Thrombomodulin Resistance May be Involved in the Prothrombotic State of COVID-19

Abstract

Introduction: Hypercoagulability and endothelial dysfunction seem to be involved in the worsening of the clinical condition of patients with COVID-19. In the most severe cases, it has been shown that the inflammatory process triggers the release of angiopoietin-2 (ANGPT2) through the endothelium, which could decrease levels of circulating thrombomodulin (TM), a key component in the activation of the protein C, one of the major regulatory mechanisms of thrombin generation. In fact, recent studies suggest ANGPT2 as a therapeutic target to improve the prothrombotic profile of patients with COVID-19 and other clinical conditions associated to a hypercoagulable state. However, there are no studies evaluating the role of resistance to TM in the hypercoagulability of COVID-19 so far. Objectives: To analyze the resistance to TM in hospitalized COVID-19 patients by thrombin generation (TG) test and its correlation with the severity of the disease. Methods: A total of 120 hospitalized COVID-19 patients were included, 47 of them with data for correlation with the clinical profile. Citrated blood samples were drawn at admission and centrifuged to obtain platelet-poor plasma and frozen at −80°C until analysis. TG test and clot formation kinetics were evaluated by GENESIA® and Quantra®, respectively. Severe adverse events (SAE) were considered non-invasive mechanical ventilation, ICU admission, encephalitis, thrombosis, or death. Results: Measurement of endogenous thrombin potential (ETP) with/without TM revealed that 39% of patients had % ETP inhibition <40%, suggesting TM resistance. In the correlation with the clinic, 23.4% of patients (n=11/47) presented an adverse event. TG at admission was higher in patients who developed SAE though differences between groups did not reach the statistical significance. TG with addition of TM showed important resistance to TM in the group who developed SAE. In this group, ETP dropped -24,3 ± 10.2 % vs no-SAE group who ETP dropped -47.3 ± 22.0 % (p< 0.001). Similar effect was observed in the Peak of TG after addition of TM. In the SAE group the Peak dropped -15.7 ± 7.9 % vs the no-SAE group who presented a Peak drop of -33.3 ± 19.6 % (p< 0.001). Both results suggest a marked resistance to TM in the group that developed SAE. Lower % inhibition of Peak of TG by TM addition and higher values of ETP were significantly correlated with higher clot stiffness (r= 0.339, p= 0.028 and r=0.322, p= 0.027, respectively). Both Peak and ETP drop by the addition of TM in TG test proved to be good predictors of SAE at admission with an AUC of 0.756 (95% CI: 0.615-0.897, p=0.015) and 0.803 (95% CI: 0.672-0.934, p= 0.004), respectively. Conclusions: Thrombin generation test can be a powerful tool for risk stratification of COVID-19 patients at admission. Increased resistance to thrombomodulin is associated with the development of severe adverse events and can be considered as a new independent prognostic marker of patients at risk of poor prognosis.