What are the causes of hepatic vein thrombosis?

Causes of Hepatic Vein Thrombosis (Budd-Chiari Syndrome)

Hepatic vein thrombosis results from a combination of systemic prothrombotic disorders (present in up to 84% of cases) and local mechanical factors, with myeloproliferative neoplasms being the single most important underlying cause. 1

Systemic Prothrombotic Disorders

Myeloproliferative Neoplasms (Most Important)

• Myeloproliferative disorders are the dominant cause of hepatic vein thrombosis, particularly in young women, even when peripheral blood counts appear normal. 1
• JAK2V617F mutation testing is 100% specific and should be performed first in all patients with hepatic vein thrombosis. 1
• When JAK2V617F is negative, calreticulin mutation screening should follow, and if both are negative, bone marrow biopsy showing clusters of dystrophic megakaryocytes or endogenous erythroid colony formation confirms the diagnosis. 1
• The combination of splenomegaly with platelet counts >200,000/mm³ strongly suggests an underlying myeloproliferative disorder even without other hematologic abnormalities. 1
• In one prospective study, 16 of 20 patients with Budd-Chiari syndrome had evidence of myeloproliferative disorder on erythroid colony testing, though only 2 met conventional diagnostic criteria. 2

Inherited Thrombophilias

• Factor V Leiden mutation increases risk and should be tested via protein C resistance assay followed by molecular confirmation if positive. 1
• Prothrombin G20210A gene mutation requires molecular biology testing. 1
• Inherited deficiencies of antithrombin, protein C, and protein S are difficult to diagnose in hepatic vein thrombosis due to decreased hepatic synthesis and require correlation with prothrombin levels and family history. 1

Acquired Thrombophilias

• Paroxysmal nocturnal hemoglobinuria must be excluded via flow cytometry for CD55 and CD59 deficient clones (or Ham-Dacie/sucrose tests where flow cytometry is unavailable). 1
• Antiphospholipid syndrome requires repeatedly detectable high levels of anticardiolipin antibodies, lupus anticoagulant, or anti-beta2 glycoprotein 1 antibodies in the setting of thrombosis. 1
• Low, fluctuating anticardiolipin antibody levels have uncertain diagnostic value and should not be over-interpreted. 1

Hormonal and Medication Factors

• Oral contraceptive use at the time of symptom onset is a recognized risk factor, particularly when combined with underlying prothrombotic disorders. 1
• Pregnancy at the time of symptom onset increases risk. 1

Local Mechanical Factors

Compression and Obstruction

• Solid malignancies or cysts that compress the hepatic venous tract or inferior vena cava can cause secondary hepatic vein thrombosis. 1
• In Asian populations, membranous obstruction (webs) of the inferior vena cava is a more common cause than in Western countries. 1

Geographic Variations

• Behçet's disease is a more prevalent cause in Asian populations and should be diagnosed using conventional criteria including IVC thrombosis. 1
• Hydatid cysts are more common in endemic regions. 1

Multifactorial Nature (Critical Clinical Point)

The etiology is multifactorial in the majority of cases, with 46% of Budd-Chiari syndrome patients having two or more prothrombotic factors, and 18% having three risk factors. 1

• Over 60% of patients with inherited thrombophilia have an additional risk factor beyond the genetic mutation. 1
• Among patients using oral contraceptives who develop hepatic vein thrombosis, the majority have an underlying prothrombotic disorder. 3
• This multifactorial nature means that finding one cause should not stop the diagnostic workup—comprehensive thrombophilia screening is mandatory in all cases. 3

Diagnostic Algorithm

1. First-line testing: JAK2V617F mutation (highest yield), flow cytometry for paroxysmal nocturnal hemoglobinuria, and antiphospholipid antibodies. 1

2. Second-line testing: Factor V Leiden, prothrombin G20210A mutation, and if JAK2V617F negative, proceed to calreticulin mutation testing. 1

3. Third-line testing: Protein C, protein S, and antithrombin levels (recognizing diagnostic limitations due to liver dysfunction), and bone marrow biopsy if myeloproliferative disorder is suspected but molecular testing is negative. 1

4. Imaging assessment: Evaluate for mechanical compression by tumors, cysts, or IVC webs, particularly in Asian patients. 1

Common Pitfalls

• Do not dismiss normal peripheral blood counts as excluding myeloproliferative disorder—latent disease without hematologic abnormalities is common in hepatic vein thrombosis, particularly in young women. 2
• Do not stop investigation after finding one risk factor—the high prevalence of multiple concurrent factors means comprehensive testing is essential for accurate risk stratification and long-term anticoagulation decisions. 1, 3
• Protein C, protein S, and antithrombin levels are often decreased due to impaired hepatic synthesis rather than true deficiency, making definitive diagnosis impossible in many cases without family history or repeat testing after liver function normalizes. 1