Increased factor VIII plays a significant role in plasma hypercoagulability phenotype of patients with cirrhosis

Abstract

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).

Whole blood thrombin generation profiles of patients with cirrhosis explored with a near patient assay

“…The TM resistance in cirrhosis is most probably due to their reduced protein C and protein S, combined with the elevated FVIII levels. [43][44][45] The high dose of TM, however, did substantially prolong the lagtime of WB-TG in both patients and controls, but this effect may be not via the anticoagulant function of the protein C pathway, but rather because TM prevented thrombin from activating platelets and consequently limited the availability of procoagulant phospholipids. 46 This study has several limitations.…”

“…Conversely, a much lower dose of TM (10 nmol/L) exhibited a much stronger inhibitory effect on the ETP of PPP‐TG and the effect was five‐fold weaker in the patients than in controls. The TM resistance in cirrhosis is most probably due to their reduced protein C and protein S, combined with the elevated FVIII levels . The high dose of TM, however, did substantially prolong the lagtime of WB‐TG in both patients and controls, but this effect may be not via the anticoagulant function of the protein C pathway, but rather because TM prevented thrombin from activating platelets and consequently limited the availability of procoagulant phospholipids…”

Hemostatic Alterations in Patients With Cirrhosis: From Primary Hemostasis to Fibrinolysis

“…(60) Coagulation factors are decreased in LC, except for factor VIII, which is increased. (61) This is reflected by routine coagulation assays. These assays, however, do not reflect total in vivo thrombin generation (62) and do not correlate with bleeding occurrence.…”

“…Contrary to the other coagulation factors, fibrinogen levels decrease only in advanced LC. (61) This could be due to underlying inflammation, as fibrinogen is an acute-phase protein. (64,65) Fibrinogen could also undergo structural modifications, leading to functional alterations in LC.…”

Mechanisms of enhanced thrombin‐generating capacity in patients with cirrhosis

“…An article by Sinegre et al in this issue of the Journal of Thrombosis and Haemostasis addresses the question of which factors determine enhanced thrombin-generating capacity in patients with cirrhosis [13]. Previous studies have demonstrated that regulation of thrombin generation by the protein C pathway is decreased in patients with cirrhosis, and that normal to increased thrombin generation in thrombomodulin-modified thrombin generation tests relates to resistance to the anticoagulant action of thrombomodulin [17].…”