About the Condition

Description/definition:

Portal vein thrombosis (PVT) is thrombosis in the trunk of the portal vein itself or in either the right or left intrahepatic branches, sometimes extending down to the superior mesenteric or splenic veins.

The most common underlying etiology of portal vein thrombosis (PVT) is cirrhosis. At initial diagnosis, it is important to distinguish between the common cirrhosis-related PVT and the much less common non-cirrhotic PVT. This distinction is vital because the evaluation, prognosis, and treatment differ between the two conditions.

Classification of PVT:

  • With or without cirrhosis:
    • As mentioned above, the presence or absence of cirrhosis has important diagnostic and therapeutic implications.
    • For example, patients with noncirrhotic PVT patients typically present with symptoms and clinicians must evaluate for thrombophilic disorders and initiate treatment in most cases.
  • Acute (also called recent) vs. chronic:
    • Acute (recent) – PVT presumed to be present for <6 months.
    • Chronic – PVT present or persistent for >6 months.
    • If cavernous transformation is present by imaging, this term is preferred to “chronic portal vein thrombosis”.
  • Percent occlusion of main PV:
    • Completely occlusive – no persistent lumen.
    • Partially occlusive – clot obstructing >50% of original vessel lumen.
    • Minimally occlusive – clot obstructing <50% of original vessel lumen.
    • Cavernous transformation – gross portoportal collaterals without original PV seen.
Gastroenterology 2019;156:1582–1599

Prevalence of PVT:

  • PVT in cirrhosis is common:
    • A large case series of 701 patients with cirrhosis undergoing investigation using routine Doppler ultrasound found a prevalence rate of 11.2%.
    • In an Italian study (PRO-LIVER), the prevalence of ultrasound-detected PVT was 17% in patients with cirrhosis, but 43% of the cases were asymptomatic.
  • PVT in patients without cirrhosis is a rare condition:
    • An autopsy study from Japan showed a PVT prevalence of 0.05%.
    • A study of almost 24,000 autopsies in Sweden revealed a prevalence of 1%.
    • Prevalence may range from 2% to 26% in patients awaiting liver transplantation.

Pathophysiology:

The portal venous system carries blood from the pancreas, spleen, and the gastrointestinal tract to the liver via the portal vein which forms at the confluence of the splenic and superior mesenteric veins (SMVs) and divides at
the liver hilum into the left and right portal vein branches.

The portal vein:

  • Supplies approximately 75% of the blood to the liver (remaining 25% through the hepatic artery.
  • Approximately 6–8 cm in length and 1 cm in diameter.
  • Divides in the hilum of the liver into the left and right portal vein branches.
  • Portal blood drains into hepatic sinusoids which drain into the inferior vena cava (IVC) through the hepatic veins.
  • Lacks valves.
  • Functions to carry (porta = to carry) nutrient-rich blood from the gastrointestinal tract (except for the upper esophagus and distal rectum) to the liver.
Am J Gastroenterol. 2020;115:18-40.

Pathogenesis of PVT is multifactorial, secondary to components of Virchow’s triad:

  • Hypercoagulability
  • Endothelial injury
  • Reduced blood flow

Risk factors:

  • Common risk factors in non-cirrhotic PVT:
    • Systemic (in about 30% of patients):
      • Myeloproliferative disorders:
        • Polycythemia vera
        • Essential thrombocythemia
        • Primary myelofibrosis
      • JAK2 V617F mutation – myeloproliferative neoplasms are present in about 25% of patients with PVT.
      • Inherited thrombophilia:
        • Factor V Leiden mutation
        • G20210A mutation
        • Protein C and S deficiency (rare)
        • Antithrombin deficiency (rare)
      • Paroxysmal nocturnal hemoglobinuria
      • Antiphospholipid syndrome
      • Recent oral contraceptive use
      • Autoimmune disease and vasculitis, for example Behçet disease
  • Local:
      • Inflammation of any of the abdominal organs:
        • Pancreatitis
        • Cholecystitis
        • Appendicitis
        • Inflammatory bowel disease
        • Any other intra-abdominal infection
      • Direct injury to the portal vein, for example occurring during:
        • Trauma
        • Splenectomy
        • Hepatectomy
        • Bariatric surgery
        • Insertion of a surgical shunt
        • Any other surgical procedure in the vicinity of the portal vein
    • Overall, risk factors are absent in up to 35% of patients.
  • Common risk factors in cirrhotic PVT:
    • Systemic:
      • Advanced portal hypertension with reduced portal flow velocity from advancing portal hypertension.
      • Inherited thrombophilia:
        • Factor V Leiden
        • Prothrombin gene G20210A mutation
      • Non-alcohol steatohepatitis
    • Local:
      • Abdominal malignancy (hepatocellular carcinoma [HCC])
      • Intrabdominal surgery (hepatectomy, surgical shunt)
      • Local regional therapy for HCC (transarterial chemoembolization [TACE], radioembolization)
      • Transjugular intrahepatic portosystemic shunt (TIPS)

Clinical Presentation:

Overview:

  • Thrombosis of the main portal vein and/or its branches can be asymptomatic or lead to a number of clinical consequences including:
    • Intestinal ischemia
    • Liver decompensation
    • Worsening portal hypertension
  • Presentation can be non-specific and include:
    • Fever
    • Colicky pain
    • Abdominal distention from ascites
    • Nausea and vomiting along with loss of appetite
    • Unexplained splenomegaly
  • Abdominal pain disproportionate to physical findings on abdominal examination should raise suspicion for PVT.

Cirrhotic portal vein thrombosis:

  • PVT often found incidentally on routine imaging in patients with cirrhosis.
  • May present with new-onset or worsening portal hypertension including ascites and variceal formation or bleeding, which should prompt evaluation for PVT.
  • Rarely, abdominal pain secondary to mesenteric ischemia can be present if there is progression of the PVT into the SMV.
  • PVT is more common in patients with decompensated cirrhosis. Thus, patients may present with typical findings of chronic liver disease such as:
    • Scleral icterus
    • Jaundice
    • Palmar erythema
    • Spider angiomata
    • Ascites
    • Caput medusae
    • Splenomegaly
    • Nail changes

Non-cirrhotic portal vein thrombosis:

  • Can present acutely with or without symptoms or after chronic progression of thrombus that leads to sequelae of portal hypertension:
    • Patients with acute PVT most commonly complain of:
      • Mild to severe abdominal pain
      • Fever
    • Severity of presentation depends on:
      • Underlying etiology
      • Extent of thrombosis (acute extension into the superior mesenteric vein much more likely to produce bowel ischemia and infarction.)
  • If undetected or left untreated, PVT may:
    • Progress to involve more proximal mesenteric veins that can result in intestinal ischemia.
    • Undergo cavernous transformation. This can result in porto–portal, meso–portal, and/or portosystemic collaterals that can lead to gastrointestinal bleeding from varices, ascites, portal biliopathy, and portosystemic encephalopathy.

Diagnosis:

Overview:

  • Important diagnostic considerations are
    • Location, extent and chronicity of the thrombus
    • Cause of the thrombus

Imaging (applies to both cirrhotic and non-cirrhotic patients):

  • Modalities:
    • Several societal guidelines recommend Doppler US as the initial diagnostic modality:
      • Advantages:
        • Good sensitivity and specificity – 98% negative predictive value
        • Wide availability
        • Low cost
        • Lack of radiation exposure
      • Disadvantages:
        • Bowel gas and obesity may obscure proper visualization.
        • Less reliable if the PVT:
          • Is incompletely occlusive.
          • Is confined to the portal trunk posterior to the duodenum.
          • Involves only the SMV (poor method of identifying thrombi in the splenic and superior mesenteric veins).
    • CT and MRI:
      • In patients with an US-confirmed PVT, further evaluation with cross-sectional imaging (contrast-enhanced CT or MRI) is required to:
        • Define extent of thrombus.
        • Map collateral circulation.
        • Rule out hepatocellular carcinoma (HCC).
        • Plan a therapeutic approach.
      • CT and MRI have the additional advantages of being able to define the extent of the thrombus, show any evidence of bowel ischemia/infarction and for looking at other organs surrounding the portal vein.
    • Endoscopic US (EUS)
  • Important considerations with imaging:
    • Clot burden:
      • Venous segments involved
      • Extension to the splenic and SMVs
    • Degree of obstruction:
      • Partial
      • Complete
    • Clot location
    • Time course of the clot:
      • Acute – acute PVTs may have a higher rate of recanalization with anticoagulant therapy
      • Chronic
    • Rule out HCC
The important components of PVT in clinical practice and research design. Hepatology. 2021;73:366-413.

When the diagnosis of PVT is made, clinicians should expedite endoscopic evaluation for new gastroesophageal varices as formation of collaterals is expected. If present, management should be in concordance with current portal hypertension management guidelines.

Diagnosis of underlying cause/trigger:

Cirrhotic portal vein thrombosis:

  • In patients with cirrhosis, an extensive evaluation for thrombophilic conditions, for example factor V Leiden and G20210A prothrombin gene mutation, is not necessary (it is rarely useful and does not change management) unless:
    • Family history of thrombosis
    • Thrombosis at unusual sites
    • Prior history of VTE
    • Routine laboratory testing that raises other concerns
  • In patients with cirrhosis, it is important to rule out malignant venous obstruction attributable to hepatocellular carcinoma (HCC) with appropriate contrast-enhanced imaging studies.

Non-cirrhotic portal vein thrombosis:

  • The diagnosis of a thrombophilic condition or hematological malignancy is much more likely in the patient without cirrhosis.
  • In patients without cirrhosis who have thrombosis of the portal venous system without a clear provoking factor, a full investigation for myeloproliferative disorders or another thrombophilic condition is warranted, usually in consultation with a hematologist.
  • Liver function tests are usually normal.
  • All patients without a clearly identifiable cause on imaging should have:
    • JAK2 V617F mutation:
      • Occult MPN is frequent.
      • Test in PVT/HVT in the absence of major provoking factor.
      • This test should be performed, even if CBC is not suggestive.
      • Myeloproliferative neoplasms are present in about 25% of patients with PVT.
  • CALR mutation:
      • Test in PVT in the absence of major provoking factor if JAK2 negative.
      • Significant positive predictive value with:
        • Platelet count >200,000/µL together
        • Splenomegaly >15 cm
        • In the context of severe portal hypertension
    • Antiphospholipid antibodies:
      • Test in PVT/BCS in the absence of major provoking factor.
      • Diagnosis of antiphospholipid syndrome requires persistence of antibodies on repeat testing ≥12 weeks.
      • Lupus anticoagulant should not be tested in the acute phase because acute changes and anticoagulation can interfere.
    • Paroxysmal nocturnal hemoglobinuria flow cytometry:
      • Test in PVT/BCS in the absence of major provoking factor.
      • Increased index of suspicion if current/preexisting hemolytic anemia and/or cytopenias.
    • Heritable thrombophilia (Factor V Leiden, Prothrombin gene mutation):
      • Not routinely recommended.
      • Results do not generally influence management.
    • Lactate dehydrogenase

Treatment:

The aims of management of PVT are to:

  • Prevent the progression of the thrombus.
  • Recanalize the thrombosed veins , which will prevent the complications of portal hypertension and mesenteric ischemia.
Cirrhotic acute PVTNon-cirrhotic acute PVT
WhoTreatment should be
considered on a case-by-case basis. Candidates for anticoagulation include those 1) with acute or recent PVT who are potential LT candidates; 2) with symptomatic acute occlusive PVT (eg, worsening portal hypertension); 3) with progression of PVT on imaging; and 4) where there is concern for risk of mesenteric ischemia; Outside of the context of LT, the benefits of anticoagulation for PVT are less clear.
Anticoagulation is the cornerstone of therapy for acute PVT and should be initiated at diagnosis in order to avoid intestinal ischemia and prevent the development of chronic PVT with portal hypertension.
WhenAfter confirmation there is no spontaneous resolution (recanalization) by observing for period and reimaging (1–3 mo); Begin after EGD assessment of portal hypertension or other mucosal lesions and subsequent prophylaxis.Successful anticoagulation
depends on early initiation of therapy.
WhyIn patients who are transplantation candidates, the goal is recanalization with the intent to allow physiologic
anastomosis; in patients who are not transplantation candidates, the goal is recanalization, but data are less clear as to overall benefit.
To prevent propagation of the thrombus and to promote recanalization.
HowAnticoagulation. If there is progression of thrombus despite medical therapy, or when there are features of imminent bowel infarction, endovascular thrombolysis or surgical intervention are necessary.Anticoagulation . If there is progression of thrombus despite medical therapy, or when there are features of imminent bowel
infarction, endovascular thrombolysis or surgical intervention are necessary.
How LongExpert consensus recommendations generally support a minimum of 6 months duration of therapy.Current guidelines from the EASL recommend a minimum treatment duration for 6 months,
commensurate with guidelines for unprovoked venous
thromboembolism. For patients with permanent thrombotic risk factors that cannot be corrected, we suggest long-term anticoagulation rather than six months anticoagulation. Long-term therapy may also be appropriate for patients with acute PVT that extends into the mesenteric veins, given the risk of intestinal infarction in such patients.
Follow upInterval imaging to assess for response to anticoagulation every 3 months on therapy is advised.
PVT, portal vein thrombosis; LT, liver transplantation; EGD, esophagogastroduodenoscopy; EASL, European Association for the Study of the Liver. Gastroenterology 2019;156:1582–1599.

Cirrhotic portal vein thrombosis:

  • In patients with cirrhosis who have recent thrombosis of small intrahepatic sub-branches of the PV or minimally occlusive (<50% obstruction of the lumen) thrombosis of the main PV, observation with serial imaging every 3 months without therapy is reasonable. Treatment for progressive clot should then be considered in this setting.
  • In patients with cirrhosis with recent occlusive or partially occlusive (>50% obstruction of the lumen) thrombosis of the main PV or mesenteric veins, antithrombotic therapy should be considered to avoid thrombosis progression that may hinder a future liver transplantation or cause progression of portal hypertension
  • In patients with chronic complete occlusion of the main PV or cavernous transformation of the PV with established collaterals, there is no established benefit of anticoagulant or interventional therapy, and treatment should be targeted at management of portal hypertension complications.
  • There is evidence to support a role of anticoagulation in patients who are transplantation candidates in order to recanalize the PV prior and preserve physiologic portal flow to the new allograft.
  • Although data to support anticoagulation outside the context of transplantation are less clear, evidence is accumulating that certain patients may benefit from recanalization of the PV.
  • Treatment options include:
    • Wait and watch
    • Systemic anticoagulation:
      • Initiation should be deferred to allow for a full work-up to proceed. Cross-sectional imaging to define thrombus extent and vascular anatomy, endoscopic evaluation and treatment of varices, and evaluation for an underlying thrombophilia (if indicated) are important initial steps.
      • Patients should be started on anticoagulation no later than 6 months after confirmed diagnosis and have demonstrated other risk factors for nonresponse to include advanced liver disease, thrombus presence > 6 months, and anticoagulation initiation > 6 months from diagnosis.
      • Regarding choice of anticoagulant, historical options have been limited to unfractionated heparin, low-molecular weight heparin (LMWH), and VKAs. However, the rise in popularity of direct oral anticoagulants (DOACs) has led to their use in this population, although data remain limited.
    • Interventional revascularization using transjugular intrahepatic portosystemic shunt (TIPS).

Non-cirrhotic acute portal vein thrombosis:

  • Immediate goals of treatment at presentation are to:
    • Prevent propagation of the thrombus prevent thrombus extension to mesenteric veins prevent complications of intestinal ischemia.
    • Promote recanalization achieve recanalization to prevent development of portal hypertension.
  • In patients without cirrhosis and with recent PVT, directed antithrombotic therapy should be considered in order to avoid intestinal ischemia and prevent the development of chronic PVT with portal hypertension.
  • Three main methods have been attempted:
    • Anticoagulation
    • Thrombolysis
    • Interventions like the transjugular intrahepatic portosystemic shunt (TIPS) procedure
  • Anticoagulation:
    • The cornerstone of therapy for acute non-tumor-related PVT, preferably with LMWH or unfractionated heparin in the acute setting followed by VKA.
    • Early retrospective studies established the efficacy of anticoagulation, revealing rates of recanalization from 40%–45%.
    • Current guidelines from the European Association for the Study of the Liver (EASL) recommend a minimum treatment duration for 6 months, commensurate with guidelines for unprovoked venous thromboembolism.
    • Anticoagulation among patients with cirrhosis and portal and/or mesenteric vein thrombosis is not associated with increased risk of variceal bleeding.
  • Thrombolysis or surgical intervention
    • If there is progression of thrombus despite medical therapy, or when there are features of imminent bowel infarction, endovascular thrombolysis or surgical intervention are necessary.
    • Local or systemic thrombolytic therapy should only be considered in very selected cases of recent PVT in whom intestinal ischemia persists despite anticoagulation.
    • PVR followed by TIPS should be considered in LT candidates with chronic PVT that hinders a physiological anastomosis between the graft and recipient PV. This decision is made as part of a multidisciplinary management process, including surgical and interventional radiology expertise.
    • PVR followed by TIPS should be considered in patients with chronic PVT and recurrent bleeding and/or refractory ascites not manageable medically or endoscopically.

Non-cirrhotic chronic portal vein thrombosis:

  • Patients with an unrecognized and untreated acute PVT or who do not respond to treatment are at risk to develop portal cavernoma, which is defined as an extrahepatic PV obstruction and includes chronic thrombosis of the main PV alone with or without thrombus in the intrahepatic and/or more proximal portions of the splanchnic mesenteric venous system.
  • Current EASL guidelines and Baveno VI consensus statement both support indefinite anticoagulation in patients with chronic PVT after prophylaxis of gastrointestinal bleeding and according to underlying prothrombotic risks and history of thrombotic events.

If septic pylephlebitis is diagnosed, prolonged treatment with antibiotics adapted to the isolated bacteria or anaerobic digestive flora is necessary. Limited retrospective data suggest that patients with septic pylephlebitis also benefit from concurrent anticoagulant therapy, with higher complete resolution rates and lower long-term portal hypertension complications.

Note: DOACs are emerging as a common therapy for general medical patients with thrombosis. PVT data remain limited regarding safety and efficacy of these agents in patients with and without cirrhosis. In patients with cirrhosis, caution is advised in patients with advanced portal hypertension, and expert consultation is recommended.

Prognosis:

PVT may either resolve with complete recanalization especially in patients with cirrhosis or evolve into a chronic thrombus, with development of periportal collaterals (portal cavernoma), PH, and portosystemic collaterals including esophagogastric varices.

Complications

  • Intestinal ischemia
    • In any patient who has been diagnosed with PVT, continuous monitoring to look for signs of intestinal ischemia is important. These may include:
      • New onset fever
      • Continuing abdominal pain
      • Ascites
      • Rebound abdominal tenderness
      • Leukocytosis
      • Elevated serum lactate levels
      • Rising inflammatory markers despite anticoagulation
  • Cavernoma (also known as cavernous transformation of the portal vein)
    • A classic feature wherein the original main portal vein is ill defined secondary to fibrosis and replaced by numerous, serpiginous collateral vessels.
    • In patients with fully thrombosed PVT, the fibroblasts form a firm, collagenous plug that develops tortuous veins. The plug is termed a portal cavernoma. This transformation usually begins within days of acute thrombus formation and develops over many months (but may be as little as 6 to 20 days). As a PVT progresses and becomes a portal cavernoma, hepatocellular collaterals connect the patent portions of the vein before and after the thrombus. The number of these collaterals varies from person to person.
  • Severe portal hypertension – although a temporal relationship is difficult to delineate, PVT may be a symptom of disease progression or may be the sentinel event causing decompensation.
  • Gastroesophageal bleeding – major complication from chronic PVT is gastroesophageal bleeding.

Cirrhotic PVT

  • Whether PVT is merely a manifestation of progressive disease or an actual cause of disease progression is still unknown, and the literature is contradictory.
  • Spontaneous recanalization has been observed in up to 40% of patients with cirrhosis who develop PVT, typically within 3 months.
  • The influence of PVT on cirrhosis disease progression and mortality is not fully elucidated.
  • In LT recipients, the presence of PVT at the time of transplant is associated with increased posttransplant mortality.
  • Outside of LT candidates, it is unknown whether PVT in an individual patient with cirrhosis is merely a reflection of progressive portal hypertension or independently causative of increased mortality
  • The literature is mixed as to whether chronic PVT increases mortality; however, it is understood that PVT increases the complexity of liver transplantation and is associated with excess postoperative morbidity and mortality.

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