Portal vein thrombosis refers to thrombosis of the main trunk of the portal vein and its branches, and its assessment mainly includes the degree of thrombosis (including partial thrombosis, complete thrombosis and fibrous streak formation), the stage of thrombosis (including acute thrombosis, chronic thrombosis and portal vein cavernous degeneration) and the extent of thrombosis (including the main trunk of the portal vein, the right and left branches of the portal vein, the splenic vein or the superior mesenteric vein).
Portal vein thrombosis is a common complication in patients with cirrhosis, with a prevalence of approximately 10-25% that increases with the severity of cirrhosis, <1% in patients with compensated cirrhosis, and approximately 8%-25% in the liver transplantation candidate population. < span="">Lin Hai, Department of Gastroenterology, Yishui Central Hospital
Portal vein thrombosis is important in the natural course of cirrhosis, and obstructive portal vein thrombosis can be an important marker of decompensated cirrhosis.
The formation of portal vein thrombosis can aggravate portal hypertension, lead to variceal bleeding, refractory ascites, and even preclude the opportunity for liver transplantation, and ultimately affect the prognosis and survival of patients.
Reduced portal blood flow velocity and increased blood flow in the largest collateral vessels are the 2 main local risk factors for portal vein thrombosis in cirrhosis, while other local risk factors include damage to the portal vein endothelium and inflammatory response. Systemic risk factors include Leiden mutation in coagulation factor V, prothrombinogen G20210A mutation, C677T mutation in methylenetetrahydrofolate reductase gene, anti-cardiolipin antibody, positive lupus anticoagulant, and reduced fibrinolytic activity.
Meta-analysis by Qi et al. showed that decreased antithrombin, protein C and protein S may not be associated with the development of portal vein thrombosis in cirrhosis, and subsequent case-control studies confirmed this conclusion.
Studies on the prevention and treatment of portal vein thrombosis in cirrhosis are relatively few and controversial. Moreover, the latest guidelines for the management of portal vein thrombosis do not provide clear recommendations for the management of portal vein thrombosis in cirrhosis. The latest advances in the prevention and treatment of portal vein thrombosis in cirrhosis are reviewed by reviewing the literature.
I. Prevention of portal vein thrombosis in cirrhosis
Several case-control studies have shown that patients with cirrhosis have a significantly increased risk of venous thrombosis (lower extremity deep vein thrombosis and pulmonary embolism). Also, in vitro experiments have shown that patients with cirrhosis are in a hypercoagulable state.
Some studies have shown that prophylactic anticoagulation in patients with cirrhotic deep vein thrombosis is safe and effective and does not increase the risk of gastrointestinal bleeding. This evidence provides theoretical support for prophylactic anticoagulation in cirrhotic portal vein thrombosis.
Recently, an Italian randomized controlled study showed that enoxaparin is effective in preventing portal vein thrombosis in cirrhosis, while reducing the incidence of cirrhotic decompensation and improving overall survival. However, there are still many unresolved issues that need to be confirmed in a large sample of double-blind randomized controlled studies, such as the appropriate population for prophylactic anticoagulation therapy, the selection of anticoagulant drugs and doses, and the duration of prophylactic anticoagulation therapy.
II. Treatment of portal vein thrombosis in cirrhosis
At present, the treatment of portal vein thrombosis in cirrhosis mainly includes anticoagulation, transjugular intrahepatic portosystemic shunt (TIPS) and thrombolysis, etc.
1. Anticoagulation: Cirrhosis is usually considered a bleeding disorder and anticoagulation has been considered a contraindication for patients with cirrhosis, but there is increasing evidence that anticoagulation for portal vein thrombosis in cirrhosis is safe and effective, see Table 1.
Endoscopic ligation is usually performed in patients with high-risk varicose veins or acute varicose veins to reduce the risk of bleeding from ruptured varicose veins before anticoagulation is applied. Anticoagulation results in recanalization in 42%-100% of patients with minimal or no anticoagulation-related adverse effects. The majority of patients with portal vein thrombosis treated with anticoagulation have partial portal vein thrombosis, with a small percentage having complete thrombosis and almost no patients with cavernous degeneration of the portal vein. Currently, a double-blind randomized controlled study comparing acenocoumarol (vitamin K antagonist) and placebo for the treatment of portal vein thrombosis in cirrhosis in India has been registered on the Clinical Trials website under registration number (NCT01631877).
There are still many unresolved issues in the anticoagulation treatment of cirrhotic portal vein thrombosis that need to be explored in further studies. First, the time window for anticoagulation therapy after the diagnosis of portal vein thrombosis in cirrhosis Delgado et al. and Senzolo et al [|5] showed that the earlier anticoagulation is started after the diagnosis of portal vein thrombosis in cirrhosis, the higher the rate of recanalization of portal vein blood tests. However, there is no consensus on the optimal time window and different studies have different time windows, which may also be related to the staging, grading and extent of portal vein thrombosis at the time of thrombosis diagnosis.
Second, the indications for anticoagulation therapy for portal vein thrombosis in cirrhosis are unclear. Spontaneous recanalization is achieved in 30%-50% of partial portal vein thrombosis in cirrhosis, but it is not clear which patients are able to achieve spontaneous recanalization, and some other patients with thrombosis may be at risk of deterioration if untimely intervention is not performed, so further studies with large samples are still needed to confirm this.
In addition, the efficacy of anticoagulation therapy for partial versus complete portal vein thrombosis in cirrhosis remains controversial; Francoz et al. showed that anticoagulation therapy may not be effective for complete portal vein thrombosis, while Senzolo et al. showed no significant difference in recanalization rates between partial and complete portal vein thrombosis.
Finally, the choice of anticoagulant, dose and duration of administration. Low relative molecular weight heparin (LMWH) and vitamin K antagonist (VKA) are the two most prominent classes of anticoagulants, with LMWH requiring long-term subcutaneous injection, which potentially reduces patient compliance, and VKA being an oral anticoagulant suitable for long-term administration. The INR needs to be monitored while taking VKA and the drug dose needs to be adjusted to maintain the patient’s INR between 2 and 3.
There is no unanimous opinion on the therapeutic dose of anticoagulant drugs for cirrhosis, and some experts suggest that reference can be made to the management protocol for lower extremity deep vein thrombosis.
The duration of anticoagulation therapy may be related to the presence of thrombophilia and the stage of portal vein thrombosis in cirrhosis, and the response to treatment. For patients with prone to thrombosis, if anticoagulation is safe and feasible, perhaps lifelong medication should be taken, while for patients with recent thrombosis without prone to thrombosis, some experts recommend 3-6 months of anticoagulation, for patients who respond to treatment, the duration of treatment should be extended to achieve complete recanalization, and for patients who do not respond, anticoagulation should be stopped or other treatment should be transferred.
2. TIPS treatment: TIPS can apply endovascular interventional techniques (balloon angioplasty, thrombus aspiration, local thrombolysis, etc.) to open the blocked portal venous blood flow channels, and at the same time implant stents to establish portal venous shunts to effectively reduce the portal venous pressure gradient in order to treat the complications of portal hypertension in cirrhosis.
In addition, the establishment of portal shunts significantly increases the velocity of portal venous blood flow, which not only prevents thrombosis, but may also reduce the degree of thrombosis through the “flow flushing effect.” Han et al. showed that conventional TIPS or portal vein opening via hepatic (splenic) puncture combined with TIPS for the treatment of portal hypertension with or without portal vein The treatment of portal vein thrombosis with or without spongy degeneration is a safe and effective method.
The key to the treatment of portal vein thrombosis is to open the portal vein and maintain its blood flow back to the portal vein. Percutaneous hepatic puncture, percutaneous splenic puncture, and/or transjugular approach are the alternative ways to deal with portal vein. When these routes fail, larger sponge-like collateral vessels can also be chosen to create a TIPS shunt.
The technical success rate of TIPS for portal vein thrombosis in cirrhosis is approximately 67%-100%, and the rate of recanalization of the portal vein after successful TIPS is as high as 80%.
In addition, complications associated with TIPS procedures in patients with cirrhotic portal vein thrombosis are relatively rare (<15%), with rates of stent dysfunction and hepatic encephalopathy ranging from 8%-33% and <50%, respectively. In recent years, the use of overlapping stents has further reduced the incidence of stent dysfunction. < span="">
Regarding the status of TIPS and anticoagulation in portal vein thrombosis in cirrhosis, there is no clear recommendation in the current guidelines. A randomized controlled trial (NCT01326949) is being conducted at the Xijing Gastroenterology Hospital of the Fourth Military Medical University to compare the safety and efficacy of TIPS with overlapping stents and endoscopic combination drug (nonselective p-blockers and anticoagulation) therapy in patients with cirrhotic portal vein thrombosis.
In addition, TIPS should also be performed in patients with cirrhotic portal vein thrombosis who have failed anticoagulation therapy or who have progressed despite anticoagulation. Clinically, it is often found that patients with partial thrombosis of liver cirrhosis have progressed or even completely obstructed or mechanized strips after regular anticoagulation therapy, and aggravated upper gastrointestinal bleeding, ascites and liver function damage, when the technical difficulty of TIPS is greatly increased, and even TIPS cannot be performed, resulting in the death of the patient.
Therefore, how to accurately determine and screen patients who are not suitable for anticoagulation therapy and timely transfer to TIPS is also an important issue. However, there are still relatively few studies in this area.
Thrombolytic therapy: Urokinase and recombinant tissue-type fibrinogen activator (recombinanttissueplasminogenactivator (n-PA)) are the two most commonly used thrombolytic agents. The main thrombolytic modalities are local thrombolysis and systemic thrombolysis. Local thrombolysis is usually performed in 2 ways, namely the indirect route via the superior mesenteric artery and the direct route via the percutaneous transhepatic or internal jugular vein, which allows the thrombolytic agent to reach the portal vein site.
The literature on thrombolytic therapy for portal vein thrombosis in cirrhosis is still relatively scarce, and the study by DeSantis et al. suggests that systemic thrombolysis is safe and effective for recent portal vein thrombosis in cirrhosis, but the sample size of this study is small, and studies with large samples are still needed to confirm the safety and efficacy of thrombolytic therapy. In addition, further studies are needed to explore issues such as the choice of thrombolytic agent, mode of administration and dose.
Combination of different therapeutic methods: Each of the above methods has its own characteristics and scope of application, and the combination between different modalities of one method and between different methods is often needed, such as short-term intravenous heparin drip followed by long-term maintenance of oral anticoagulants, percutaneous puncture to the portal vein thrombosis site combined with thrombolysis and balloon dilation.
III. Conclusion
Therefore, the prevention and treatment of portal vein thrombosis in cirrhosis should not be limited to the evidence provided in the current literature, and each treatment method has its own advantages and disadvantages, and individualized treatment plans should be used according to the different clinical characteristics of patients.
In patients with acute or subacute portal vein thrombosis, anticoagulation and thrombolytic therapy are mostly advocated, and the thrombus should be closely monitored by ultrasound and CT.
For chronic portal vein thrombosis, different therapies should be chosen according to the degree of thrombosis and portal hypertension. If the thrombosis is partial, anticoagulation and thrombolytic therapy can be used first, and the changes of thrombus should be monitored closely by ultrasound and CT, and other treatments should be performed if necessary.
TIPS should be performed as soon as possible in the following cases: (i) no significant change or progression of thrombus after a period of anticoagulation or thrombolytic therapy; (ii) complete thrombosis with or without spongy degeneration; (iii) recurrent variceal bleeding or intractable ascites.
If future studies can find specific markers for the development of portal vein thrombosis in cirrhosis and eventually screen out high-risk patients, reasonable methods can be taken to prevent the occurrence and progression of portal vein thrombosis and possibly its complications.