Testing for the JAK2 V617F activating mutation is the most appropriate next step. This patient presents with acute portal hypertension caused by thrombosis of the hepatic veins, or Budd-Chiari syndrome (BCS), which is one of the few noncirrhotic causes of portal hypertension. Clinically, this syndrome can present acutely as fulminant hepatic failure or subacutely with tender hepatomegaly and rapid-onset ascites, as in this patient. Upon discovery of the JAK2 activating mutation in 2005, it became apparent that up to half of patients with idiopathic BCS had an acquired mutation in JAK2, without overt suggestion of a myeloproliferative neoplasm. Therefore, testing for JAK2 is part of the diagnostic testing protocol that includes consideration of paroxysmal nocturnal hemoglobinuria in the differential diagnosis of splanchnic vein thrombosis.

Antiphospholipid antibodies have been associated with BCS, but they are notoriously nonspecific, and much of the literature concerning antiphospholipid antibodies was written before more specific acquired causes were discerned. Diagnosis of antiphospholipid antibody syndrome requires persistent elevation of antibodies in association with a clinically consistent clot. Because deep venous thrombosis (DVT) and pulmonary embolism (PE), arterial thrombosis, and placental clots are more commonly associated with antiphospholipid antibody syndrome than splanchnic vein thrombosis, testing for this disorder is not indicated until other more likely diagnoses are excluded.

Factor V Leiden most characteristically presents as DVT, with or without PE. Less commonly, patients may experience cerebral, mesenteric, and portal vein thrombosis.

Patients with the prothrombin gene mutation (G20210A) are at increased risk for DVT and, less commonly, cerebral vein thrombosis. In patients with splanchnic vein thrombosis, testing for the more common JAK2 mutation is the most appropriate initial step.