Thrombotic Risk and Coagulation Imbalance in Cirrhosis and Hepatocellular Carcinoma: Clinical Implications and Management

Abstract

Hepatocellular carcinoma (HCC) is characterized by a complex disruption of hemostatic balance, increasing the risk of both thrombotic and hemorrhagic events. Thrombotic complications, most notably portal vein thrombosis (PVT) and venous thromboembolism (VTE), have a significant impact on clinical outcomes and therapeutic strategies. Cirrhosis contributes to the precarious equilibrium between pro- and anticoagulant forces through impaired synthesis of coagulation factors, endothelial dysfunction, and systemic inflammation. In the presence of HCC tumor-driven mechanisms, such as tissue factor expression, extracellular vesicle release, platelet activation, and suppression of fibrinolysis exacerbate this prothrombotic state. In this scenario, advanced diagnostic tools such as thrombin generation assay (TGA) and rotational thromboelastometry (ROTEM) offer a more accurate assessment of coagulation dynamics than conventional tests, enabling better risk stratification especially for therapeutic purposes. Anticoagulant therapy has demonstrated clinical benefit in selected cases of non-malignant PVT and VTE, particularly when liver function is preserved. While prophylactic strategies are still under investigation, data suggest they may be safely implemented in selected surgical patients. In the setting of immunotherapy, especially regimens involving anti-VEGF agents, anticoagulation may be considered with careful management of bleeding risk due to portal hypertension. An individualized approach to anticoagulation, supported by functional coagulation testing, is gaining acceptance as a means to safely reduce thrombotic burden and potentially improve outcomes in patients with HCC.

Keywords: anticoagulation; cirrhosis; hemostasis; hepatocellular carcinoma; immunotherapy; liver cancer; portal vein thrombosis; systemic therapy; thrombosis; venous thromboembolism.

Figure 1

PVT and DVT/PE prevalence in HCC across studies, with weighted mean (blue for PVT, red for DVT/PE) [11,12,13,14,15,19,20,21,23,24,27,28,29,30,31].

Figure 2

Molecular mechanisms of PVT and VTE in HCC. Created in Biorender. Abbreviations. TF: Tissue Factor; TPO: Thrombopoietin; CSC (EpCAM⁺): Cancer Stem Cells (Epithelial Cell Adhesion Molecule positive); YAP: Yes-associated protein; uPA/uPAR: Urokinase-type Plasminogen Activator/uPA Receptor; TMPs: Tumor-derived Microparticles; EVs/MVs: Extracellular Vesicles/Microvesicles; P-selectin: Platelet-selectin; pEV: Platelet-derived Extracellular Vesicle; CD61/CD62P: Cluster of Differentiation 61/62P; MP: Microparticles; miR-126: MicroRNA-126; Fibrinogen: Fibrinogen; Factor VIII: Coagulation Factor VIII; vWF: von Willebrand Factor; MP–TF: Microparticle–Tissue Factor; PAI-1: Plasminogen Activator Inhibitor-1; TAFI: Thrombin-Activatable Fibrinolysis Inhibitor; ET-1: Endothelin-1; AnxA5/PS: Annexin A5/Phosphatidylserine; VEGF/VEGFR: Vascular Endothelial Growth Factor/VEGF Receptor; Ang-2: Angiopoietin-2; lncRNA: Long Non-Coding RNA; IL-6: Interleukin-6; CRP: C-Reactive Protein; ICAM-1: Intercellular Adhesion Molecule-1; TNF-α: Tumor Necrosis Factor-alpha; HMGB1: High-Mobility Group Box 1; miR-381: MicroRNA-381; CXCL1/CXCL8 (IL-8): C-X-C Motif Chemokines 1 and 8 (Interleukin-8); NETosis: Neutrophil Extracellular Trap Formation; 8-OHdG: 8-Hydroxy-2’-deoxyguanosine; MDA: Malondialdehyde; ROS: Reactive Oxygen Species; TM: Thrombomodulin; EPCR: Endothelial Protein C Receptor; NO: Nitric Oxide; PGI₂: Prostacyclin (Prostaglandin I₂); Antithrombin III: Antithrombin III; Protein C/S: Protein C/Protein S; ADAMTS13: A Disintegrin And Metalloproteinase with Thrombospondin Motifs 13; Plasminogen: Plasminogen; fXIII: Coagulation Factor XIII; PAP complex: Plasmin–Antiplasmin Complex.