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.
An acute infusion reaction is a major event in the history of inflammatory bowel diseases patients treated with infliximab as it could lead to drug discontinuation and thus limits the therapeutic armamentarium considerably. The resumption of infliximab after drug holiday is a major risk factor for an acute infusion reaction. Premedication efficacy remains questionable and should be limited to these high-risk patients.
Context: Cirrhosis impacts the coagulation cascade since the first stage of the liver disease. For years, a procoagulant imbalance, related to the severity of cirrhosis, has been demonstrated. This procoagulant imbalance is detected when coagulation assays are sensibilised to the protein C pathway. A resistance to thrombomodulin (TM) is consistently found in thrombin generation assays. TM and endothelial protein C receptor (EPCR) are two transmembrane proteins involved in the anticoagulant protein C pathway. A soluble form of EPCR (sEPCR) is release of the endothelial surface upon cleavage by mettaloprotease. Soluble EPCR have a procoagulant and proinflammatory effects: bound to PC or activated PC (APC), PC is unavailable for activation by thrombin-TM complex and APC is unable to inactivate FVa and FVIIIa. The aim of this study was to evaluate the plasma levels of sEPCR in non-complicated cirrhotic patients as a potential marker for procoagulant imbalance, compared to healthy controls.
Materials and Methods: Patients prospectively included were confirmed cirrhotic patients (prothrombin time <70% and/or liver dysmorphia and/or fibroscan > 20 kPa and/or histology and/or association of portal hypertension and liver failure). Patients were free of hepatocellular carcinoma and were not anticoagulated. Patients with on-going infection or inflammatory complication were excluded. None of them had a thromboembolic event or a familial history of thromboembolism. Controls were free of anticoagulation, coagulation disorders and without oral contraceptives. All ethical requirments were obtained and patients and controls gave their written informed consent. Kruskal-Wallis test and Dunn post test were used for statistical analysis. Results are expressed as mean (Q1 - Q3) values of sEPCR.
Results: Fifty two cirrhotic patients (24 Child-Pugh A, 21 Child-Pugh B and 7 Child-Pugh C) and 32 healthy controls were prospectively included in our hospital. The sEPCR values for healthy controls were 100 ng/mL (81 - 135 ng/mL). Comparatively to controls, Child-Pugh A patients and Child-Pugh B patients had statistically significant higher values of sEPCR : 169 ng/mL (117-225 ng/mL, p < 0.01) and 176 (135 - 230 ng/mL, p < 0.001) respectively (Figure 1). Compared to healthy controls, Child-Pugh C patients had an increased level of sEPCR : 174 ng/mL (78 - 254 ng/mL, not significant but probably underpowered). These data are in lines with the thrombin generation profiles showing a resistance to TM in cirrhotic patients increasing from Child-Pugh A to C. No patient have developed thrombosis during the follow-up period.
Conclusion: Patients with Child-Pugh A and B cirrhosis had significantly higher values of sEPCR compared to healthy controls (p < 0.01 for both). The putative role of sEPCR as a marker of the procoagulant imbalance associated to cirrhosis remains to be accurately evaluated.
Figure 1. sEPCR levels in plasma of cirrhotic patients. Figure 1. sEPCR levels in plasma of cirrhotic patients.
Disclosures
No relevant conflicts of interest to declare.
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.