Portal and Mesenteric Venous Thrombosis

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Abbreviations

aPTT

activated partial thromboplastin time

BB

beta blocker

EGD

esophagogastroduodenoscopy

EVL

endoscopic variceal ligation

INR

international normalized ratio

LMWH

low molecular weight heparin

LT

liver transplantation

MR

magnetic resonance

MVT

mesenteric vein thrombosis

PV

portal vein

PVT

portal vein thrombosis

TIPS

transjugular intrahepatic portosystemic shunt

Prevalence and Etiology

The main portal vein (PV) is formed with superior mesenteric and splenic veins joining at the posterior aspect of pancreas; it carries blood from the gastrointestinal tract to contribute 70% of the hepatic blood supply. Similar to venous thrombosis at any other site, PV thrombosis (PVT) and/or mesenteric vein thrombosis (MVT) can be caused by vascular endothelial injury, sluggish blood flow, or underlying thrombophilia (Table 1). ¹ , ² , ³ , ⁴ Cirrhosis is the underlying etiology in about 22% to 28% of cases based on a large population‐based autopsy study. ⁵ Among patients with cirrhosis, the prevalence rate of PVT varies depending on the severity of the liver disease (1% in compensated cirrhosis to 25% among patients listed for liver transplantation [LT]), ³ , ⁵ modality used for diagnosis, etiology of cirrhosis (more common among patients with nonalcoholic steatohepatitis), ⁶ and length of follow‐up of patients with cirrhosis. In a recent longitudinal study, the cumulative incidence rate of PVT was 4.6%, 8.2%, and 10.7% at 1, 3, and 5 years, respectively. ⁴ PVT may be acute or chronic, partial or complete, occlusive or nonocclusive, when all etiologies for PVT are considered. Further, among patients with cirrhosis, this could be caused by bland or tumor thrombus.

TABLE 1.

Etiology of PVT and MVT

A. Thrombophilia

Intra‐abdominal malignancy Myeloproliferative neoplasm Inherited thrombophilia Pregnancy Oral contraceptive use

B. Local intra‐abdominal trauma or injury to vessel wall

Acute intra‐abdominal process: pancreatitis, inflammatory bowel disease, diverticulitis, cholecystitis, appendicitis Intra‐abdominal surgery: splenectomy, colectomy, cholecystectomy, splenectomy, portosystemic shunting Abdominal trauma

C. Sluggish blood flow

Cirrhosis Congestive heart failure

Clinical Features

Abdominal pain is the most common symptom of PVT or MVT, and abdominal examination is relatively benign compared with the severity of pain. Other nonspecific symptoms, such as nausea, vomiting, and diarrhea, can occur because of involvement of mesenteric veins. Fever can occur in 10% to 15% of cases because of an underlying inflammatory intra‐abdominal process, pylephlebitis with liver abscess, or intestinal infarction from MVT. ¹ Among patients with cirrhosis, PVT can be asymptomatic or patients may present with abdominal pain and/or with worsening of liver disease. It is important to exclude tumor thrombus when a new‐onset PVT is encountered in patients with cirrhosis. Chronic PVT often presents with features of portal hypertension. In approximately 1% of patients, chronic PVT can result in biliary cholangiopathy because of peribiliary vascular collaterals compressing on extrahepatic bile ducts, which manifests with features of cholangitis. ⁷

Diagnosis

Routine hematological and biochemical assessment including hypercoagulable workup is recommended among patients with PVT and/or MVT. For specific diagnosis of PVT, Doppler ultrasound examination is recommended as the initial screening test. Its advantages are high negative predictive value of 98%, inexpensive cost, and lack of radiation exposure. However, the technique is operator dependent, and the finding of a filling defect in the PV has a positive predictive value of only 86% to 97%. ⁸ Contrast‐enhanced computed tomography or magnetic resonance (MR) scan is recommended before starting specific treatment with anticoagulation to confirm the diagnosis, differentiate bland versus tumor thrombus, and assess the mesenteric vasculature (MVT, bowel ischemia, gangrene, and bowel perforation). An intraluminal filling defect on computed tomography or MR scan is 90% accurate for diagnosis of MVT, which increases to 100% with use of the multidetector technique. ⁸ Portosystemic collaterals and cavernoma with serpiginous vessels replacing the PV suggest diagnosis of chronic PVT. MR cholangiography coupled with MR portography is an accurate noninvasive modality to diagnose biliary cholangiopathy among patients with chronic PVT. Thrombophilia workup (Table 2) is recommended for patients without cirrhosis if there is no obvious etiology (Table 1). ¹ Among patients with cirrhosis, thrombophilia workup should be considered for patients with a family history of thrombosis and if the thrombosis involves an unusual site, such as hepatic veins. ¹

TABLE 2.

Workup for Thrombophilia or Hypercoagulable State

Thrombophilia	Workup
Myeloproliferative disease	V617F JAK2 mutation
Paroxysmal nocturnal hemoglobinuria	Flow cytometry CD55‐ and CD59‐deficient clone
Factor V Leiden	Increased protein C resistance
Antiphospholipid syndrome	Anticardiolipin antibodies or lupus anticoagulant
Hyperhomocysteinemia	Increased serum homocysteine level prior to disease
Inherited protein S deficiency	Protein S level
Inherited protein C deficiency	Protein C level
Inherited antithrombin deficiency	Antithrombin level
Oral contraceptives	History
Pregnancy	History and examination
Factor II gene mutation	Molecular biology for G20210A mutation
Behçet disease	Conventional criteria

Treatment

Anticoagulation is recommended to be initiated as soon as possible for the management of acute thrombosis, except in patients suspected to have bowel gangrene or perforation, which require urgent surgical intervention. Thrombophilia workup, if indicated, should be obtained prior to starting anticoagulation. Among patients with acute MVT, anticoagulation improves recanalization rates, prevents bowel ischemia or need for surgical intervention, and improves survival. ¹ In one study, anticoagulation resulted in complete recanalization in 44% and partial recanalization in 56% of patients. ⁹ Anticoagulation for chronic PVT is used among patients with cirrhosis if there is underlying thrombophilia or with extension to mesenteric veins with features of bowel ischemia. In one retrospective study on 60 patients with chronic thrombosis of PVs or superior mesenteric veins (39 with variceal bleeding), 18 with thrombophilia (9 with variceal bleeding) received anticoagulation, with recanalization of veins in 3 patients, whereas none of the patients who were not anticoagulated recanalized the veins. ¹⁰ Further, recurrent bleeding was observed in only 2 anticoagulated patients and in 16 patients without anticoagulation. ¹⁰ In the pooled data of observational studies, anticoagulation for the management of PVT and/or MVT improved survival without increased risk for bleeding, including variceal bleeding. ¹¹ Among patients who require anticoagulation who have large varices, data on the prophylaxis approach with beta blockers (BBs) versus band ligation are scant. As practiced among patients with cirrhosis and portal hypertension with varices, BBs or band ligation can be used before starting anticoagulation (Fig. 1). BBs should be continued as maintenance therapy to prevent recurrent variceal bleeding.

FIG 1.

Algorithmic approach to anticoagulation management of PVT and/or MVT.

Anticoagulation should be continued among patients with PVT and listed for LT until they receive the transplant, because complete PVT may negatively impact posttransplant survival. ⁶ , ¹² In a randomized clinical trial among patients with Child‐Pugh class B or C cirrhosis, prophylactic anticoagulation reduced the frequency of PVT with improvement in liver function. ¹³ However, larger multicenter studies are needed before using this in routine practice. For patients with contraindication for anticoagulation or worsening clinical situation in spite of adequate anticoagulation, transcatheter thrombolytic injection therapy or transjugular intrahepatic portosystemic shunt (TIPS) are alternative approaches; however, these are associated with high morbidity and increased risk for bleeding complications. ¹⁴

Many anticoagulation agents are available (Table 3), and the pros and cons of these should be considered in choosing the appropriate agent for induction regimen and later for maintenance of the anticoagulation regimen. Duration of anticoagulation is recommended to be 3 to 6 months for reversible etiology and indefinite for underlying thrombophilia.

TABLE 3.

Advantages and Disadvantages of Various Anticoagulants

	Unfractionated Heparin	LMWH	Vitamin K Antagonists	DOAC
Route and frequency	Intravenous infusion	Subcutaneous bid	Oral daily	Oral daily
Indication	Induction	Induction, maintenance	Maintenance	Maintenance
Absorption	Not affected	Affected in shock	Affected in bowel edema	Affected in bowel edema
Renal disease	No change	C/I renal failure, dialysis	No change	No change
Liver disease	No change	No change	No change	No data in cirrhosis
Monitoring	aPTT or Xa	INR	INR	None
Thrombocytopenia	Yes	Maybe	None	None
Reversibility	Minutes to an hour	6‐12 hours	2‐3 days	2‐3 days
Antidote	Protamine	Protamine	Vitamin K	Monoclonal antibody
Cost	Inexpensive	Inexpensive	Inexpensive	Expensive

Abbreviations: C/I, contraindicated; DOAC, direct oral anticoagulants.

Among patients with portal cholangiopathy who present with jaundice or recurrent biliary symptoms such as cholangitis, endoscopic retrograde cholangiopancreatography with biliary stenting and/or stone extraction is helpful. Portosystemic shunting with TIPS or surgical modalities can be used when endoscopic treatment is ineffective or difficult. ¹⁵

Conclusion

PVT occurs in about a fourth of patients with cirrhosis. Patients with acute complete PVT require anticoagulation. Among patients with cirrhosis, it is prudent to exclude and perform screening for varices. Anticoagulation is beneficial in recanalization of the PV and improves outcomes. Patients with chronic PVT and cirrhosis are not anticoagulated unless there is presence of thrombophilia or extension to mesenteric veins with features of mesenteric ischemia. Anticoagulation is initiated with unfractionated or low molecular weight heparin (LMWH) and maintained with warfarin, LMWH, or direct‐acting oral anticoagulants. Advantages and disadvantages of each of the agents should be considered in a given situation before choosing the medication. Given the limited data of direct‐acting oral anticoagulants, larger prospective studies are needed to examine the safety of these drugs among patients with decompensated cirrhosis with Child‐Turcotte‐Pugh class B or C.