Background In cirrhosis, thrombin generation (TG) studied in the presence of thrombomodulin (TM) indicates plasma hypercoagulability. Although the role of protein C (PC) deficiency has been investigated, the influence of an increase in the factor VIII 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 (5 pm), phospholipids, and TM (4 nm). 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 929 nm min to 621 nm min (CTP-A), 1122 nm min to 1082 nm min (CTP-B), and 1221 nm min to 1143 nm min (CTP-C); after PC normalization, it decreased from 776 nm min to 566 nm min (CTP-A), 1120 nm min to 790 nm min (CTP-B), and 995 nm min to 790 nm min (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 929 nm min to 340 nm min (CTP-A), 1122 nm min to 506 nm min (CTP-B), and 1226 nm min to 586 nm min (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).
In the presence of activated protein C, no hypercoagulability was observed, adding to the current evidence that acquired protein C deficiency plays a key role in the coagulation imbalance.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.