Can a prothrombotic state in a patient with a history of cirrhosis (liver scarring) be a manifestation of developing hepatocellular carcinoma (HCC, liver cancer)?

Prothrombotic State as a Manifestation of Developing HCC in Cirrhosis

Yes, a prothrombotic state in a cirrhotic patient can be a manifestation of developing HCC, as HCC independently shifts the hemostatic balance toward hypercoagulability beyond what cirrhosis alone produces. 1, 2

Evidence for HCC-Driven Hypercoagulability

Patients with cirrhosis and HCC demonstrate a significantly more prothrombotic hemostatic profile compared to cirrhotic patients without HCC, independent of cirrhosis stage. 2 This distinction is critical because it means the prothrombotic state is not simply a reflection of worsening liver disease, but rather a specific consequence of the malignancy itself.

Specific Hemostatic Alterations in HCC

The mechanisms through which HCC tips the hemostatic balance include:

• Enhanced thrombin generation with reduced activation of fibrinolysis 2
• Increased fibrinogen concentration and polymerization 1, 3
• Thrombocytosis and increased platelet activation/function 1, 3
• Release of tissue factor-expressing extracellular vesicles from tumor cells 1, 3
• Hypofibrinolysis with elevated plasminogen activator inhibitor-1 levels 2
• Elevated serum homocysteine levels significantly higher than in cirrhotic patients without HCC 4

Clinical Implications

Patients with HCC are at increased risk for both portal vein thrombosis (PVT) and non-splanchnic venous thromboembolism (VTE), indicating that both local and systemic factors foster site-specific thrombosis. 1 The portal vein is the most frequent thrombotic site in HCC patients 1, but the systemic hypercoagulable state extends beyond the splanchnic circulation.

Distinguishing Cirrhosis-Related from HCC-Related Prothrombotic States

Cirrhosis itself creates a prothrombotic condition due to increased factor VIII (procoagulant driver) combined with decreased protein C (anticoagulant driver). 5 However, the key distinction is that HCC produces additional and more pronounced hypercoagulable changes beyond baseline cirrhosis 2.

Important Diagnostic Considerations

When evaluating a cirrhotic patient with new thrombotic events:

• PVT prevalence in cirrhotic patients without HCC ranges from 2.1% to 23.3% 5
• The presence of cirrhosis alone confers a relative risk of 7.3 for developing non-neoplastic PVT 5
• However, HCC further amplifies this thrombotic risk through tumor-specific mechanisms 1, 2

Clinical Pitfalls and Surveillance Implications

A critical pitfall is assuming that new thrombotic events in cirrhotic patients are simply due to worsening portal hypertension rather than investigating for occult HCC. 1 When a cirrhotic patient develops:

• New or progressive PVT
• Unexplained systemic VTE
• Laboratory evidence of enhanced hypercoagulability (elevated fibrinogen, thrombocytosis, elevated homocysteine)

These findings should prompt HCC surveillance imaging with multiphasic CT or MRI, even if routine surveillance is not yet due. 5

Surveillance Recommendations

For cirrhotic patients at risk of HCC:

• Six-month surveillance intervals with ultrasound or multiphasic CT/MRI are recommended 5
• Approximately 1-8% of cirrhotic patients develop HCC per year (2% in HBV-infected, 3-8% in HCV-infected) 5
• One-third of cirrhotic patients will develop HCC during their lifetime 5

Management Considerations

Currently, there are no specific guidelines on thromboprophylaxis for cirrhotic patients with HCC, representing an urgent unmet clinical need. 1, 3 However, the recognition of HCC-driven hypercoagulability has important implications:

• Anticoagulation with heparins or vitamin K antagonists, once considered contraindicated in cirrhosis, is now recognized as feasible and appropriate for thrombotic complications 5
• The 2025 AGA guidelines note that anticoagulation does not increase portal hypertensive bleeding risk 5
• Prophylactic anticoagulation in cirrhotic patients without PVT has shown reduced incident PVT, decompensation, and mortality 5

Risk Stratification Needs

There is urgent need for prospective studies to identify which HCC patients have the highest prothrombotic profile and would benefit from early thromboprophylaxis. 1 Until such data exist, clinicians should maintain heightened awareness that new thrombotic events may signal either developing HCC or progression of existing HCC.