Current clinical research status and future treatment directions for liver cirrhosis combined with portal vein thrombosis

Abstract

Portal vein thrombosis (PVT) is one of the most common serious complications in patients with liver cirrhosis. The occurrence of PVT not only aggravates the condition of liver cirrhosis but can also cause several serious complications, such as portal hypertension, esophagogastric variceal bleeding, and refractory ascites. All these factors have a serious impact on patients’ quality of life and prognosis. This article evaluates the current evidence on the management of PVT in cirrhosis and explores the role of direct oral anticoagulants, but data on individualized anticoagulation strategies are limited and lacking for the treatment of PVT in cirrhosis, and it is hoped that it will inform a broad range of clinicians on the treatment of cirrhosis combined with PVT.

Key Words: Liver cirrhosis; Portal vein thrombosis; Anticoagulation; Edoxaban; Direct-acting oral anticoagulants; Portal hypertension; Thrombolysis

Core Tip: Portal vein thrombosis represents a significant complication of liver cirrhosis and contributes to the exacerbation of portal hypertension and results in severe clinical outcomes including oesophageal variceal bleeding and refractory ascites. This review presents a comprehensive overview of the aetiology, diagnosis, clinical manifestations, and treatment options for portal vein thrombosis in cirrhotic patients. Furthermore, this highlights the emerging role of direct oral anticoagulants, such as edoxaban, which offer promising therapeutic potential because of their efficacy, safety, and convenience. Future research should address individualized treatment strategies to optimize the balance between anticoagulation benefits and bleeding risks, which improves patient prognosis.

INTRODUCTION

Portal vein thrombosis (PVT) is among the most common serious complications in patients with liver cirrhosis. PVT not only aggravates liver cirrhosis[1] but can also cause several serious complications such as portal hypertension, esophagogastric variceal bleeding, and refractory ascites. All of these factors strongly affect the quality of life and prognosis of patients. This article evaluates the current evidence on the management of PVT in patients with cirrhosis and explores the role of direct oral anticoagulants (DOACs). However, data on individualized anticoagulation strategies for the treatment of PVT in patients with cirrhosis are limited and lacking, and it is the hope that this review will inform a broad range of clinicians on the treatment of cirrhosis combined with PVT. To systematically review the current research status and therapeutic progress of cirrhosis combined with PVT; summarize its aetiology, diagnosis, clinical manifestations and therapeutic strategies; and discuss the progress and future direction of current therapeutic research to provide reference information for clinical diagnosis and treatment. This study comprehensively collected and analyzed the relevant literature at home and abroad. This information was combined with clinical research data and guideline consensus, pathological mechanisms, diagnostic methods (e.g., imaging tests and laboratory indices), clinical manifestation characteristics and therapeutic means (including anticoagulant therapy, interventional therapy, liver transplantation, etc.) of liver cirrhosis combined with PVT, which can be systematically summarized and analyzed. Moreover, limitations of existing treatment options and emerging research directions (such as anticoagulant optimization, thrombolytic technology, and targeted therapy) are discussed. Results revealed that the main cause of PVT in combination with cirrhosis is the haemodynamic factors; the main diagnostic method is ultrasound, and the core therapeutic strategy is anticoagulation, which significantly reduces all-cause mortality and improves prognosis. New oral anticoagulants (DOACs), such as edoxaban, have become a hot research topic because there is no need to monitor the international normalized ratio, and there is a low risk of bleeding and a low degree of hepatic metabolism dependence. Anticoagulation in cirrhosis combined with PVT requires balancing efficacy with bleeding risk, which is particularly challenging in the context of coagulation disorders in cirrhotic patients. In the future, genetic testing and multifactorial prediction models are needed to optimize individualized drug regimens to accurately assess drug metabolism and dose adjustment. DOACs, such as edoxaban, are promising for use in patients with cirrhosis combined with PVT, but larger clinical trials are needed to validate their long-term safety.

CAUSES OF COMBINED PVT IN PATIENTS WITH LIVER CIRRHOSIS

PVT involves thrombosis in the main trunk of the portal vein and/or the left and right branches of the portal vein with or without thrombosis in the mesenteric vein and splenic vein[2]. Its formation constitutes a complex pathological process involving the interplay of multiple factors. In patients with cirrhosis, alterations in portal vein haemodynamics serve as a crucial foundation for the emergence of PVT. Studies have revealed that a specific risk factor for PVT is blood flow velocity in the main trunk of the portal vein that is lower than 15 cm/second[3]. Beyond the main trunk of the portal vein, blood flow velocity in the largest collateral vein above 10 cm/second or blood flow above 40 mL/minute is also considered a high risk factor for PVT[4]. Bleeding disorders are also extremely important. The ratio of factor VIII to natural anticoagulants and protein C in patients with cirrhosis and PVT is significantly elevated and it is regarded as a marker of high coagulability in patients with cirrhosis and significantly increases the risk of thrombosis[5]. The severity of cirrhosis and the prediction of PVT development can also be indirectly reflected by this ratio[6]. The formation of PVT is closely associated with inflammatory and immune mechanisms[7]. Inflammatory responses facilitate thrombosis by activating inflammatory cells, damaging endothelial cells, and activating the nuclear factor kappa B signalling pathway[8]. Immune mechanisms also play crucial roles in the occurrence and development of PVT through the involvement of immune cells, activation of platelets, and induction of immune responses in the vessel wall. Thus, the development of PVT involves multiple factors, and the occurrence of PVT in patients with cirrhosis is related mainly to haemodynamic factors, which is also the conclusion drawn from numerous experimental studies. Some reports also suggest that genetic and metabolic factors are related to this disease[9]. Deficiencies in proteins S and C are relatively rare genetic predispositions to thrombosis[10], and this outcome predisposes the organism to a hypercoagulable state, which increases the likelihood of the disease. Additionally, there is evidence that infection with severe acute respiratory distress syndrome corona virus-2 induces PVT[11]. Additionally, certain hereditary thrombosis diseases and gene mutations may also increase the risk of PVT in patients with cirrhosis. With respect to metabolic factors, the caspase-4-dependent activation of neutrophil-gasdermin D promotes the production of neutrophil extracellular traps in cirrhosis[12], which increases the incidence rate of this disease. High homocysteine levels are prevalent among cirrhosis patients with gallbladder disease who undergo laparoscopic cholecystectomy, which might also be a potential pathogenic mechanism.

DIAGNOSIS OF CIRRHOSIS COMBINED WITH PVT

The diagnosis of PVT primarily depends on imaging examinations. All guidelines[13,14] suggest that ultrasound is the preferred screening approach for hepatocellular carcinoma, while PVT is typically an incidental discovery during ultrasound inspection. Portal vein ultrasound is the preferred clinical examination method because it is noninvasive and simple to perform. Furthermore, the use of colour Doppler ultrasound and contrast agents has significantly increased the sensitivity and accuracy of ultrasound in the diagnosis of PVT[15]. Moreover, the use of contrast-enhanced ultrasound has demonstrated high sensitivity in differentiating between benign and malignant PVT[16]. Although ultrasound cannot directly predict the nature of PVT, liver lesions in its vicinity can strongly predict whether it is benign or malignant. Hence, portal vein ultrasound plays an indispensable role in the examination of PVT. Furthermore, portal vein computed tomography angiography or magnetic resonance angiography can also be employed as the main evaluation method for PVT prior to surgical treatment[17], which holds more precise diagnostic significance in the assessment of intestinal ischaemic and necrosis compared to ultrasound. An evaluation prior to vascular intervention can be accomplished via direct or indirect angiography of the portal vein, but it is typically not adopted as a routine examination because of its invasiveness. Overall, a specific examination method should be selected on the basis of an individualized examination plan according to the patient’s actual condition.

CLINICAL MANIFESTATIONS OF CIRRHOSIS COMBINED WITH PVT

Clinical manifestations of cirrhosis combined with PVT can be categorized into chronic and acute symptoms. When the diagnosis of PVT is confirmed, more than half of patients present signs of oesophageal varices or portal hypertension-related gastric diseases. Therefore, chronic symptoms include splenomegaly, gastroesophageal varices, and other complications associated with portal hypertension[18,19]. Furthermore, approximately 30% of cases indicate that potential chronic symptoms of gastrointestinal bleeding[20] may be caused by PVT and lead to rupture of varices. Liver displacement is another clinical manifestation triggered by PVT -induced portal hypertension and splenomegaly. Acute cirrhosis combined with PVT occurs abruptly because of thrombotic occlusion of the portal vein[21], and symptoms, such as abdominal pain, abdominal distension, and ascites, can be observed. Abdominal pain is among the most common symptoms and can be attributed to hepatic ischaemia. Abdominal distension and ascites result from portal hypertension-induced intestinal oedema and ascites. When thrombosis extends to the superior mesenteric vein in acute PVT, the main manifestations are acute abdominal pain and intestinal bleeding due to intestinal ischaemia and necrosis. Both acute and chronic symptoms are clinical manifestations of cirrhosis combined with PVT. When these patients are encountered, their clinical manifestations should be fully analyzed to clarify the type of diagnosis and select the most reasonable and optimal treatment plan.

TREATMENT OPTIONS AND PROGRESSION IN CIRRHOSIS COMBINED WITH PVT

PVT is highly prevalent among patients with cirrhosis and is among the most common complications. If left untreated, this combination can lead to other complications, such as mesenteric ischaemia, chronic cavernous transformation of the liver, and portal hypertension, and can even be life threatening. According to most guidelines and the literature[16,22,23], anticoagulation therapy is the preferred treatment modality and can significantly reduce the overall mortality rate of patients[24]. Hence, regardless of the presence of acute or chronic PVT, anticoagulation therapy is appropriate for reversing or preventing PVT and has certain effects on the treatment of PVT-related complications. For patients with acute PVT, anticoagulation therapy directly[25] recommended to prevent further thrombosis and facilitate recanalization of the obstructed veins. For patients with chronic PVT, anticoagulation is also the undoubted treatment of choice to prevent the progression of portal spongy degeneration and portal hypertension[26]. Although anticoagulation therapy can achieve portal vein recanalization and improve the prognosis of patients with liver diseases, the choice is rather difficult because of the coexistence of hypocoagulable and hypercoagulable states in patients with cirrhosis along with a tendency for bleeding. Common anticoagulant drugs include warfarin, low-molecular-weight heparin, and new oral anticoagulants. For example, direct-acting oral anticoagulants (DOACs)[27-31] have become a hotspot in the research of alternative therapies owing to the convenience of oral administration and no requirement to monitor the international normalized ratio. Moreover, its therapeutic effect on PVT has recently been widely reported[32] and it is gradually becoming more accepted. This is only because it can alleviate the inconvenience caused by traditional injectable drugs but also because it can reduce the risk of bleeding during anticoagulation and does not require monitoring. Additionally, DOACs have no obvious interactions with other drugs, which suggests that DOACs constitute a new anticoagulation treatment option. The American Association for the Study of Liver Diseases indicated[33] that for PVT patients, regardless of whether they have cirrhosis, the use of anticoagulant drugs should last for at least 3 months and DOACs significantly reduce the operational difficulty during this period, which provides greater convenience. Among the DOACs used for treating PVT, edoxaban is the most researched drug[27-29,34,35]. Its metabolic pathway indicates that approximately 50% is metabolized by the kidneys; thus, it is not easily influenced by liver metabolism[36,37] and can be safely used in patients with cirrhosis. We conducted a comprehensive and systematic search on PubMed. To date, few relevant English-language articles have been identified. We also manually explored the reference sections of the extracted articles to retrieve relevant publications. After the aforementioned databases were searched, a total of 16 manuscripts were identified and duplicate studies were excluded. Among these articles, 10 were excluded because of irrelevance, which left 4 that were included (Table 1)[30,38-40]. Overall, Data that were retrieved thus far are not abundant and have several limitations; the sample size is small, and more studies are needed to support these findings. As shown in Table 1, edoxaban resulted in the highest recanalization rate (χ² = 48.5, P < 0.01) and fewer adverse effects (mainly bleeding) (χ² = 7.9, P < 0.05), as the portal vein flow velocity is reduced in patients with cirrhosis with PVT, which might be related to severe deficiency of protein C and result in a local thrombotic environment[38]. Compared with other Xa factor inhibitors[41], edoxaban has high bioavailability and local anticoagulant effects; thus, its bleeding effects are not significant. Studies have indicated[39] that edoxaban is effective when used alone for patients with cirrhosis and PVT and it can prevent thrombosis while preserving liver reserve and improve the prognosis of cirrhosis patients. It can also be applied in the early stage of diagnosis and treatment. The convenience and effectiveness of edoxaban indicates that it likely will become the preferred treatment method in the future. However, while anticoagulation prevents thrombosis or enlargement, it also increases the risk of bleeding[42]. Therefore, in patients who are inherently at risk of coagulation disorders and bleeding, more care should be taken in implementing this treatment. When antithrombotic therapy is complete, interventional treatment, including thrombolysis, vascular intervention, and surgery, can be used as a secondary option for PVT. Thrombolysis, such as portal vein catheter thrombolysis and indirect thrombolysis through the superior mesenteric artery, can be performed directly or indirectly. Transjugular intrahepatic portosystemic shunt is also an effective interventional treatment method that is especially suitable for patients with ineffective antithrombotic therapy or antithrombotic contraindications. Experimental studies have shown that transjugular intrahepatic portosystemic shunt can improve the prognosis of PVT patients[43]. In the above treatments, it is also necessary to monitor and manage related risk factors[44] such as haemoglobin content, platelet count, and prothrombin time. Additionally, appropriate nutritional support and the prevention of complications should be areas of focus.

Table 1 Recanalization ratio and prognosis of patients receiving anticoagulants, n (%).

Ref.	Medicine	Number of patients	Reconnection rate	Adverse reactions
Tadokoro et al[38]	Edoxaban	n = 43	33 (76.7)	7 (16.3)
Zhou et al[39]	Rivaroxaban	n = 52	39 (75.0)	9 (23.1)
Ai et al[30]	Dabigatran + rivaroxaban	n = 39	7 (17.9) (6 months)	2 (5.1) (6 months)
Loffredo et al[40]	Warfarin	n = 353	250 (71.0)	28 (7.9)

The recanalization rate of edoxaban is high compared with that of other anticoagulants, whereas adverse effects (mainly bleeding) are relatively low.

FUTURE OUTLOOK FOR CIRRHOSIS COMBINED WITH PVT

Certain recent advancements have been made in the study of cirrhosis accompanied by PVT. On the one hand, a more comprehensive understanding of the pathogenesis of PVT has provided a solid theoretical foundation for clinical treatment. On the other hand, novel treatment methods and strategies, such as the utilization of DOACs and the advancement of interventional treatment techniques, have emerged and provide additional options for patients with cirrhosis and PVT. Nevertheless, despite the progress achieved in this area, the treatment of cirrhosis combined with PVT still faces numerous challenges. For example, issues such as how to balance the efficacy of anticoagulation treatment against the risk of bleeding, how to optimize the outcome of interventional treatment, and how to formulate individualized treatment plans, are significant directions for future research. With the development of genetic testing technology, molecular imaging technology, etc., it will be possible in the future to more accurately assess a patient’s condition, genetic characteristics, metabolic status, etc., to formulate a complete individualized treatment plan. In accordance with the patient’s specific situation, the treatment method, drug type and dosage should be precisely selected to achieve the best therapeutic effect while minimizing side effects. For example, a more appropriate anticoagulation or thrombolysis regimen may be used for patients with specific genetic characteristics. Predictive modelling can also be attempted[45], where clinical data can be collected from a large number of patients with cirrhosis combined with PVT to establish an accurate predictive model to predict the progression of thrombosis, respond to treatment, and determine the risk of complications in patients. For example, a multifactorial prediction model was established on the basis of the patient’s liver function classification, portal haemodynamic parameters, and coagulation indices. New access therapies, such as more precise local thrombolysis techniques and intravascular thrombus removal techniques, are also worth exploring. These new technologies can more directly and effectively remove portal vein thrombi, restore portal vein blood flow, and reduce portal vein pressure with less trauma to the patient and faster recovery. In the future and with further development and popularization of genetic testing technology, the metabolism ability and responsiveness of patients to DOACs can be more accurately understood through the detection of genes related to drug metabolism and transport such as cytochrome P450 enzyme family genes and drug transporter genes. On the basis of the results of genetic testing, individualized initial dosage and adjustment regimens can be formulated for patients[46], which will avoid underdosage or overdosage due to abnormal drug metabolism caused by genetic differences which will improve the efficacy and safety of treatment. While DOACs show promise, larger trials are needed to validate their safety in cirrhotic patients. The literature we searched was mainly from Western populations and there were fewer Asian populations, and it is possible that there are differences in body mass and more evidence from Asian populations is needed to determine if both populations are similar and support the findings of this study.

CONCLUSION

In conclusion, cirrhosis in conjunction with PVT is a complex and challenging clinical issue that demands multidisciplinary team collaboration and individualized treatment strategies. With advancements in research and technological progress, more effective and safer treatment plans can be provided for patients.