Continuing Education Activity

Portal vein thrombosis, characterized by the narrowing or blockage of the portal vein by a blood clot, often presents with cirrhosis of the liver but can also be associated with various conditions such as malignancy, abdominal sepsis, pancreatitis, systemic lupus erythematosus, and hypercoagulable states. Portal vein thrombosis is relatively common in clinical practice. Early anticoagulation has a 5-year survival rate of 85%; the acute condition has a better prognosis than chronic portal vein thrombosis, where the liver function is often compromised. Although transjugular intrahepatic portosystemic shunt and open surgery procedures were commonly used, percutaneous techniques are now more frequently utilized and associated with fewer complications.

In this course, participants explore the complexities of portal vein thrombosis, from its anatomy and etiology to the management and treatment options. Learners gain a better understanding of portal vein thrombosis, the need for prompt diagnosis, knowledge of current treatment approaches, and how working as part of an interdisciplinary team will lead to better patient care and outcomes. Because portal vein thrombosis has enormous morbidity and mortality if left untreated, prompt diagnosis and treatment are necessary and are best managed by a team of interprofessional healthcare professionals.

Objectives:

• Implement evidence-based treatment protocols for portal vein thrombosis management to optimize patient outcomes.

• Assess the efficacy of anticoagulation therapy and other interventions in patients with portal vein thrombosis to adjust treatment plans as needed.

• Apply percutaneous techniques and other minimally invasive procedures for portal vein thrombosis management to minimize complications.

• Implement a structured interprofessional team approach to provide effective care and appropriate surveillance for patients with portal vein thrombosis.

Introduction

Portal vein thrombosis (PVT) is a narrowing or blocking of the portal vein by a blood clot. Thrombosis can develop in the main body of the portal vein or its intrahepatic branches and may even extend to the splenic or superior mesenteric veins. PVT frequently occurs with cirrhosis of the liver but may also occur without an associated liver disease like malignancy, abdominal sepsis, or pancreatitis. The extrahepatic portal venous obstruction terminology should be considered a separate entity that refers to developing portal cavernoma or collaterals around chronic portal vein thrombosis.

The portal venous system, originating from the vitelline venous system, close to the umbilical venous system, from the fourth to the twelfth weeks of gestation, drains blood from the gastrointestinal tract (excluding the lower third of the rectum) and biliopancreatic apparatus, including the spleen, pancreas, and gallbladder, to the liver.[1][2]

The veins that drain the gastrointestinal organs parallel the major arteries that supply the foregut, midgut, and hindgut, including the celiac, superior mesenteric, and inferior mesenteric arteries, respectively. These veins eventually convene at the portal vein, forming a single venous inflow tract into the liver. The celiac vein drains the foregut structures, including the stomach, through the second part of the duodenum. The superior mesenteric vein drains the third part of the duodenum through the initial two-thirds of the transverse colon. The inferior mesenteric vein drains the remaining one-third of the transverse colon through the rectum. These veins comprehensively drain nutrients and toxins from the digestive intake and ultimately provide approximately 75% of the liver's blood supply, with the remaining blood coming from the hepatic artery—eventually draining into the hepatic veins and systemic circulation.[1][3]

The portal vein forms the confluence of the splenic and superior mesenteric veins, draining the spleen and small intestine, respectively. Portal vein occlusion with thrombosis formation typically occurs in 2 main groups of patients: patients with cirrhosis and patients with prothrombotic disorders. Acute PVT occurs with abrupt thrombotic portal vein occlusion. Portal vein thrombosis can result in complete or partial occlusion of the vein and consequent clot propagation into the mesenteric and splenic tributaries. Features of chronic PVT, such as collateral circulation (eg, cavernous portal transformation) or portal hypertension, have not developed in acute PVT. If the patient's knowledge of when the clot developed is unknown and the patient does not have features of chronic PVT, the PVT can be referred to as being "recent."[1] Managing recent PVT is the same as managing acute PVT.

Etiology

The most common cause of PVT is cirrhosis; in a non-cirrhotic liver, PVT is mainly due to inherited or acquired pro-thrombotic states. Primary myeloproliferative disorders are the most common procoagulant state found. Other pro-thrombotic conditions that cause PVT include paroxysmal nocturnal hemoglobinuria, antiphospholipid syndrome, hyperhomocysteinemia, inherited pro-thrombotic disorders such as protein C, S, and antithrombin III deficiencies, and less frequently, factor V Leiden mutation, factor II mutation, and methylenetetrahydrofolate reductase gene mutation.[4] 

Rare conditions associated with PVT are pregnancy, chronic inflammatory diseases, oral contraceptives, and malignancies with or without the above pro-thrombotic causes.[5] Malignancy is responsible for PVT in approximately 25% of cases.

Intra-abdominal inflammatory conditions leading to vascular endothelial injury can cause PVT. These include pancreatitis, cholangitis, appendicitis, and liver abscesses. Local injury to the portal venous axis following splenectomy, laparoscopic colectomy, or abdominal trauma with the above acquired or inherited pro-thrombotic conditions can lead to PVT.

The etiology of extrahepatic portal venous obstruction (EHPVO) in children is phlebosclerosis, with thrombosis as a secondary event. Omphalitis, neonatal umbilical sepsis, umbilical vein cannulation, repeated abdominal infections, sepsis, abdominal surgery, and trauma later progress to EHPVO.[6]

Collectively, the etiological factors for portal vein thrombosis can be categorized as follows:

• Complications of abdominal surgeries, including but not limited to bariatric surgeries [7][8]
• Vascular thrombotic complications of Behçet's syndrome [9] 
• Cirrhosis [10]
• Collagen vascular disease, including systemic lupus erythematosus, with rheumatoid arthritis, polymyositis and dermatomyositis, systemic sclerosis, mixed connective tissue disease, and polyarteritis nodosa [11]
• Malignancies, including hepatocellular carcinoma and pancreatic cancer with and without identified thrombophilic risk factors [12]
• Iatrogenic following endoscopic sclerotherapy [13]
• Inflammatory bowel disease-related PVT [14]
• Inherited thrombophilia, including factor V Leiden and PTG20210A mutation [15]
• Myeloproliferative disease and related thrombophilia [16]
• Omphalitis and portal vein thrombosis [17]
• Oral contraceptive drugs [18]
• Total pancreatectomy with islet autotransplantation [19]
• Acute pancreatitis [20]
• Paroxysmal nocturnal hemoglubinuria [21]
• Pregnancy [22]
• Retroperitoneal fibrosis [23]
• Transjugular intrahepatic portosystemic shunt [24]
• Portal vein thrombosis following trauma [25]

Epidemiology

The prevalence of PVT in cirrhosis has been reported to be 0.6% to 16% and is more common in patients awaiting liver transplantation. PVT is in up to 35% of patients with cirrhosis and hepatocellular carcinoma. The lifetime risk of PVT in the general population is 1%.[26] A systematic review and meta-analysis evaluated 8549 papers to probe the epidemiology of portal vein thrombosis in patients with cirrhosis. The PubMed, Excerpta Medica Database, and Cochrane Library databases were included. Fifty-four studies evaluated the prevalence of PVT in patients with cirrhosis, and a prevalence of 13.92% was reported. (95% confidence interval= 11.18%–16.91%).[27] Factors associated with a higher risk of portal vein thrombosis in patients with cirrhosis include Child-Pugh class B/C, higher levels of D-dimer, history of non-selective beta-blockers intake, patients at risk for moderate to severe esophageal varices, and presence of ascites.[27]

Pathophysiology

The pathophysiology of portal vein thrombosis encompasses 1 or more features of Virchrow triad, which include reduced portal blood flow, a hypercoagulable state, or vascular endothelial injury. A confluence of splenic and superior mesenteric veins forms a portal vein, which carries blood from the spleen and small intestine to the liver. Patients with cirrhosis usually have slow blood flow through the severely scarred liver. These altered portal hemodynamics are more likely to produce clots and can cause portal vein thrombosis. Malignant portal vein obstruction occurs by direct vascular invasion by hepatocellular carcinoma, and cholangiocarcinoma or compression by tumor mass or lymph node are the other potential mechanisms involved.

The underlying pathophysiological mechanism involved in portal vein thrombosis can be categorized into 2 major conditions: inherited and acquired.[28][29][30]

Inherited thrombophilia conditions associated with PVT include the following principal reasons:

• Factor V Leiden mutations [31]
• Prothrombin G20210A mutations [31][32]
• Protein C deficiency [33]
• Protein S deficiency [31][34]
• Antithrombin deficiency [35] 
• Elevated factor VIII levels
• Mutations in the methylenetetrahydrofolate reductase gene [36]

Acquired thrombophilia conditions associated with PVT include the following:

• Complications of abdominal surgeries, including but not limited to bariatric surgeries [7][8]
• Vascular thrombotic complications of Behçet syndrome [9]
• Cirrhosis [10]
• Collagen vascular disease, including systemic lupus erythematosus, with rheumatoid arthritis, polymyositis and dermatomyositis, systemic sclerosis, mixed connective tissue disease, and polyarteritis nodosa [11]
• Malignancies, including hepatocellular carcinoma and pancreatic cancer with and without identified thrombophilic risk factors [12]
• Iatrogenic following endoscopic sclerotherapy [13]
• Inflammatory bowel disease-related PVT [14]
• Inherited thrombophilia, including factor V Leiden and PTG20210A mutation [15]
• Myeloproliferative disease and related thrombophilia [16]
• Omphalitis and portal vein thrombosis [17]
• Oral contraceptive drugs [18]
• Total pancreatectomy with islet autotransplantation [19]
• Acute pancreatitis [20]
• Paroxysmal nocturnal hemoglubinuria [21]
• Pregnancy [22]
• Retroperitoneal fibrosis [23]
• Transjugular intrahepatic portosystemic shunt [24]
• Portal vein thrombosis following trauma [25]

History and Physical

Portal vein thrombosis is asymptomatic in a majority of patients. Clinically, PVT may be acute or chronic, although no time frame exists to distinguish acute from chronic. Portal hypertension develops due to chronic obstruction to the flow within the portal venous system. Portal hypertension can present with left upper quadrant abdominal fullness due to splenomegaly or upper gastrointestinal (GI) bleeding from esophageal or gastric varices.

Non-cirrhotic, non-malignant acute PVT usually presents with abdominal pain (91%), fever (53%), and ascites (38%).[37] Extension of portal vein thrombus into a superior mesenteric vein may lead to intestinal ischemia, bowel infarction, and ileus presenting as hematochezia, fever, and sepsis and is responsible for high mortality in this subset of patients. 

If new portal vein thrombosis develops in people with cirrhosis, they present with hepatic decompensation in ascites, jaundice, or variceal bleeding. In patients with underlying cirrhosis, ascites usually develop when large amounts of fluids are given intravenously to treat massive bleeding from ruptured esophageal or gastric varices. Patients with EHPVO present with only portal hypertension-related complications like a well-tolerated upper GI bleed, splenomegaly, anemia, and thrombocytopenia, or they may be asymptomatic with incidental detection following an imaging procedure.

Evaluation

Liver Function Tests

The liver functions are normal or near normal unless PVT occurs in a patient with cirrhosis. Portal hypertension due to chronic PVT may cause thrombocytopenia due to splenomegaly. Patients with portal biliopathy may show a rise in alkaline phosphatase and bilirubin.

Doppler Ultrasound

Doppler ultrasound is an investigation of choice with sensitivity and specificity ranging from 80% to 100% with 88% to 98% accuracy. The Doppler ultrasound will show solid isoechoic or hypoechoic material within the portal vein, partially or entirely filling the lumen without reduced portal venous flow. Portal cavernoma will be seen as multiple tortuous small vessels replacing the portal vein, which is suggestive of chronic PVT. Ultrasound will also pick up associated with splenomegaly. Contrast-enhanced ultrasound and endoscopic ultrasound are other modalities that are superior to ultrasound in demonstrating the presence or absence of flow in the portal vein when it is very small.

Computed Tomography and Magnetic Resonance Imaging

Computed tomography (CT) and magnetic resonance imaging (MRI) provide additional information, such as the extension of the thrombus, evidence of bowel infarction, and the status of adjacent organs. A CT scan with contrast also helps distinguish a bland thrombus from a malignant one. A bland thrombus is typically seen as a low-density, non-enhancing defect within portal veins. In contrast, a tumor thrombus enhances following contrast administration with distension of the vessel wall or intra-thrombus contrast enhancement due to neovascularization. The sensitivity and specificity of MRI for detecting the main PVT are 100% and 98%, respectively and is valuable in determining the resectability of neoplasm involving the portal venous system and follow-up after therapeutic procedures.[38] Positron emission tomography CT also has been shown to help differentiate benign and malignant portal vein obstruction.

Splenoportovenography

This is an invasive but obsolete procedure done in the past, involving injecting dye into the splenic pulp and visualizing the splenoportal venous axis that helped in diagnosing PVT and identifying the patency of the splenoportal axis for future splenorenal or mesocaval shunt surgery. In the pre-ultrasound/CT/MRI era, it was proven to be a safe procedure that also helped measure portal pressure.

Endoscopy

An endoscopy is essential in patients with PVT, as portal hypertensive gastropathy is often present in acute PVT with cancer or cirrhosis. Large ectopic/esophageal/gastric varices are present more frequently in patients with chronic PVT.

Procoagulant Workup

Once the diagnosis of PVT is made, an extensive investigation of prothrombotic disorders and local factors is recommended, including antiphospholipid syndrome, protein C, S, antithrombin III levels, factor V, and Leiden mutation, among others.

Treatment / Management

Anticoagulation

The treatment aims to reverse or prevent the advancement of thrombosis in the portal venous system and to treat complications of established PVT. There is a clear recommendation for using anticoagulation in non-cirrhotic acute PVT with reasonable safety and efficacy data for low molecular weight heparin and new oral anticoagulants. However, the data on cirrhosis is limited.

Anticoagulation is indicated with impending intestinal ischemia, decompensated liver disease awaiting liver transplantation, and a compensated liver disease with a new diagnosis of acute PVT or PVT with asymptomatic mesenteric venous occlusion. In contrast, anticoagulation in non-transplant candidates with advanced liver disease and patients with portal cavernoma formation without thrombotic risk factors may not benefit survival. Enoxaparin was safe, with no significant side effects or hemorrhagic events in cirrhosis. There is still insufficient data on newer oral anticoagulants in cirrhosis, as most are metabolized in the liver.

Thrombolysis

Thrombolytic therapy in recent non-cirrhotic portal vein thrombosis can be done via indirect intra-arterial infusion of tissue plasminogen activator, urokinase, or streptokinase into the superior mesenteric artery (SMA) or directly via the catheter introduced into a portal vein either transhepatically or through the transjugular approach.[39] 

However, prolonged catheterization of SMA may pose a risk of embolizing SMA and its arterial branches. Hence, direct access to the portal vein via the transjugular or percutaneous intrahepatic route is the preferred mode as being less time-consuming and a more efficient technique with a requirement of a reduced dose of thrombolytics, thereby reducing the thrombolysis-related complications.

Thrombectomy

Surgical thrombectomy or mechanical thrombectomy by percutaneous transhepatic route is associated with the recurrence of thrombosis from intimal or vascular trauma to the portal vein.[40] Percutaneous transhepatic thrombo-aspiration within 72 hours has been done successfully in some patients.

Transvenous Intrahepatic Portosystemic Shunt

Transvenous intrahepatic portosystemic shunt placement in the setting of portal vein thrombosis is technically challenging for radiologists. However, when placed successfully, there is a possibility of achieving recanalization by disrupting the thrombus and mechanical thrombectomy. The management of acute portal vein thrombosis should be initiated with anticoagulation therapy. However, the treatment of predisposing factors should not be underestimated.[41]

The main and essential objective of the treatment is to limit clot extension and to provide the optimal environment for clot recanalization.[41][42] Notwithstanding the significant impact of managing acute portal vein thrombosis with anticoagulant therapy, anticoagulant therapy's direct role and effectiveness in patients with chronic PVT are yet to be established.[6] Anticoagulation should be triggered with low molecular weight heparin, and the ultimate goal should be switching to warfarin or directly-acting oral anticoagulation. The goal of treatment is to maintain an international normalized ratio (INR) of 2 to 3.[43]

Moreover, a group of patients with cirrhosis may have esophageal varices. Therefore, screening the esophageal varices should be prioritized before starting the medical management with anticoagulation therapy.[44] The level of impact and risk-benefit of anticoagulation in patients with chronic portal vein thrombosis and cirrhosis is yet to be established. However, the studies have shown comparable outcomes for patients with and without thrombosis.[45]

The results from several studies were suggestive of downregulated treatment efficacy with factor Xa inhibitors, including rivaroxaban, and direct factor Xa inhibitors, including apixaban.[46] Moreover, studies demonstrated a relative bleeding risk between natural factor Xa inhibitors and conventional treatments.[47] Accordingly, further investigations are required to provide an evidence-based recommendation for treating acute PVT with natural factor Xa inhibitors.

Considering the treatment duration, 3 to 6 months is generally recommended. However, more prolonged treatment should be considered for most patients with inherited underlying thrombophilia disorders.[48] Moreover, the extended portal vein thrombosis with mesenteric vein involvement should be managed with a longer duration of anticoagulation. The latter circumstances harbor the risk of intestinal infraction. Patient care should be individualized since the INR does not necessarily reflect the level of anticoagulation management with non-warfarin medication.

Differential Diagnosis

Differential diagnosis of this condition includes:

• Arsenic toxicity 

• Budd-Chiari syndrome 

• Cirrhosis

• Sarcoidosis

• Schistosomiasis [49]

Prognosis

In acute non-cirrhotic portal vein thrombosis, with an early diagnosis, improved diagnostic techniques, and early anticoagulation, the 5-year survival rate has now improved to 85%. Mortality is primarily due to an underlying cause or as a consequence of portal hypertension. Acute PVT usually has a good prognosis if it does not progress to intestinal infarction.

In chronic extrahepatic portal vein thrombosis, bleeding-related mortality is much lower due to preserved liver function compared to cirrhosis. In contrast, in portal vein thrombosis in a patient with cirrhosis, the 2-year survival is reduced by 55%, secondary to hepatic dysfunction.[50]

Complications

Portal Hypertension

Portal hypertension is responsible for most complications in patients with chronic PVT. It presents with splenomegaly, varices, or ascites. Portal vein thrombosis commonly forms varices in sites other than the esophagus and stomach (ectopic varices).

Intestinal Ischemia

Intestinal ischemia is typically seen when acute PVT progresses to obstruction of the mesenteric venous outflow with reflex arterial constriction and occlusion.

Septic Portal Vein Thrombosis

Septic portal vein thrombosis (acute pylephlebitis) occurs when PVT develops in a patient with an abdominal focus of infection, such as appendicitis and diverticulitis.

Portal Cholangiopathy

Portal cholangiopathy is a complication that may develop with longstanding PVT due to extrinsic compression of large bile ducts from venous collaterals around the portal vein, and it may progress to ischemic strictures of bile ducts, presenting obstructive jaundice and cholangitis.[51]

Enhancing Healthcare Team Outcomes

Portal vein thrombosis is a relatively common presentation in clinical practice. Because the disorder has enormous morbidity and mortality if left untreated, the condition is best managed by a team of interprofessional healthcare professionals of clinicians, nurses, and pharmacists. Nurses and pharmacists should be empowered to make suggestions to the clinician staff in managing these patients, utilizing open communication and shared decision-making. This interprofessional approach will result in the best patient outcomes for portal vein thrombosis. To reduce morbidity, prompt diagnosis and treatment are necessary. Patients treated with early anticoagulation have a 5-year survival of 85%. The acute condition has a much better prognosis than chronic portal vein thrombosis, where the liver function is often compromised. TIPS and open surgical procedures are much less used today because of the availability of percutaneous techniques associated with much fewer complications.