Contact System Activation and Neutrophil Extracellular Trap Markers: Risk Factors for Portal Vein Thrombosis in Patients With Hepatocellular Carcinoma

Abstract

Although portal vein thrombosis (PVT) commonly occurs in patients with hepatocellular carcinoma (HCC), the hypercoagulability mechanism in patients with HCC is not entirely clear. Recently, tumor-induced formation of neutrophil extracellular traps (NET) has been shown to trigger contact system activation, and contact system activation has been shown to be a new mechanism of thrombosis. Therefore, we investigated whether contact system activation and NET formation occurred in relation to PVT in HCC patients. The circulating levels of NET formation markers (DNA–histone complex, double-stranded DNA, neutrophil elastase) and contact system activation markers (factor XIIa and high-molecular-weight kininogen) were measured in 177 patients who had been diagnosed with HCC and 48 healthy controls. Presence of PVT was confirmed in 77 HCC patients. The levels of NET formation and contact system activation markers were significantly higher in patients than in healthy controls and they increased significantly with the increase in the model for end-stage liver disease (MELD) scores. Of note, these markers were significantly higher in HCC patients with PVT than in those without PVT. These NET formation markers and the contact system activation markers were significant thrombotic risk factors in HCC patients. The well-known liver injury markers (alanine transaminase, prothrombin time) significantly contributed to factor XIIa level. Contact system activation and NET formation are well correlated with liver disease severity and the markers of these can be used as thrombotic risk factors in HCC patients. In addition, therapeutics inhibiting the contact system can be potentially used to manage PVT in HCC patients.