A 79-year-old with acute portal vein thrombosis

FINDING THE CAUSE

3. Which of the following is not a common cause
of portal vein thrombosis?

• A hypercoagulable state
• Immune deficiency
• Intra-abdominal infection
• Malignancy
• Portal hypertension

Once portal vein thrombosis has been diagnosed, the cause should be identified (Table 2). The differential diagnosis is broad, including both local factors (eg, injury to the portal vein, local inflammation, infection) and general factors (eg, inherited and acquired hypercoagulable conditions). Thrombophilias are identified in 60% of patients with portal vein thrombosis and local factors in 40%.⁷ Moreover, the etiology is often  multifactorial. However, immune deficiency is not a common cause.

Hypercoagulability

Prothrombotic disorders can be either inherited or acquired.

Inherited deficiencies in the natural anticoagulants antithrombin, protein C, and protein S are associated with a high risk of thrombosis but have a low prevalence in the general population. In the setting of liver abnormalities, familial testing may be helpful to distinguish inherited causes of portal vein thrombosis from defective liver function as a consequence of portal vein thrombosis. The factor V Leiden mutation (G1691A) and the G20210A mutation in the prothrombin gene are more prevalent (> 2%) but generally confer a lower thrombosis risk.¹⁶ The prothrombin gene mutation G20210A is the most common risk factor for portal vein thrombosis, with prevalence of 2% to 22% in adults with nonmalignant, noncirrhotic portal vein thrombosis.³

Hyperhomocysteinemia due to a methylene tetrahydrofolate reductase (MTHFR) mutation (C677T) is another inherited associated risk factor for portal vein thrombosis, but hyperhomocysteinemia can also arise as a complication of portal vein thrombosis-related liver disease.³

Acquired prothrombotic disorders, particularly myeloproliferative diseases, are found in 22% to 48% of cases of portal vein thrombosis. Many young patients with myeloproliferative disorders present with portal vein thrombosis as the first symptom, and testing for the G1849T point mutation in JAK2 can make the diagnosis.¹⁷ Splenectomy with underlying myeloproliferative disorder confers a particularly high risk for portal vein thrombosis.¹⁸

Other thrombophilic disorders including antiphospholipid antibody syndrome, paroxysmal nocturnal hemoglobinuria, and malignancy can contribute to portal vein thrombosis.³  Pregnancy and oral contraceptive use have also been associated with hypercoagulability, and cessation of oral estrogen is recommended in such cases. The risk may be further increased in patients on oral contraceptives who have a previously unrecognized hypercoagulable state.³ 

Inflammation and infection

Inflammation and infection are local risk factors for portal vein thrombosis. Acute portal vein thrombosis has been associated with intra-abdominal infections (eg, appendicitis, cholecystitis) and with inflammatory conditions such as inflammatory bowel disease and pancreatitis.^16,19 From 3% to 5% of all portal vein thrombosis cases result from pancreatitis, either from a single acute episode or from repeat inflammation of chronic pancreatitis.¹⁰ Portal vein thrombosis in the setting of inflammatory bowel disease can occur even when the disease is in remission, particularly in ulcerative colitis.^20,21

Injury to the portal venous system

Abdominal surgery, particularly splenectomy, portosystemic shunting, colectomy, and blunt abdominal trauma can cause injury to the portal venous system, resulting in portal vein thrombosis. This is usually seen only in patients with portal hypertension, an underlying prothrombotic condition such as myeloproliferative disease, or inflammatory bowel disease.^10,19,22

Impaired portal vein flow

Cirrhosis and malignancy are major risk factors for portal vein thrombosis. In case series, cirrhosis was found in 24% to 32% of patients with portal vein thrombosis.^2,23 However, the overall prevalence of portal vein thrombosis in cirrhotic patients varies widely, from 0.6% to 28%, depending on the degree of cirrhosis.¹⁰

The pathogenesis of portal vein thrombosis in cirrhosis is unclear but may be multifactorial. Decreased portal blood flow (with subsequent stasis) and periportal lymphangitis and fibrosis are thought to stimulate thrombus formation.^3,10 Additionally, patients with advanced cirrhosis are prothrombotic because of reduced hepatic synthesis of antithrombin, protein C, protein S, and coagulation factors.

Malignancy is associated with 21% to 24% of cases of portal vein thrombosis in adults, with pancreatic cancer and hepatocellular carcinoma being the most common.^2,3 Others include cholangiocarcinoma and carcinomas of the stomach, lung, prostate, uterus, and kidney. Cancer causes portal vein thrombosis through a combination of tumor invasion into the portal vein, extrinsic compression by the tumor, periportal fibrosis following surgery or radiation, and hypercoagulability secondary to malignancy.^9,16,24

Idiopathic portal vein thrombosis

Portal vein thrombosis is usually caused by one or more of the underlying factors mentioned above but is idiopathic in 8% to 15% of cases.¹⁰

Back to our patient

The cause of this patient’s portal vein thrombosis is unclear. He did not have a history of cirrhosis, inflammatory bowel disease, trauma, or abdominal surgery. His febrile illness could have precipitated the formation of a thrombus, but no definitive source of infection or inflammation was discovered. His workup was negative for pancreatitis, appendicitis, cholecystitis, diverticulitis, and prostatitis. No occult malignancy was found. It is also possible that his fever was the result of the thrombosis.

A full hypercoagulability panel revealed no striking abnormalities. He did have elevated fibrinogen and factor VIII levels that were consistent with an acute-phase reaction, along with an elevated erythrocyte sedimentation rate (> 90 mm/hr) and C-reactive protein level. Aside from the portal vein thrombosis, no potential source of inflammation could be identified.

Mildly reduced levels of antithrombin III activity were attributed to enoxaparin therapy and ultimately normalized on repeated testing. The patient had very minimally elevated titers of anticardiolipin immunoglobulin G (1:10 GPL) and anti-beta-2 glycoprotein immunoglobulin M (21 SMU), which were not thought to be significant. Tests for lupus anticoagulant, prothrombin gene mutation, activated protein C resistance, and JAK2 mutation were negative.

TREATMENT

4. Treatment of symptomatic portal vein thrombosis generally includes which two of the following?

• Anticoagulation
• Intravenous gamma globulin
• Broad-spectrum antibiotics

Anticoagulant therapy

Treatment of acute, symptomatic portal vein thrombosis involves anticoagulant therapy to prevent extension of the thrombus and, ultimately, to allow for recanalization of the obstructed veins. Anticoagulant therapy is initially intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin, eventually bridged to an oral agent such as warfarin.^3,9 Currently, there are inadequate data on the use of oral or parenteral factor Xa inhibitors or direct thrombin inhibitors in the treatment of this disease.

When started immediately, anticoagulation therapy is associated with complete recanalization in 38.3% and partial recanalization in 14% of patients presenting with complete thrombosis. Without anticoagulation, spontaneous recanalization is unusual.²⁵

Although the optimal duration of anticoagulant therapy is unclear, a minimum of 3 months is generally recommended.^9,26 If a hypercoagulable state is present or if the portal vein thrombosis is unprovoked (eg, by surgery, trauma, or an intra-abdominal infection), long-term treatment should be considered.²⁶

Experience with thrombolytic therapy or mechanical recanalization has been limited, but the use of catheter-based techniques for pharmacomechanical thrombolysis has been reported.^27–29 Transjugular intrahepatic portosystemic shunting is also an alternative to anticoagulation, but its role in treating portal vein thrombosis is complicated by technical difficulties of the procedure, postoperative complications, and recurrent occlusion of the shunt.²⁵

Currently, there are no data comparing the risk-benefit ratio of early anticoagulation and that of invasive procedures. These more aggressive treatments are generally considered only when there is extensive thrombosis or ascites (which are both predictive factors of poor response to anticoagulation alone) and in patients for whom anticoagulation has failed.³ Surgical thrombectomy is rarely indicated, typically only in instances in which laparotomy is being performed for suspected bowel infarction.³

Antibiotics

In addition to anticoagulation, broad-spectrum antibiotics covering gram-negative and anaerobic bacteria are indicated for those cases of portal vein thrombosis associated with underlying infection.⁹

For chronic cases, the goals of management are to prevent and treat gastroesophageal variceal bleeding and to prevent recurrent thrombosis.⁹ Nonselective beta-blockers (eg,  propranolol) and endoscopic band ligation have shown evidence of reducing the incidence of recurrent bleeding and prolonging survival in retrospective studies.^9,30,31 Long-term anticoagulation is generally indicated to prevent further thrombosis and to increase the likelihood of recanalization only for patients with a permanent prothrombotic condition.⁹ In patients with clinically significant portal hypertension, the benefit of continued anticoagulation therapy must be weighed against the risk of esophageal and gastric variceal bleeding.

There is controversy regarding how to manage portal vein thrombosis that is incidentally identified and asymptomatic (eg, if it is discovered on an imaging study for another indication). Current guidelines recommend against anticoagulation in patients with incidentally discovered and asymptomatic splanchnic vein thrombosis, including portal vein thrombosis.²⁶

Intravenous gamma globulin is not part of the treatment.

CASE CONTINUED

The patient’s presenting symptoms of fever, chills, and abdominal pain completely resolved after a course of antibiotic therapy. The erythrocyte sedimentation rate subsequently normalized and factor VIII activity improved. We believed that an underlying infectious or inflammatory process had contributed to the development of portal vein thrombosis, though the specific cause could not be identified. The patient was treated with enoxaparin 1 mg/kg twice a day and transitioned to warfarin.

Magnetic resonance venography done 3 months after diagnosis showed persistent right portal vein thrombosis that was largely unchanged. Anticoagulation was continued for 1 year with no change in his portal vein thrombosis on sequential imaging and was subsequently discontinued. To date, no malignancy or infectious process has been found, and the patient continues to do well 2 years later.