Clinical significance of portal vein thrombosis in patients with decompensated cirrhosis: A still matter of debate

Introduction

Portal vein thrombosis (PVT) is an uncommon yet clinically important complication in liver cirrhosis progression. Its prevalence varies widely, ranging from 2% to 40%, and increases with disease severity.^[1] The interplay between reduced portal blood flow velocity and the altered coagulation dynamics characteristic of cirrhosis is central to the pathogenesis of PVT. However, the prognostic implications of PVT in cirrhosis remain controversial, especially in acute variceal bleeding (AVB), prompting debate on its inclusion as a ‘high-risk’ factor for preemptive transjugular intrahepatic portosystemic shunt (TIPS) placement.

The clinical significance of PVT may be more complex than previously thought and may be more than just an independent prognostic factor. Balancing the benefits of anticoagulation therapy with the increased risk of bleeding in patients with advanced cirrhosis underscores the complexity of treatment decisions. Current therapeutic options, including anticoagulants, thrombolysis, and TIPS, vary in efficacy and safety, necessitating careful patient selection and multidisciplinary evaluation.

Risk factors of PVT in cirrhosis

The pathophysiology of PVT involves multiple factors aligning with Virchow’s triad: blood stasis, increased coagulability, and damage to the endothelium. However, its specific mechanisms in cirrhosis are less well defined. Patients with decompensated cirrhosis exhibit a more precarious coagulation balance, tilting toward hypercoagulability, than do those with compensated cirrhosis. The incidence of PVT is less than 1% in compensated cirrhosis but increases to 7.4%–16% in decompensated patients.^[2] The risk factors of PVT in cirrhosis are presented in Figure 1.

Figure 1

Algorithmic management and risk factors associated with PVT in decompensated cirrhosis. The figure was created with BioRender.com.

A portal vein (PV) blood flow velocity of less than 15 cm/s independently predicts PVT development, likely due to blood stasis. Additionally, large portosystemic collaterals, which can divert blood flow from the PV, increase PVT risk.^[3] While the use of nonselective β-blockers for variceal bleeding prophylaxis may also increase the risk of PVT, this effect is likely attributable more from the severity of portal hypertension than the medication itself.^[4]

Although congenital and acquired thrombophilia are recognized risk factors for noncirrhotic PVT, current guidelines do not recommend routine screening for these disorders in cirrhotic patients.^[5] Recent research has not demonstrated a direct association between prothrombotic factors, whether genetic or acquired, and PVT in cirrhosis patients. Genetic mutations like Factor V Leiden and prothrombin G20210A may elevate PVT risk in cirrhotic patients. Assessing inherited deficiencies of natural anticoagulant proteins like protein C, protein S, or antithrombin III in cirrhotic patients is challenging due to liver synthetic dysfunction, and their link to PVT development remains unclear. The role of other acquired prothrombotic disorders in cirrhotic PVT, such as myeloproliferative disorders and antiphospholipid syndrome, remains inconclusive.

Bacterial translocation, inflammation, and endotoxemia, frequently observed in cirrhosis due to portal hypertension, can worsen endothelial damage and promote PVT formation. Cirrhotic patients face a heightened risk of bacterial infections due to impaired immune function and frequent exposure to bacteria from enteric translocation and gut dysbiosis. These infections can lead to chronic systemic inflammation, which not only affects the liver but also predisposes patients to splanchnic thrombosis. Lipopolysaccharide (LPS), a component of gram-negative bacteria, can activate platelets, leukocytes, and endothelial cells involved in thrombosis, increasing PVT risk in cirrhotic patients.

Influence of PVT on prognosis

The prognostic implications of PVT in cirrhosis remain controversial. Occlusive PVT can be a marker of decompensated cirrhosis, given its role in exacerbating portal hypertension and diminishing hepatic blood flow. PVT in decompensated cirrhosis not only increases variceal hemorrhage rates but also leads to longer times to eradicate varices and a propensity for rebleeding. Conversely, some studies report no differences in outcomes between patients with and without PVT. A multicenter prospective longitudinal study found that PVT development did not contribute to liver disease progression or increased mortality in cirrhosis patients.^[6] The presence of PVT may be associated with the natural course of cirrhosis, not just its direct consequence. While PVT may worsen portal hypertension in noncirrhotic livers, its effects on cirrhosis are less straightforward.

Prior to PVT development, significant portal pressure increases due to fibrosis nodule formation and sinusoidal remodeling can reduce portal flow velocity and lead to portosystemic collateral formation. Consequently, the eventual occurrence of PVT might minimally affect portal pressure due to the pre-existing extensive portosystemic collaterals. The impact of occlusive PVT on prognosis may be greater, as partial PVT may be resolved spontaneously during the course of the disease. This complexity necessitates individualized prognostic assessments on the basis of cirrhosis severity and the extent of thrombosis.

Anticoagulation therapy

With the rising incidence of PVT correlating with the severity of liver disease, the clinical challenge lies in identifying patients who will gain the most from anticoagulation treatment. Partial thrombosis of PVT is common in cirrhosis patients, typically resulting in less than 50% luminal occlusion, with spontaneous resolution observed in two-thirds of cases during follow-up. For patients with thrombosis affecting less than 50% of the portal vein trunk and/or branches, it is advised to conduct follow-up abdominal ultrasounds with Doppler every three months to monitor thrombus progression or resolution.^[5] For patients with chronic complete blockage of the main portal vein or cavernous transformation of portal vein (CTPV) with developed collaterals, anticoagulant or interventional therapy has no proven benefit, and treatment should focus on managing portal hypertension complications (Figure 1).

Low-molecular-weight heparin (LMWH) and vitamin K antagonist (VKA) are primary treatments for patients with cirrhosis and PVT, though patient profiling remains essential. As achieving an international normalized ratio of 2 to 3 may be difficult during the use of VKA, direct oral anticoagulants (DOACs) are increasingly considered an alternative, supported by cohort studies demonstrating their efficacy and safety. A meta-analysis of cirrhotic patients using DOACs indicated a low bleeding risk, which correlates with age, treatment duration, and CTP class.^[7]

Anticoagulation significantly decreases all-cause mortality compared to no treatment, with this advantage being independent of PVT recanalization. In a study of 19, 524 liver cirrhosis patients with PVT, those receiving anticoagulation therapy (n = 4, 224) exhibited significantly lower mortality rates compared to those who did not receive such treatment (27.9% vs. 34.2%). Compared with the VKA group, the DOACs group presented significantly lower mortality rates (17.7% vs. 26.5%).^[8] A small prospective randomized controlled trial demonstrated that enoxaparin, compared to placebo, effectively prevented PVT development in high-risk cirrhosis patients, while also enhancing survival and reducing decompensation risk over a 1-year period.^[9]

To minimize bleeding risks, it is crucial to screen and manage varices before starting anticoagulation. If necessary, initiate primary or secondary prophylaxis for variceal bleeding prior to anticoagulation. Recent AASLD guidelines indicate that endoscopic band ligation is safe with therapeutic anticoagulation, suggesting that anticoagulant therapy should not be postponed until varices are eradicated, despite the lack of consensus on this recommendation.^[5] Anticoagulation significantly reduces the incidence of variceal bleeding in cirrhosis patients with PVT compared to untreated individuals, underscoring its role in preventing future decompensation.

The pathophysiology of PVT is distinct from systemic venous thrombosis, as many patients exhibit tunica intima thickening instead of fibrin-rich thrombus, potentially accounting for the reduced recanalization rates with anticoagulant treatment^[10] This finding explains the limitations of anticoagulant therapy in certain patients; however, further research is required to validate this new paradigm in PVT pathophysiology.

Intravascular therapy

Thrombolysis, which is commonly employed in other venous thrombosis cases, has demonstrated efficacy in cirrhosis-associated PVT but is associated with bleeding risk. Current guidelines do not routinely recommend thrombolysis for recent or acute PVT unless intestinal ischemia persists despite anticoagulation.^[5] When performed within a specific timeframe from the onset of thrombosis, thrombolytic therapy can lead to improved outcomes in selected patients. Local thrombolysis can be achieved directly by the percutaneous transhepatic, transjugular, or transmesenteric routes, or indirectly through the superior mesenteric artery with access from the radial or femoral arteries.

TIPS offers an alternative approach, creating a low-pressure pathway to bypass the portal vein and alleviate complications related to portal hypertension. The TIPS can be positioned in either a recanalized main portal vein or a dominant collateral. Although TIPS primarily targets complications like variceal bleeding and refractory ascites, it is not specifically designed for thrombus recanalization. A recent meta-analysis verified the safety and effectiveness of TIPS for PVT recanalization, achieving technical success rates around 95%. TIPS with portal vein recanalization (TIPS-PVR) can be especially advantageous for liver transplant candidates or patients with occlusive PVT or CTPV experiencing recurrent bleeding or refractory ascites unmanageable by medical or endoscopic means. Post-TIPS anticoagulation remains controversial. TIPS alone may enhance recanalization by increasing splanchnic blood flow velocity, and anticoagulation is typically preferred for extensive thrombosis, particularly when the superior mesenteric vein is affected.

Future directions and knowledge gaps

Despite recent advancements, substantial gaps persist in the management of PVT in patients with decompensated cirrhosis. The optimal timing, duration, and therapeutic strategies remain unclear, particularly for novel anticoagulants and emerging interventions. Reliable biomarkers to stratify thrombotic risk and predict treatment outcomes are urgently needed. Future research should explore the mechanistic underpinnings of PVT in cirrhosis, focusing on factors such as endothelial dysfunction, bacterial translocation, and systemic inflammation. These studies will be instrumental in developing personalized management approaches and improving long-term patient outcomes.