Background In cirrhosis, thrombin generation (TG) studied in the presence of thrombomodulin (TM) indicates plasma hypercoagulability. Although the role of proteinC (PC) deficiency has been investigated, the influence of an increase in the factorVIII level has never been addressed.Objectives We investigated the roles of high FVIII and low PC levels in increased TG in the presence of TM.Methods Blood samples were prospectively collected from 35 healthy controls and 93 patients with cirrhosis (Child-Turcotte-Pugh [CTP]-A, n=61; CTP-B, n=19; and CTP-C, n=13) and FVIII levels >150% (n=48) and/or PC levels <70% (n=88). TG was performed with tissue factor (5pm), phospholipids, and TM (4nm). FVIII and PC levels were normalized by adding an inhibitory anti-FVIII antibody and exogenous PC, respectively.Results The endogenous thrombin potential (ETP) in the presence of TM was higher in patients than in controls. After FVIII normalization, the ETP (median) decreased from 929nmmin to 621nmmin (CTP-A), 1122nmmin to 1082nmmin (CTP-B), and 1221nmmin to 1143nmmin (CTP-C); after PC normalization, it decreased from 776nmmin to 566nmmin (CTP-A), 1120nmmin to 790nmmin (CTP-B), and 995nmmin to 790nmmin (CTP-C). The ETP was reduced by 17% and 30%, respectively, but normal TG was not restored. When both FVIII and PC levels were normalized, the ETP decreased from 929nmmin to 340nmmin (CTP-A), 1122nmmin to 506nmmin (CTP-B), and 1226nmmin to 586nmmin (CTP-C), becoming similar to control levels.Conclusion Cirrhosis-induced plasma hypercoagulability, as demonstrated in these experimental conditions, can be partly explained by opposite changes in two factors: PC level (decrease) and FVIII level (increase).