Coagulation Proteins Influencing Global Coagulation Assays in Cirrhosis: Hypercoagulability in Cirrhosis Assessed by Thrombomodulin-Induced Thrombin Generation Assay

Abstract

Background. Liver disease is accompanied by profound hemostatic disturbances. We investigated the influences of pro- and anticoagulation factors on global coagulation tests including prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin generation assay (TGA) in cirrhosis. We also investigated whether cirrhotic patients exhibit hypo- or hypercoagulability using the TGA. Methods. The TGA was performed on a calibrated automated thrombogram, given lag time, endogenous thrombin potential (ETP), and peak thrombin in 156 cirrhotic patients and 73 controls. Results. PT was determined according to the factor (F) II, FV, FVII, FIX, and protein C levels. We observed that aPTT was dependent on FII, FIX, and FX levels. The ETP was dependent on FII, antithrombin, and protein C with 5 pM tissue factor (TF) stimulation, and FIX and protein C at 1 pM TF. The ETP ratio with 1 pM TF increased significantly in cirrhosis, indicating hypercoagulability, whereas that with 5 pM TF did not increase in cirrhosis. Conclusion. PT and the TGA are sensitive to protein C levels. Even with prolonged PT, the TGA can detect hypercoagulability in cirrhosis. Further studies should evaluate global coagulation status in cirrhosis patients using the newly devised TGA system.

Prominent protein Z‐induced thrombin inhibition in cirrhosis: A new functional assay for hypercoagulability assessment

“…As TM is a physiologic activator of the protein C anticoagulant pathway, adding TM to the TGA reduces ETP generation depending on protein C or protein S levels. Therefore, the high ETP ratio in cirrhosis suggests a defective protein C system . The present results also confirm the ETP ratio–TM is higher in patients with advanced cirrhosis than in healthy controls.…”

“…In contrast, some patients with cirrhosis have an increased risk of developing thrombosis. Therefore, defective anticoagulant systems play important roles in cirrhosis . In the present study, thrombotic tendency was assessed using a new functional assay of modified TGA, demonstrating for the first time that the PZ anticoagulant system is defective in cirrhosis.…”

“…As the TGA measures the total amount of thrombin generation through the clotting process, imbalances between coagulation and anticoagulation factors can be more precisely assessed by adding certain anticoagulants such as thrombomodulin (TM). For example, TGA with exogenous TM addition revealed that patients with cirrhosis have hypercoagulability due to acquired protein C deficiency …”

Portal vein clamping alone confers protection against hepatic ischemia–reperfusion injury via preserving hepatocyte function in cirrhotic rats

“…Blood coagulation also decreased in cirrhotic rats. These may contribute to the increased blood loss observed in the PVC group [29,30]. Therefore, in terms of blood control efficacy, PTC was superior to PVC and IC; however, this occurred at the cost of more severe liver injury and decreased liver function.…”

Diverse Utility of Endogenous Thrombin Potential and Thromboelastometry in the Assessment of Patients with Alcoholic Cirrhosis

“…There is a growing interest in using more global hemostatic assays such as thrombin generation and thromboelastometry/thromboelastograhy. [20][21][22][23][24][25] Thrombin generation assays measure the in vitro capacity of plasma to produce thrombin over time, known as endogenous thrombin potential (ETP). Thrombin generation assays differ from thromboelastometry.…”