these disorders is less evident in the development of PVT in cirrhosis. A recent meta-analysis of nine studies found a greater prevalence of inherited thrombophilia in cirrhotics compared to the general population, with rates between 5 and 17%. In general, prothrombin G20210A mutations or factor V Leiden mutations have been associated with a two-fold higher risk of PVT. However, the methyltetrahydrofolate reductase (MTHFR) C677T mutation did not increase the PVT risk.
Hence, a low level of these proteins may be secondary to advanced liver disease rather than a primary disturbance contributing to PVT. Janus Kinase 2 (JAK2) gene mutation was seen in a higher proportion of cirrhotics with PVT in one study.
Routine testing for thrombophilic conditions in cirrhotics is not recommended but is helpful for high-risk patients with a family history of the prothrombotic state, patients with multiple sites of thrombosis, history of recurrent thrombosis, and presence of splenomegaly with normal or elevated platelet count (screen for myeloproliferative disorder in the latter).
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.
Hepatobiliary Disease Study Group Chinese Society of Gastroenterology, Chinese Medical Association. Consensus for management of portal vein thrombosis in liver cirrhosis (2020, Shanghai).
Vascular endothelial dysfunction also plays a crucial role in the pathogenesis of PVT in cirrhosis. Endothelial dysfunction in cirrhosis results from reduced bioavailability of nitric oxide (NO) due to reduced intrahepatic endothelial nitric oxide synthase (eNOS) activity. Reduced eNOS activity can be due to: (i) inhibition by accumulated asymmetric dimethylarginine (ADMA) in the systemic circulation triggered by inflammation and oxidative stress synergistically and (ii) complex posttranslational modifications of eNOS due to hepatic dysfunction reducing its enzymatic activity.
Conversely, NO overproduction by splanchnic vascular endothelium occurs in response to various stimuli such as shear stress, inflammatory cytokines, and vascular endothelial growth factors (VEGF), culminating in a hyperdynamic circulation.
Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state.
Am J Physiol Gastrointest Liver Physiol.2006; 290: G980-G987
The resultant portal system congestion leads to an increase in the vascular shear stress with consecutive endothelial injury and vascular dysfunction. Markers of endothelial dysfunction like vWF, p-selectin, and isoprostane are upregulated in patients with cirrhosis, and circulating levels of vWF have been shown to have a significant direct correlation with hepatic venous pressure gradient (HVPG).
The surgical intervention leads to venous injury as well as altered portal venous blood flow, which promotes thrombus formation.
Other Associated Factors
During the late stages of cirrhosis, bacterial translocation increases the possibility of infection by intestinal bacteria. Intestinal bacterial translocation into portal circulation leading to low-grade endotoxemia and inflammation has been proposed as a potential clotting trigger. Bacterial lipopolysaccharide (LPS) has been shown to increase factor VIII secretion from endothelium and platelet activity while decreasing thrombomodulin activity, leading to a hypercoagulable state.
High altitude has also been described as a risk factor for the development of SVT. In a study from India, symptomatic PVT has been described in soldiers posted at high altitude areas, presenting as an acute emergency.
Several different classifications have been proposed for PVT. The first classification was by Stieber et al. in 1991, followed by other commonly used classifications like the Yerdel classification and the Baveno VI classification.
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
All these classification systems are anatomical and hence, easy to use and interpret. Yerdel's classification has been shown to have prognostic value in patients undergoing liver transplantation.
However, these classification systems lack functional relevance and cannot be utilized to guide therapy for the patient. To overcome these limitations, an anatomico-functional classification has been proposed by Sarin et al. (Table 1) which includes the site of PVT, degree of portal venous system occlusion, extent of PVT, duration and presentation, and type and presence of underlying liver disease.
This system helps in the assessment of the severity of PVT and planning therapeutic options for the patients. However, the same remains to be confirmed by future prospective studies.
Table 1Anatomico-functional Classification of Portal Vein Thrombosis in Cirrhosis.
Type 2: Only branch: 2a—one branch and 2b—both branches
•
Type 3: Trunk and branches
Degree of portal venous system occlusion (O, NO)
•
O: Occlusive: No flow visible in PV lumen on imaging/Doppler study
•
NO: Non-occlusive: Flow visible in PV lumen through imaging/Doppler study
Duration and presentation (R, C)
•
R: Recent (first time detected in previously patent PV, presence of hyperdense thrombus on imaging, absent or limited collateral circulation, dilated PV at the site of occlusion)
•
Asymptomatic: (As)
•
Symptomatic: (S), acute PVT features (with or without ABI)
•
Ch: Chronic (no hyperdense thrombus; previously diagnosed PVT on follow-up, portal cavernoma, and clinical features of PHT)
•
Asymptomatic
•
Symptomatic: features of portal hypertension (with or without PHT)
The majority of PVT in cirrhosis are non-occlusive and are found incidentally during routine US, CT, or magnetic resonance imaging (MRI) evaluation. Among those symptomatic, clinical presentation of PVT in cirrhosis varies with the duration of thrombus formation (acute vs. chronic), degree of involvement (occlusive vs. non-occlusive), nature of thrombus (benign vs. malignant), and the underlying liver condition. Partially occlusive acute PVT may be asymptomatic or may present with non-specific features like nausea, vomiting, mild abdominal pain, diarrhea, and loss of appetite. However, complete PVT may present as acute onset abdominal or lumbar pain, with progression over days, without peritoneal signs, and/or with signs of decompensation of underlying chronic liver disease, which include variceal bleeding or ascites.
In case of an extension of acute PVT into the SMV and its branches, the patient may present with abdominal pain and bloody diarrhea due to intestinal ischemia or can present with paralytic ileus or peritonitis due to intestinal infarction.
In a study of cirrhotics with PVT, two-third of the symptomatic patients presented with portal hypertensive bleed and one-third with abdominal pain. Among 14 patients with abdominal pain, ten patients had intestinal infarction, of which four patients died.
As intestinal infarction is associated with a high mortality rate, patients presenting with the above symptoms should undergo surgical evaluation as bowel resection could be indicated.
Cirrhotic patients with worsening of clinical status in the forms of development of new-onset ascites, or diuretic resistant ascites, or bacterial peritonitis should be evaluated for PVT. Recently, PVT precipitating acute-on-chronic liver failure (ACLF) has been proposed as a novel concept.
APASL ACLF Research Consortium (AARC) for APASL ACLF working Party. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update.
Acute PVT is associated with a reduction of hepatic blood flow, which may lead to ischemic liver injury, thus, precipitating an ACLF. Also, ACLF may be associated with systemic inflammation and endotoxemia, which predisposes to vascular thrombosis.
In the absence of PV recanalization after the development of acute PVT, venous collaterals are formed after a period of 3–5 weeks to bypass the obstructed portion of PV, known as portal cavernoma.
This network of collateral PVs characterizes chronic PVT. However, due to the presence of prior portal hypertension and collaterals, it is difficult to determine whether PVT is acute or chronic in a cirrhotic. Chronic PVT is asymptomatic in most cases. It clinically presents with features of portal hypertension, including gastroesophageal varices with or without bleeding, splenomegaly, and hypersplenism. Among cirrhotics with or without PVT, a higher risk of variceal bleeding has been reported in the former group,
A pretest probability assessment tool for PVT in cirrhosis has been proposed by Sarin et al. which is based on three major and seven minor criteria (Table 3).
The presence of two major or one major and two minor or four minor criteria indicates a high probability of PVT in cirrhosis. However, the pretest scoring system requires assessment and validation in prospective clinical studies.
Table 3Pretest Probability Assessment Tool for PVT in Cirrhosis.
Underlying chronic liver disease and typical imaging characteristics are needed to diagnose PVT in cirrhosis.
Ultrasound
Doppler US is the first-line investigation in a suspected case of PVT in cirrhosis, as it is rapid, inexpensive, and widely available. The grayscale US allows determination of the age of thrombus as acute thrombus appears hypoechoic compared to subacute to chronic thrombus, which has an iso- or hyperechoic appearance within the PV due to thrombus organization. The addition of a Doppler helps in the estimation of the degree of the thrombus (occlusive vs. non-occlusive), the extent of the thrombus, and the presence of collaterals.
Visualization of multiple serpiginous para-portal collaterals indicates a diagnosis of portal cavernoma, which is highly suggestive of chronic PVT. Doppler also helps differentiate bland PVT from a tumoral thrombosis, with the latter showing color Doppler flow and arterial waveforms (often hepatofugal in direction).
Assessment of portal venous system patency in the liver transplant candidate: a prospective study comparing ultrasound, microbubble-enhanced colour Doppler ultrasound, with arteriography and surgery.
However, the presence of ascites, obesity, and bowel gas may obscure the evaluation of all of these parameters, which warrants the use of cross-sectional imaging for confirmation of diagnosis and staging of PVT.
Contrast-enhanced Computed Tomography
The gold standard imaging method for diagnosing PVT is the contrast-enhanced CT scan due to its excellent spatial resolution of vascular anatomy. Also, it allows assessment of the involvement of the mesenteric venous system, bowel ischemia, and associated malignancy. On an unenhanced scan, acute PVT appears as increased attenuation in the PV and may be dilated, while on a contrast-enhanced scan, it appears as a low-density central zone surrounded by an intense peripheral enhancement. Inflammatory response of the PV wall causing enhancement of the vasa vasorum or patchy flow around the thrombus is responsible for this peripheral enhancement. Associated hepatic perfusion changes can also be seen in the form of increased hepatic parenchymal enhancement in the arterial phase and reduced enhancement during the portal phase.
Characterization of portal vein thrombosis (neoplastic versus bland) on CT images using software-based texture analysis and thrombus density (Hounsfield units).
The most common radiological manifestation of bowel ischemia in PVT is bowel wall thickening due to submucosal edema or hemorrhage, which appears as alternating areas of high- and low-density giving rise to a target sign.
Bowel wall infarction is suggested by the triad of mesenteric vein hypodensity, bowel wall thickening, and ascites. Other less common findings include bowel dilatation due to aperistalsis, intestinal pneumatosis, and portal venous gas due to dissection of intramural gas into the venous system by bowel infarction.
Differentiation of tumoral thrombosis from bland thrombosis in a cirrhotic is essential to both decisions regarding further management of HCC and determination of LT candidacy. Previous studies have reported that neovascularity of PV thrombus, arterial phase hyperenhancement with rapid venous washout, direct invasion by adjacent hepatic mass, and PV diameter of ≥23 mm have been associated with malignant PVT.
A-VENA criteria have been recently proposed by Sherman et al. with 100% sensitivity and 93.6% specificity when three or more of the following features are present: AFP ≥ 1000 ng/dL; Venous expansion; thrombus Enhancement; Neovascularity; and PVT Adjacent to HCC.
On MRI, acute PVT is seen as an area of abnormal signal within the lumen of the PV. Acute thrombus shows hyperintensity compared to the hepatic parenchyma or the surrounding muscle in both T1-and T2-weighted images.
Although MRI is not widely used to assess PVT, it is a helpful modality for the differentiation of malignant PVT from bland PVT. Apart from the standard multiphasic postcontrast imaging, diffusion-weighted imaging (DWI) has been evaluated for differentiating benign from malignant PVT. On DWI, tumor thrombi appear hyperintense on DWI and hypointense on the apparent diffusion coefficient (ADC) map, which is similar to the adjacent primary tumor.
However, results are conflicting about the utility of DWI for the diagnosis of malignant PVT, and thus, more extensive studies are required before recommending DWI for evaluation of suspected malignant PVT.
Differentiation of malignant thrombus from bland thrombus of the portal vein in patients with hepatocellular carcinoma: application of diffusion-weighted MR imaging.
Usefulness of conventional MRI sequences and diffusion-weighted imaging in differentiating malignant from benign portal vein thrombus in cirrhotic patients.
MRI in differentiating malignant versus benign portal vein thrombosis in patients with hepatocellular carcinoma: value of post contrast imaging with subtraction.
In patients without cirrhosis, acute PVT may either resolve or undergo a cavernous transformation of PV. However, PV flow stasis in patients with cirrhosis prevents collateral channel dilatation, and hence, portal cavernoma is uncommon in cirrhosis.
PVT in cirrhosis may undergo regression/resolution, may remain stable, or have progression. Data regarding each of these outcomes are variable. Maruyama et al. reported improvement in 47.6%, unchanged status in 45.2%, and progression in 7.2%.
However, the majority of the patients in these studies were compensated cirrhotics. A meta-analysis comparing the effect of the anticoagulant therapy vs. no treatment in patients with cirrhosis and PVT reported a recanalization and complete recanalization rate of 42% and 33% respectively.
Hence, patients should continue to monitor the PV patency even after spontaneous PV recanalization. Figure 3 summarizes the natural history of PVT in cirrhosis.
Figure 3Natural history of portal vein thrombosis in cirrhosis.
Impact of PVT on Complications/Outcomes in Patients with Cirrhosis
The effects of PVT on the natural history of cirrhosis have been extensively debated. Theoretically, the development of PVT in a patient with cirrhosis will further worsen portal hypertension leading to further complications. However, multiple studies have shown that the presence of PVT may not influence the outcome of patients with cirrhosis.
Patients with cirrhosis may already have extensive portosystemic collaterals with very low or absent hepatopetal portal blood flow, and the development of PVT may be of no consequence. In a study of the long-term outcome of PVT in cirrhosis, patients with progressive PVT had worsening of ascites compared to those without PVT. However, the cumulative survival rate was similar between both groups.
Patients with PVT had lower mortality than those without PVT in another large dataset derived from the United Network for Organ Sharing (UNOS) registry of patients awaiting LT.
Other studies have shown a negative impact of the development of PVT in patients with cirrhosis. In a large retrospective study, the prevalence of PVT in patients with cirrhosis and acute decompensation was significantly higher than cirrhotics without acute decompensation, and a substantially higher proportion of patients with PVT had variceal bleeding compared with those without PVT.
According to another study, 39% of cirrhotic patients diagnosed as newly suffering from PVT presented with gastrointestinal (GI) bleeding related to portal hypertension.
Regarding the outcome of treatment of PVT in cirrhosis, multiple studies have reported improvement in the clinical status by reducing portal pressure and reducing the risk of decompensation.
In a study evaluating the long-term outcome of cirrhotics with SVT, the anticoagulation therapy was found to increase the likelihood of vessel recanalization and reduce the risk of mortality in decompensated cirrhosis without increasing the risk of bleeding.
A recent meta-analysis also concluded that anticoagulation in SVT improved recanalization and reduced the risk of progression of thrombus, major bleeding, and overall mortality.
Although anticoagulation in cirrhotics with PVT has been reported to improve the outcome, cirrhotic patients without PVT also benefit from anticoagulation. In a randomized controlled trial (RCT) by Villa et al., the use of anticoagulation for 1-year was associated with a reduction in hepatic decompensation and improvement in survival. A reduction in bacterial translocation and liver inflammation has been suggested as a possible explanation for this improvement rather than a decrease in the incidence of PVT.
Hence, prospective studies with a large cohort are required to substantiate this postulation further.
Impact of PVT on Liver Transplant Outcomes
Significant increases in operative technical difficulties, rate of re-thrombosis, graft loss, and mortality have been observed in cirrhotics with PVT undergoing LT.
Portal vein thrombosis is a risk factor for poor early outcomes after liver transplantation: analysis of risk factors and outcomes for PV thrombosis in waitlisted patients.
However, with the advances in medical management and surgical techniques, this poor outcome is limited to only patients with advanced PVT, and if physiologic flow to the graft is maintained during surgery, mortality is similar, irrespective of the presence of PVT during the operation.
In a meta-analysis, pre-LT PVT, especially complete PVT, reduced the 1-year survival rate after LT. However, a meta-analysis of high-quality studies and studies in which LT was performed after 2000 did not show any significant difference.
Association between portal vein thrombosis and survival of liver transplant recipients: a systematic review and meta-analysis of observational studies.
J Gastrointestin Liver Dis.2015 Mar; 24 (51-9, 4 p following 59)
Subsequently, another meta-analysis reported that patients with PVT had higher 30-days and 1-year mortality than those without PVT, and patients with complete PVT had higher 30-days and 1-year mortality compared to those with partial PVT.
PV thrombosis with extension into SMV poses a different challenge. Failure to perform end-to-end PV anastomosis in these patients leads to non-anatomical portal anastomoses (cavoportal hemitransposition; renoportal anastomosis; PV arterialization), which have been associated with poor outcomes.
Hence, cirrhotics with portomesenteric thrombosis should be referred to high-volume transplant centers with expertise in managing this specific group.
The presence of PVT before LT is a risk factor for the development of PVT in the post-LT period. It has reduced from 36% in previous days to 2–3% in recent years.
Multiple factors determine the rate of re-thrombosis, which include higher degree and extent of pre-LT PVT, severe pre-LT portal hypertension, extensive portosystemic collaterals, donor and recipient PV size mismatch, severe graft edema, non-anatomical anastomosis, and pediatric transplantation.
The decision to treat a PVT in cirrhosis is determined by the age and extent of thrombus, the presence of symptoms, and the patient's transplant status. A patient of liver cirrhosis developing acute PVT either can have prior significant portal hypertension with varices or may not have clinically significant portal hypertension. In the former scenario, the rapid development of ascites, variceal bleeding, and bowel ischemia can adversely affect the clinical outcome and require early intervention.
The clinical outcome in such patients is also determined by the Child status, presence of collaterals, and the rapidity of increase in HVPG. Early prevention (with beta-blockers) and endoscopic management of variceal bleed are indicated and need to be tailored on a case-to-case basis against the need to initiate the anticoagulant therapy. The role of interventional procedures to unblock the occluded PV is still not established.
The main goal of the anticoagulation therapy is recanalization and prevention of thrombus extension, which may adversely affect the surgical outcome. Hence, the Baveno VI guidelines recommend the anticoagulation therapy in potential LT candidates with PVT to facilitate liver transplantation and reduce posttransplant morbidity and mortality.
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
The Shanghai consensus for the management of PVT in cirrhosis recommends the anticoagulation therapy for patients with acute symptomatic PVT, patients listed for liver transplantation, and extension of thrombus into the SMV.
Hepatobiliary Disease Study Group Chinese Society of Gastroenterology, Chinese Medical Association. Consensus for management of portal vein thrombosis in liver cirrhosis (2020, Shanghai).
These recommendations are based on multiple cohort studies showing the efficacy and safety of anticoagulation in cirrhotics with PVT. Meta-analyses of these studies have shown that the use of the anticoagulation therapy for PVT in cirrhosis is associated with a PV recanalization rate of 66–71%, a complete PV recanalization rate of 41.5–53%, and thrombus progression in 5.7–9%.
Currently available treatment options for PVT include vitamin K antagonists (VKAs), low molecular weight heparin (LMWH) as well as direct-acting oral anticoagulants (DOACs), with LMWH being the initial anticoagulant of choice. However, each of these agents has its advantages and disadvantages. Warfarin is the main type of VKA used with close monitoring of international normalized ratio (INR) to maintain it in the range of 2–3.
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.
However, patients with end-stage liver disease can still have a high INR in the absence of warfarin use, and thus, monitoring becomes difficult. Additionally, elevated levels of INR in conjunction with VKA increase the Model for End-Stage Liver Disease (MELD) score, which is used widely in several countries to determine organ allocation. The genotype of the patient also determines the warfarin dose. Mutations in genes for vitamin K epoxide reductase complex 1 (VKORC1) and the liver enzyme CYP2C9 are responsible for underdosing or overdosing in patients on VKA, and such mutations have been seen in approximately 45% of patients with BCS, which included cirrhotic patients.
LMWH is the most commonly used anticoagulant in the setting of acute PVT, with the advantages being fixed dosing and no requirement for laboratory monitoring. However, low levels of antithrombin III in patients with advanced cirrhosis may lead to unpredictable responses and daily subcutaneous injections may reduce the patient's compliance.
The presence of renal dysfunction also requires dose modification of LMWH. Short-term therapy with LMWH followed by oral VKA can be given to patients with poor compliance with LMWH. In an RCT of cirrhotics with PVT, a 1-month subcutaneous injection of nadroparin calcium followed by 5-months oral warfarin was found to be effective without increasing the bleeding risk.
Efficacy and safety of nadroparin calcium-warfarin sequential anticoagulation in portal vein thrombosis in cirrhotic patients: a randomized controlled trial.
DOACs, including direct thrombin inhibitor (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), have recently evolved as safe alternatives to VKAs for conditions requiring long-term anticoagulation. DOACs do not require monitoring and can be safely given to patients with mild to moderate renal dysfunction. In a recent RCT of patients with compensated HCV-related cirrhosis and PVT, the use of rivaroxaban was associated with a lower incidence of bleeding and mortality (0% vs. 43.3% and 0% vs. 36.4%, respectively) while achieving higher rates of both complete and partial PV recanalization (85% vs. 45% and 15% vs. 0%, respectively) when compared with warfarin.
However, there is a lack of large-scale data on the safety and efficacy of DOACs in patients with advanced cirrhosis. Defects in various steps of drug metabolism like plasma protein binding, cytochrome p450 function, and biliary excretion due to the underlying cirrhosis can also affect the pharmacokinetics of DOACs. Hence, the use of DOACs is limited to Child A patients, with cautious use in Child B and avoidance in Child C patients.
Faculty of the 7th international coagulation in liver disease. Concepts and controversies in haemostasis and thrombosis associated with liver disease: proceedings of the 7th international coagulation in liver disease conference.
Data regarding the timing of anticoagulation after diagnosis of PVT in cirrhosis are scarce. In a study, initiation of early anticoagulation within a week was associated with a higher rate of recanalization (62.5% vs. 18.18%, P < 0.05).
Early initiation of the anticoagulation therapy within 2 weeks of diagnosis of PVT was the only significant factor associated with recanalization in another study.
However, Amitrano et al. reported a high rate of recanalization (75%) despite the anticoagulation therapy being delayed by 4 months for 50% of the patients.
Hence, delayed anticoagulation is still beneficial in cirrhotic PVT requiring anticoagulation. Further RCTs are required to make a recommendation regarding the optimal timing of initiation of anticoagulation.
Anticoagulation for a duration of at least six months is recommended by the Baveno VI consensus and European Association for the Study of the Liver (EASL) clinical practice guidelines.
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
Even after recanalization of the PV, anticoagulation therapy should be continued for several months or up to LT to reduce the risk of recurrence. Patients with SMV thrombosis or history of intestinal ischemia and necrosis, patients listed for liver transplantation, or those with hereditary prothrombotic states are candidates for long-term anticoagulation.
Hepatobiliary Disease Study Group Chinese Society of Gastroenterology, Chinese Medical Association. Consensus for management of portal vein thrombosis in liver cirrhosis (2020, Shanghai).
Studies have shown that the majority of recanalization occurs within six months. However, for patients failing to achieve so, the duration of therapy can be extended to one year.
Because the mechanisms that initially caused the thrombosis might remain unchanged, it is reasonably possible for re-thrombosis to occur after discontinuing the anticoagulation treatment. Hence, patients should be followed up with interval imaging 3–6 months after the first diagnosis and every 6 months thereafter to assess for response to therapy and even after stopping the therapy to assess for recurrence.
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
The chief concern of anticoagulant use in cirrhotic patients is the risk of bleeding, especially from varices. In a meta-analysis, the proportions of patients with major or minor bleeding were similar between cirrhotic patients with PVT who received anticoagulants and those who did not receive. The rate of spontaneous variceal bleeding was lower in patients who received the anticoagulation therapy.
However, cirrhotic patients receiving the anticoagulation therapy for other indications apart from PVT have been found to have a higher risk of variceal bleeding.
Although the use of anticoagulation does not increase the risk of variceal bleeding significantly, the risk still remains. Hence, patients should be screened for variceal status, and adequate prophylaxis for prevention of gastrointestinal bleeding in the form of NSBBs or band ligation should be used before initiation of anticoagulation therapy.
Early endoscopy should be performed in patients presenting with gastrointestinal bleeding for identification of the source of bleeding (variceal vs. non-variceal), and standard treatment guidelines should guide further management. Development of life-threatening bleed warrants immediate discontinuation of anticoagulation therapy with prompt initiation of rescue treatment along with the use of antagonists.
2020 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American college of cardiology solution set oversight committee.
Major bleeding is defined as one involving a critical site, associated hemodynamic instability, hemoglobin decline by ≥ 2 g/dL, or requirement of ≥2 units of red blood cell transfusion. Failure of resolution of major bleeding with the initial management of development of life-threatening bleeding warrants the use of reversal agents. However, they should not be used for patients with a non-major bleeding event.
Anticoagulant
Reversal agent
Vitamin K antagonist (VKA)
Intravenous vitamin K and four-factor prothrombin complex concentrate (4f-PCC) (25–50 U/kg) are advised for reversalFresh frozen plasma can be used if a 4f-PCC is not available
Low molecular weight heparin (LMWH)
Protamine sulfate reverses most, but not all, of the effects of LMWHIf protamine is given within 8 h of the last LMWH dose, use 1 mg protamine/100 units of LMWHA dose of 0.5 mg protamine/100 units of LMWH is given if protamine is given more than 8 h after the last LMWH dose
Dabigatran
Idarucizumab 5 mg IV should be used for reversalPCC or activated PCC can be used if idarucizumab is not available
Factor Xa inhibitors
Andexanet alpha is recommended for reversalPCC can be used if andexanet alpha is not available
Thrombolysis in PVT can be achieved by either a local or systemic approach. Therapeutic agents used for thrombolysis include streptokinase, urokinase, or recombinant tissue plasminogen activator (rTPA). Local approaches include the percutaneous transhepatic, transjugular, or transmesenteric route. Indirect thrombolysis can be achieved via the superior mesenteric artery (SMA) approach. Systemic thrombolysis is performed by continuous intravenous infusion of a thrombolytic agent combined with LMWH.
and there is a paucity of data regarding the safety of thrombolysis in patients with cirrhosis. In a small study of nine cirrhotic patients who received a continuous intravenous infusion of rTPA with LMWH for a maximum of 7 days, four patients achieved complete recanalization with partial recanalization in another four.
In a study of 40 cirrhotic patients with acute PVT, randomized to urokinase infusion through SMA vs. TIPS, both procedures had significant improvement in PV patency without any difference between the two procedures.
Clinical outcomes of transcatheter selective superior mesenteric artery urokinase infusion therapy vs transjugular intrahepatic portosystemic shunt in patients with cirrhosis and acute portal vein thrombosis.
However, owing to their potential risk of complications, thrombolysis cannot be recommended at present in cirrhotics with acute PVT.
Mechanical Recanalization
The options include mechanical thrombectomy and balloon angioplasty of the PV, which can also be combined with local thrombolysis. Small studies have reported a 100% success rate with combined mechanical and pharmacological thrombolysis without bleeding complications.
Percutaneous transhepatic balloon angioplasty and/or stent placement has been studied in patients with postoperative PV and SMV thrombosis with 93% technical success and a re-thrombosis rate of 43% at 16.3 months.
TIPS involves the creation of a low-resistance pathway for blood flow from an intrahepatic portion of PV to hepatic veins through the placement of a stent. The technical complexity of the procedure increases in the presence of PVT (narrowing or occlusion of intrahepatic branches of the PV) or in the presence of cavernoma. However, over the years, advances in interventional techniques have allowed stent placement through transsplenic or transhepatic routes with an increasing technical success rate.
The present indications of TIPS for PVT in cirrhosis include (1) inadequate response to or contraindication of anticoagulation and (2) recurrent variceal bleeding and/or refractory ascites, which cannot be managed medically or endoscopically.
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.
Hepatobiliary Disease Study Group Chinese Society of Gastroenterology, Chinese Medical Association. Consensus for management of portal vein thrombosis in liver cirrhosis (2020, Shanghai).
In a recent meta-analysis, the technical success rate of TIPS was reported to be 95% in cirrhotics and PVT, with a one-year recanalization rate of 79% and a patency rate of 84%.
PV recanalization followed by TIPS (PVR-TIPS) has been used in LT candidates with chronic PVT, allowing physiological anastomosis between the graft and recipient PV.
In a retrospective study, access of thrombosed PV through the transsplenic route was found to be superior to the transhepatic approach with a higher success rate and a lower rate of adverse events.
Pretransplantation PV recanalization and transjugular intrahepatic portosystemic shunt creation for chronic portal vein thrombosis: final analysis of a 61-patient cohort.
In addition, those cirrhotics with advanced PVT and recurrent bleeding and/or refractory ascites can also benefit from TIPS-PVR after the failure of medical or endoscopic therapy.
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.
However, more data are needed about the potential utility of TIPS-PVR in patients with chronic PVT. Figure 4 provides the algorithm for management of non-tumoral PVT in cirrhosis.
Figure 4Approach to management of portal vein thrombosis in cirrhosis.
PVT is a common phenomenon in patients with liver cirrhosis and is being increasingly recognized due to increased radiological techniques. The principal diagnostic consideration is to differentiate benign PVT from tumoral PVT. It is controversial whether PVT impacts the natural history of cirrhosis. However, in a subset of the population, it can lead to complications and warrants timely management to prevent these complications. In patients with PVT leading to life-threatening conditions, management should be aggressive, including newer radiological techniques for recanalization.
Credit authorship contribution statement
Akash Shukla: Conceptualization, Methodology, Supervision, Reviewing and Editing. Suprabhat Giri: Data curation, Writing - Original draft preparation, Software, Visualization, Writing - Reviewing and Editing.
Conflicts of interest
The authors have none to declare.
Financial disclosures
None.
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Clinical outcomes of transcatheter selective superior mesenteric artery urokinase infusion therapy vs transjugular intrahepatic portosystemic shunt in patients with cirrhosis and acute portal vein thrombosis.
Pretransplantation PV recanalization and transjugular intrahepatic portosystemic shunt creation for chronic portal vein thrombosis: final analysis of a 61-patient cohort.
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