Impaired whole blood thrombin generation is associated with procedure-related bleeding in acutely decompensated cirrhosis

Background & Aims: 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. Methods: 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. Results: 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). Conclusions: 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. Impact and implications: 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.