Hospital Medicine

Portal vein thrombosis

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Portal Vein Thrombosis

I. What every physician needs to know.

Portal vein thrombosis (PVT) is the occlusion of the portal vein by a thrombus. The portal vein is a vital vessel that provides up to 75% of blood supply to the liver. While PVT occurs in both the pediatric and adult populations, this chapter will focus on the adult patient.

Acute and chronic PVT are considered distinct clinical entities although they represent the progression of the same disease state. Acute PVT represents an abrupt total or partial occlusion of the portal vein, and patients may present with no symptoms, or with abdominal pain, nausea and/or vomiting, diarrhea, low back pain, and fever in the setting of pylephlebitis (septic PVT). Chronic PVT may present with sequelae of portal hypertension, most commonly esophageal, and gastric variceal bleeding in the acute hospital setting, although hypersplenism and ascites are also seen.

Predisposing factors for PVT include stasis of hepatic venous blood flow, vessel wall damage, and hypercoagulability (Virchow's Triad). In adults, the most common causes of PVT can be divided into localized or systemic etiologies (see History - Part I below). Approximately one-fourth of cases have no identifiable cause.

Recommendations for treatment are limited by a paucity of controlled studies. Systemic anticoagulation is indicated for a select group of patients with severe symptoms and extensive blood clot burden if no contraindication to anticoagulation exists. A multidisciplinary approach is extremely important in finalizing treatment for patients with PVT, particularly for patients with hepatic cirrhosis since they often have multiple co-morbidities.

II. Diagnostic Confirmation: Are you sure your patient has Portal Vein Thrombosis?

A. History Part I: Pattern Recognition Potential causes of portal vein thrombosis can be classified as localized or systemic

  1. Localized: cirrhosis; malignancy - hepatocellular carcinoma, gastric and pancreatic adenocarcinoma; abdominal infection; abdominal inflammatory conditions - pancreatitis, cholecystitis, inflammatory bowel disease, injury to portal vein due to surgery or trauma.

  2. Systemic: hypercoagulable states, such as antiphospholipid antibody syndrome; prothrombin G20210A gene mutation, hyperhomocysteinemia, myeloproliferative disease, such as JAK2V617f mutation, and protein C or S deficiency.

These potential causes of PVT can be further classified into three large groups, which is important to acknowledge for treatment discussion: 1) Cirrhotic-related PVT in the setting of underlying liver disease or cirrhosis; 2) Malignancy-related PVT, i.e., in hepatocellular carcinoma, and gastric and pancreatic adenoma; 3) Non-cirrhotic PVT, i.e., a genetic hypercoagulable condition, antiphospholipid antibody syndrome, and myeloproliferative disease.

In many cases, the symptoms of acute PVT are masked by the precipitating disease process (e.g., pancreatitis), and PVT is frequently discovered incidentally on radiographic imaging. Acute PVT may be marked by abdominal pain, nausea, and/or vomiting, low back pain, and fever in the setting of septic portal vein thrombus (pylephlebitis).

While a systemic inflammatory response may be seen in PVT, if there is evidence of high fever, chills, and bacteremia, pylephlebitis may be present. Pylephlebitis is condition that could be a result from propagation of suppurative thrombophlebitis from small veins draining an area of intra-abdominal or pelvic infection to the portal vein.

Severe abdominal pain and hematochezia may indicate intestinal infarction secondary to associated mesenteric venous thrombosis.

Chronic PVT most often presents with sequelae of portal hypertension, most notably, gastric and esophageal variceal bleeding, and splenomegaly. Ascites, jaundice, encephalopathy, and other stigmata of chronic liver disease are found in patients with concomitant hepatic cirrhosis, but are relatively uncommon in non-cirrhotic PVT.

B. History Part 2: Prevalence:

PVT was discovered in approximately 1% of cases in a large autopsy series. The majority of cases were associated with hepatic cirrhosis (28%) and/or hepatobiliary malignancy (67%), while 10% of cases were associated with major abdominal infections or inflammatory disease. Myeloproliferative disease was discovered in 3% of cases, and no identifiable cause was found in 14% of cases.

In patients with hepatic cirrhosis, the prevalence of PVT appears to be associated with the severity of the liver disease and has been reported to be as high as 25% in patients referred for liver transplant evaluation. Prevalence of of PVT increases with progression of liver cirrhosis.

C. History Part 3: Competing diagnoses that can mimic Portal Vein Thrombosis.

Malignant invasion of the portal vein, such as in the setting of hepatocellular carcinoma, gastric carcinoma, pancreatic adenocarcinoma, and cholangiocarcinoma, can mimic thrombotic occlusion of the portal vein. For patients under consideration for liver transplantation, this distinction is critically important, as malignant invasion of the portal vein is a contraindication to transplantation.

D. Physical Examination Findings.

The physical examination findings of acute PVT may be absent or masked by the underlying disease process. Abdomen distension may accompany ileus or ascites. Peritoneal signs are rarely present in isolated PVT, although they may accompany other inflammatory intra-abdominal processes such as pancreatitis, cholecystitis, and diverticulitis. Severe pain out of proportion to exam findings suggests the possibility of mesenteric venous thrombosis and infarction, which warrants urgent management. In cases of cirrhosis-related PVT, a fluid wave may be detected on exam; however, this finding is only rarely seen in acute PVT from non-cirrhotic causes.

On the other hand, the most common hallmarks of chronic PVT are splenomegaly and gastrointestinal bleeding. The rare complication of portal cholangiopathy - biliary dysfunction in the setting of portal hypertension - may result in jaundice, abdominal tenderness due to biliary colic, cholangitis, or pancreatitis. Other exam findings of chronic liver disease are seen in the setting of cirrhotic PVT but are relatively uncommon in non-cirrhotic PVT.

E. What diagnostic tests should be performed?

The American Association for the Study of Liver Disease (AASLD) recommends a sequential approach in investigating the etiology of PVT:

  1. Assess for underlying cirrhosis, abdominal malignancy, or intra-abdominal infection or inflammation.

  2. In patients without evident cirrhosis or malignancy, assess for other pro-thrombotic states, such as myeloproliferative disorders, anti-phospholipid antibody syndrome, factor V Leiden mutation, factor II mutation, protein C deficiency, and protein S deficiency.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Laboratory studies rarely contribute to the diagnosis of the PVT, but may assist in identifying risk factors for and causes of PVT. In cirrhotic PVT, there will be abnormal INR, APTT, pancytopenia, and hyperbilirubinemia. In non-cirrhotic PVT, there may be elevation of lipase and amylase in the setting of acute pancreatitis, and leukocytosis and positive blood cultures point to the possibility of pylephlebitis. There may be a mild transaminitis in the setting of PVT. Elevated lactate may point toward concomitant mesenteric venous infarction, which may indicate the need for urgent surgical evaluation if consistent with the clinical presentation.

If there is concern for a hypercoagulable disorder, consider checking as an outpatient the following studies: antiphospholipid antibody, beta-glycoprotein, protein C & S, etc. Outpatient hematology referral is important upon discharge.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

PVT is confirmed by radiographic studies, and is often discovered incidentally. Doppler ultrasound of the abdomen, computed tomography (CT) angiography, and magnetic resonance (MR) angiography are the most commonly employed modalities. Digital subtraction angiography offers the gold standard but is rarely required to establish the diagnosis.

When acute PVT is clinically suspected, the AASLD advises initial imaging with a pre- and post-contrast enhanced CT scan, or Doppler ultrasound if CT is unavailable. CT images characteristically demonstrate absence of portal vein enhancement. CT and MR angiography provide superior assessment of thrombus extension to the mesenteric veins. Imaging may also provide evidence of underlying precipitants for the PVT, such as hepatic cirrhosis, malignancy, or an intra-abdominal inflammatory process. In patients with end-stage liver disease and/or kidney impairment, caution should be taken with using contrast for further diagnosis, so ultrasound abdomen with Doppler would be the test of choice.

When evaluating for chronic PVT, the AASLD advises initial imaging with Doppler ultrasound, then contrast-enhanced CT scan or MRI. Imaging in chronic PVT may demonstrate replacement of the portal vein by a portal cavernoma: a tortuous structure of collateral veins in the absence of a visible portal vein. The hepatic arteries may be enlarged. Again, radiographic imaging may reveal potential underlying causes such as hepatic cirrhosis.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Evaluation for concomitant hypercoagulable disorders in the setting of established cirrhosis or malignancy is likely to be challenging to interpret and is unlikely to affect treatment decisions. It is best to avoid an extensive hypercoagulable evaluation if a patient already has the diagnosis of cirrhosis or malignancy.

III. Default Management.

There are no randomized clinical trials to assist in the management of acute or chronic PVT. Most treatment evidence comes from case series and observational studies.

Treatment of PVT, especially in the setting of cirrhotic PVT, requires a multi-disciplinary approach with extensive risk/benefit discussion with consultants, patient, and family.

A. Immediate management.

Consider urgent surgical intervention if there is concern for bowel infarction, perforation from diverticulitis, or cholecystitis. Early initiation of antibiotics is appropriate in the presence of sepsis or suspicion for pylephlebitis.

The American College of Chest Physicians (ACCP) and AASLD have separate clinical guideline recommendations for the treatment of PVT. ACCP recommends anticoagulation (grade 1B level of evidence) for the treatment of symptomatic PVT. ACCP, however, does not recommend anticoagulation in asymptomatic, incidental diagnosed PVT (grade 2C level of evidence). AASLD clinical guidelines suggest anticoagulation for all acute PVT regardless of symptomatology.

Consideration of anticoagulation initiation in PVT should include the grade of occlusion (partial or occluded), extent of PVT, clinical presentation, and potential consequences of outcomes, such as in cirrhotic PVT, whether the patient is eligible or not for the liver transplant. For example, patients with occlusive PVT, which extends proximally and deeply into the superior mesenteric vein, will likely result with an intestinal infarction, a poor outcome that requires prompt anticoagulation.

For a PVT related to a malignancy, anticoagulation is recommended in the majority of cases, unless there is minimal thrombus burden, active bleeding, or a severe bleeding risk.

In cirrhotic or chronic PVT, endoscopic screening and management of varices are important, especially prior to the initiation of anticoagulation for an acute PVT in a cirrhotic patient. Prophylactic medical therapy with nadolol or carvedilol has been advised in patients with identified varices.

If there is no contraindication to anticoagulation, such as active bleeding or a high bleeding risk, anticoagulation should be initiated in patients with extensive PVTs, symptoms, or a non-modifiable hypercoagulable state. Long-term anticoagulation options include vitamin K antagonist (warfarin), low molecular weight heparin (LMWH) subcutaneous injection, and direct oral-acting anticoagulation drugs (DOACs), such as dabigatran (thrombin inhibitor) or rivaroxaban, apixaban, and edoxaban (inhibited activated factor X). Intravenous heparin can be used temporarily during inpatient stay pending discussions for further intervention.

There is expert consensus on continuing anticoagulation until transplantation in the setting of end-stage liver disease/cirrhosis if there is no contraindication to anticoagulation. Literature for PVT in non-cirrhotic, non-malignant individuals is limited. There are no randomized trials. Pylephlebitis (PVT in the setting of fever, leukocytosis, and positive blood cultures) case reviews show recanalization of portal vein was higher in anticoagulated and lower death rate.

Provoked portal vein thrombosis related to surgery or infectious etiology or hormonal therapies with non-reversible risk factors

Warfarin, LMWH, or DOACs are agents of choice for anticoagulation. Duration 3-6 months. Six months of anticoagulation therapy has been suggested and practiced by some hepatologists. There is evidence that at the sixth month of anticoagulation, there is complete or partial recanalization in 33-45% while low incidence thrombus progression, <10%. It is important to also acknowledge that PVT recurred up to 40% after stopping anticoagulation. In non-cirrhotic and non-malignant PVT clinical cases, patients with reversible risk factors such as pancreatitis and cholecystitis have been suggested as reasonable to monitor without anticoagulation unless there is progression.

Portal vein thrombosis related to liver cirrhosis

LMWH; warfarin can be considered if unable to administer LMWH; DOACs generally not recommended. Indefinite anticoagulant therapy with periodic bleeding and thrombosis risk assessment. Expert consensus on continuing anticoagulation until transplantation for liver transplant candidates if there is no contraindication to anticoagulation. At this point of time, DOACs' safety and efficacy in the treatment of PVT, especially in cirrhosis, are unknown due to the risk of bleeding. Patients with abnormal liver function tests were excluded from studies on DOACs. DOACs are convenient and do not interfere with MELD score as do vitamin K antagonists so they may become a great drug of choice pending further available evidence and study. In a clinical setting, DOACs has been used in some selected cirrhotic patients after discussion of risk and benefits.

Portal vein thrombosis related to malignancy

LMWH, warfarin, or DOACs can be considered if unable to administer LMWH. LMWH is the agent of choice if there is no significant renal impairment. Anti-coagulate until active malignancy resolves with no ongoing persistent risk factors.

Portal vein thrombosis with persistent risk factors

Risk factors include: inflammatory bowel disease, autoimmune disorders, antiphospholipid antibodies, factor V Leiden mutation, G20210A mutation - warfarin or LMWH and/or DOACs. Indefinite anticoagulant therapy with periodic bleeding and thrombosis risk assessment

Unprovoked portal vein thrombosis

Warfarin or LMWH or DOACs. Indefinite anticoagulant therapy with periodic bleeding and thrombosis risk assessment.

Most often, non-occlusive PVT is associated with high rate of spontaneous recanalization.

Other potential treatments of PVT are thrombectomy and/or thrombolysis and TIPS (transjugular intrahepatic porto-systemic shunt). These procedures are more invasive and are usually only available at a tertiary medical center. TIPS may be feasible or an alternative to anticoagulation if intrahepatic branches of portal vein are patent. A case series of 70 patients with non-tumor PVT were treated with TIPS for the management of complications due to portal hypertension. More than half of the patients achieved complete recanalization, 30% a marked decrease in thrombus, and there was no improvement in 13%. This success rate is similar to that observed for anticoagulation.

B. Physical Examination Tips to Guide Management.

N/A

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

INR monitoring for coumadin and factor Xa level for LMWH in the setting of anticoagulation therapy for PVT. However, it is important to acknowledge that cirrhosis affects production of both pro-coagulant and anti-coagulant and the monitoring of INR and anti-factor Xa assay may be affected.

Untreated potential transplant candidates with PVT may benefit from imaging follow-up every 3 months, and consider anticoagulation in case progression.

D. Long-term management.

Close monitoring for the risk of bleeding especially in cirrhotic PVT. Surveillance with endoscopic screening and treatment for varices.

E. Common Pitfalls and Side-Effects of Management.

N/A

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

In patients with significant renal insufficiency (creatinine clearance less than 30), anticoagulation with LMWH should be avoided.

B. Liver Insufficiency.

Hepatic cirrhosis is commonly associated with PVT. Particular attention is warranted to assessing the risks and benefits of anticoagulation in patients with cirrhosis.

C. Systolic and Diastolic Heart Failure.

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

No change in standard management.

F. Malignancy.

The AASLD notes that peripheral blood manifestations of myeloproliferative disorders may be absent in a substantial percentage of patients, and further investigation with bone marrow biopsy may be needed to establish the diagnosis.

Careful assessment for malignant invasion of the portal vein - possibly including biopsy of the thrombus is warranted especially if there is no known history of liver disease, no known hypercoagulable state, and a high clinical suspicion for malignancy with clinical presentation.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

See discussion above.

K. Dementia or Psychiatric Illness/Treatment.

In patients with advanced dementia and psychiatric illness, compliance and risk of recurrent falls should be discussed prior to initiation of anticoagulation.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

Be aware of signs or symptoms of gastrointestinal bleeding, especially in patients who have recently started on anticoagulation. Also observe for worsening abdominal pain and distension, pain, fever/chills, and jaundice.

B. Anticipated Length of Stay.

The anticipated length of stay for patients with acute PVT is highly variable and primarily related to the underlying cause of the PVT; however, expect at least 3-4 days in simple cirrhotic and non-cirrhotic PVT, and a few weeks if it is a new diagnosis of malignant PVT.

C. When is the Patient Ready for Discharge.

Patients are ready to be discharged when symptoms of abdominal pain, nausea, and/or vomiting and bleeding are resolving and etiology of PVT is determined. Hemoglobin level and vital signs should be stable. The patient needs to understand the discharge and management plan. Appropriate follow-up for anticoagulation monitoring and referrals to appropriate specialists - hepatology, hematology, oncology - should be discussed prior to discharge.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom?

INR should be checked in 2-3 days upon discharge; however, the patient should be seen by his or her primary care physician in 1-2 weeks for a post-hospital follow-up. Specialist follow-up appointments vary depending on the patient's diagnosis. Malignant PVT may need closer follow-up for malignancy treatment if none has been determined.

Consultation with a hematologist is recommended for patients with non-cirrhotic, non-malignant PVT to assist in the evaluation and treatment of any underlying hypercoagulable state.

Outpatient follow-up with hepatology in cirrhotic PVT for close endoscopic surveillance of varices, and further discussion of transplant evaluation if appropriate.

Appropriate follow-up with an oncologist transplant surgeon for intra-abdominal malignancy.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

N/A

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

For patients discharged on warfarin, order follow-up PT/INR in 2-3 days to ensure a goal INR of 2-3. BMP to assess renal function or anti-factor Xa assay may be needed if the patient is discharged home on LMWH.

E. Placement Considerations.

N/A

F. Prognosis and Patient Counseling.

The outcomes for acute and chronic PVT are influenced primarily by the underlying disease state or associated co-morbidities. Overall mortality for acute PVT has been reported to be 10%. Patients with chronic PVT who have underlying cirrhosis and malignancy have substantially higher mortality (26%) compared to others (8%).

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

The Joint Commission has issued a National Patient Safety Goal (NPSG.03.05.01) with the goal to "reduce the likelihood of patient harm associated with anticoagulant therapy." In order to meet the standard, a hospital must fulfill the following elements of performance:

  1. Use approved protocols for the initiation and maintenance of anticoagulant therapy.

  2. Before starting a patient on warfarin, assess the patient's baseline coagulation status; for all patients receiving warfarin therapy, use a current INR to adjust this therapy. The baseline status and current INR are documented in the medical record.

  3. Use authoritative resources to manage potential food and drug interactions for patients receiving warfarin.

  4. When heparin is administered intravenously and continuously, use programmable pumps in order to provide consistent and accurate dosing.

  5. A written policy addressing baseline and ongoing laboratory tests that are required for anticoagulants.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

A prophylactic dose of enoxaparin during hospitalization can prevent PVT without increasing the rate of bleeding. A prophylactic dose of enoxaparin can be given if the patient has no contraindication to prophylaxis anticoagulation such as active bleeding. Platelet <40,000-50,000 is recommended.

VII. What's the evidence?

Plemmons, RM, Dooley, DP, Longfield, RN. "Septic thrombophlebitis of the portal vein (pylephlebitis): Diagnosis and management in the modern era". Clinical Infectious Diseases. vol. 21. 1995. pp. 1114-1120.

(In this classic article on pylephlebitis, the authors review 19 cases of pylephlebitis. They found bacteremia in 88% of cases, a nidus of infection in 68% of cases, and an overall mortality of 32%.)

Primignani, M1, Tosetti, G1, La, Mura. "Therapeutic and clinical aspects of portal vein thrombosis in patient with cirrhosis". World J Hepatol. vol. 7. 2015 Dec 18. pp. 2906-12.

(This is a review article on cirrhotic PVTs' clinical aspects and treatment strategies. The authors discuss the risks and benefits of different anticoagulation therapies, including the limited safety and efficacy data on new direct oral anticoagulant agents.)

Sharma, AM, Zhu, D, Henry, Z. "Portal vein thrombosis: When to treat and how". Vasc Med. vol. 21. 2016 Feb. pp. 61-9.

(This is a review article that provides the current data available to guide the therapy of PVT in different settings and co-morbidities. It proposes treatment of PVT with duration of anticoagulation and anticoagulation of choice, along with discussion of other treatment modalities.)

Spaander, VMCW, Van Buuren, HR, Janssen, HLA. "Review article: The management of non-cirrhotic non-malignant portal vein thrombosis and concurrent portal hypertension in adults". Aliment Pharmacol Ther. vol. 26. 2007. pp. 203-209.

(This recent literature review offers concise management recommendations for acute and chronic PVT and complications thereof.)
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