Low Sensitivity to Thrombomodulin Correlates with Liver Stiffness in Advanced Chronic Liver Disease

Advanced chronic liver disease (ACLD) is characterized by changes in the coagulation system that embrace not only hypo-, but also hyper-coagulability. Global hemostatic tests such as thrombin generation (TG) assays are used to evaluate the hemostatic balance, in order to better assess bleeding and thrombotic risks. In addition, procoagulant state in ACLD patients has been demonstrated using modified TG assays with thrombomodulin (TM), a cofactor for protein C activation.

Evaluation of the liver stiffness by transient elastography (Fibroscan) is a reliable method for the diagnosis of cirrhosis and disease staging. Increased liver stiffness is associated with clinically significant portal hypertension (PVT) in patients with ACLD. Here, we aimed to investigate whether TG parameters in patients with ACLD could be associated to liver stiffness.

Of 147 enrolled patients with ACLD, we excluded 69 patients (5 patients received anticoagulation, 3 were on chemotherapy, 48 with other liver diseases and 13 had a history of orthotopic liver transplantation), leaving a study sample of 78 patients.

Liver stiffness measurement (LSM) was performed by transient elastography in each patient. Cut-offs of 13 and 21 kPa were used to subgroup the studied ACLD patients sample, as a LSM of ≥13 kPa has been associated with the diagnosis of cirrhosis and ≥21 kPa with the development of a clinically significant PVT (Deillon et al., 2019). TG was evaluated by ST Genesia® Thrombin Generation System (STG) using Thromboscreen with/without TM (TS-TM/+TM) assay and the Calibrated Automated Thrombography (CAT) using PPP reagent low (Stago) with/without TM.

TG was measured by STG in 50 patients with ACLD. ETP inhibition by TM correlated with LSM (r =-0.339, p=0.0184). The discriminant analysis (ANOVA with multiple comparison) among the study groups showed that ETP inhibition by TM was higher in ACLD patients with LSM <13 kPa than in those with LSM ≥13 but <21 kPa (p=0.003), indicating a lower sensitivity to TM in patients with liver stiffness values ≥13 but <21 kPa. However, there was no difference in ETP inhibition by TM between the group with LSM ≥13 but <21 kPa and the group with LSM ≥21 kPa (p=0.995).

TG was measured by CAT in 56 patients with ACLD and ETP inhibition by TM was evaluated using a normalized ETP ratio in presence and in absence of TM. Similarly to STG data, ETP inhibition by TM measured by CAT correlated with LSM (r=0.4108, p=0.0018). The discriminant analysis among the study groups revealed that ETP inhibition by TM was higher in ACLD patients with LSM <13 kPa than in those with ≥13 but <21 kPa (p=0.0098) as well as with the group with LSM ≥21kPa (p=0.0022), indicating a lower sensitivity to TM in patients with liver stiffness values ≥13 kPa. However, there was no difference in ETP inhibition by TM between the group with LSM ≥13 but <21 and the group with LSM ≥21 kPa (p=0.721).

In addition, TG was measured by both by STG and CAT in 35 patients with ACLD in order to compare the two methods. ETP inhibition by TM measured by STG correlated with the normalized ETP inhibition determined by CAT (r = -0.61, p<0.0001).

Low sensitivity to TM measured in ST Genesia® and CAT, correlated with liver stiffness in patients with ACLD. Sensitivity to TM discriminated between ACLD groups with low (≤13 kPa) and high (≥13 kPa) LSM, confirming a procoagulant state in patients with ALCD. However, it did not differ between patients with ACLD with high LSM (≥13 and <21 kPa) and patients prone to the decompensation defined by higher (≥21 kPa) LSM. Sensitivity to TM measurements determined by ST Genesia® correlated with those obtained with CAT. Further studies are needed to determine whether sensitivity to TM and LSM in patients with ACLD could help to identify patients at higher risk of portal vein thrombosis