Hyper-functional platelets are being proposed as a potential therapeutic target in multiple cancers. Whether this can be considered in patients with cirrhosis and hepatocellular carcinoma (HCC) is unknown as their platelet function has not yet been investigated. We evaluated platelet function in cirrhosis patients with HCC. Patients with cirrhosis with and without HCC were prospectively recruited. Platelet aggregation, a marker of platelet function, was assessed by impedance aggregometry with adenosine diphosphate (ADP), arachidonic acid (ASPI), and thrombin (TRAP) stimulation. Plasmatic levels of Von Willebrand factor antigen (VWF) were also determined. One-hundred patients were recruited (50 cirrhotics with and 50 without HCC). Cirrhosis severity by Child class and platelet count were comparable between cirrhotics with and without HCC. Cirrhotics with HCC had higher ADP- (45 vs. 28; p < 0.001), ASPI- (47 vs. 28; p < 0.001), and TRAP- (85 vs. 75; p = 0.01) induced platelet aggregation than cirrhotics without HCC, all indicative of platelet hyper-function. The relatively increased platelet aggregation in patients with HCC was confirmed after adjusting the analysis for platelet count/severity of thrombocytopenia. Levels of VWF were higher in patients with vs. without HCC (348 vs. 267; p = 0.006), particularly in compensated cirrhosis. In patients with cirrhosis, HCC is associated with increased platelet aggregation and higher VWF. The clinical implications of these findings deserve further investigation.

The clinical utility of thrombomodulin-modified thrombin generation (TM-TG) in cirrhosis is uncertain. We conducted a prospective study to evaluate the prognostic value of TM-TG in cirrhosis. Patients were recruited during outpatient clinics (compensated and stable decompensated cirrhosis) or if admitted to our inpatient service (acutely decompensated cirrhosis). We performed whole blood (WB) and platelet-poor plasma (PPP) TM-TG at recruitment. All patients were prospectively followed-up for bleeding/thrombosis, hepatic decompensation, and liver-related death. We included 231 patients: 80 with compensated, 70 with stable decompensated, and 81 with acutely decompensated cirrhosis. Median follow-up was 414 days (range: 77-668). Eleven patients, all with acutely decompensated cirrhosis, experienced procedure-related bleeding. Both WB-TG and PPP-TG were more altered in bleeding vs. non-bleeding individuals (lower endogenous thrombin potential [ETP] and peak-height). However, only WB-TG could identify - at the individual patient level - those experiencing major bleeding (all having pre-procedural ETP <350 nmol/L∗min). In acutely decompensated cirrhosis, the AUC of WB-TG ETP for bleeding was 0.854 (95% CI 0.732-0.976), which was higher than that of PPP-TG ETP (0.676; 95% CI 0.524-0.809). Neither WB-TG nor PPP-TG could predict development of thrombosis, mostly portal vein thrombosis (n = 15). In compensated cirrhosis, WB-TG and PPP-TG were comparable between patients who experienced decompensation and those who did not. In decompensated cirrhosis, WB-TG and PPP-TG were more significantly altered in patients experiencing further decompensation/ACLF/liver-related death. A higher WB-TG ETP was linked to a lower risk of progression independently of MELD, Child-Pugh, and C-reactive protein (hazard ratio 0.4, 95% CI 0.21-0.79, p <0.01). In compensated cirrhosis, WB-TG and PPP-TG do not improve risk stratification. In decompensated cirrhosis, WB-TG may be a promising tool for estimating procedure-related bleeding risk. Thrombomodulin-modified thrombin generation (TM-TG) in cirrhosis is a well-established research tool to assess the complex coagulopathy of cirrhosis; however, its clinical utility is uncertain. In acutely decompensated cirrhosis, a TM-modified whole blood (WB)-TG ETP <350 nmol/L∗min predicted major bleeding after invasive procedures, whereas platelet-poor plasma TG indicated a hypo-coagulable state in bleeding patients but could not identify those at risk. Neither WB-TG nor platelet-poor plasma-TG could predict development of portal vein thrombosis, which was predicted by cirrhosis and portal hypertension severity. In decompensated cirrhosis, a better WB-TG capacity was associated with a lower risk of further decompensation, acute-on-chronic liver failure, and liver-related death independently of MELD score/Child-Pugh stage and C-reactive protein.