P1693: THROMBOMODULIN RESISTANCE: A NEW PROTHROMBOTIC PATHWAY IN COVID-19

Abstract

Background: Hypercoagulability and endothelial dysfunction have been shown to be closely related and both are considered as one of the main factors influencing the severity of COVID-19 patients. Thrombomodulin, among other factors, plays a key role as an anticoagulant factor through activation of protein C and subsequent limitation of thrombin generation. The endothelium also exerts anticoagulant activity under normal conditions. However, in COVID-19 patients, especially the most severe ones, the inflammatory process has been shown to trigger the release of the cytokine ANGPT2 through the endothelium, leading to the arrest of thrombomodulin and thus contributing to the prothrombotic state. Indeed, recent studies suggest that ANGPT2 inhibition may be explored as a therapeutic target for COVID-19 patients and other hypercoagulable diseases. However, to date there are no studies evaluating the role of thrombomodulin in COVID-19 hypercoagulability. Aims: To analyze thrombomodulin resistance in hospitalized COVID-19 patients by thrombin generation test and correlation with disease severity. Methods: Forty-two hospitalized COVID-19 patients on admission were included in the study. Blood samples were anticoagulated by trisodium citrate, and immediately centrifugated for platelet poor plasma, and frozen at -80ºC until analysis. The hemostatic profile of patients was determined by routine laboratory techniques and the Quantra® Hemostasis Analyzer. Thrombomodulin resistance was assessed by comparing Endogenous Thrombin Potential (ETP) with/without thrombomodulin using GENESIA® analyzer. Student’s t-test or Mann-Whitney U-test were used for comparison of means. Correlation was evaluated by Spearman correlation coefficient. Need for mechanical ventilation, ICU admission, encephalitis, thrombosis or death were considered as adverse events. Results: 23.8% of patients (n=10) had an adverse event during hospitalization. Patients with and without adverse events showed similar ETP (1615 vs 1486; P=0.257). However, the thrombin generation study with thrombomodulin revealed a higher ETP in patients with adverse event (1237.8 vs 786.9 mA; P=0.002). Consistent with this result, these patients showed a higher resistance to thrombomodulin with a lower % inhibition of ETP compared to patients without adverse event (24.3 vs 47.6; P=0.003). In fact, 100% of patients with adverse events showed <40% inhibition of ETP with thrombomodulin (P<0.001). Patients with a poor prognosis also showed a higher thrombin-peak (352.9 vs 310.6 nM; P=0.038), with an even more notable difference in the presence of thrombomodulin (308.6 vs 197.9 nM; P=0.006). In addition, these patients had a significantly higher thrombin generation velocity (247.8 vs. 144.3 nM/min; P=0.004) and consequently a shorter time to peak (4.4 vs 5.4 min; P=0.042). Notably, lower % inhibition by thrombomodulin and higher thrombin peak correlated significantly with higher clot stiffness measured by Quantra® (R=0.372, P=0.017 and R=0.320, P=0.042, respectively). ETP in the presence of thrombomodulin proved to be a good predictor of an adverse event during admission with an AUC of 0.791 (P<0.001). Summary/Conclusion: Measurement of thrombin generation can be a powerful tool for the analysis of patients with COVID-19 on admission and thus for risk stratification. Increased thrombomodulin resistance is associated with the presence of an adverse event in patients and may be considered as new independent prognostic marker.