PB0059 - Thrombomodulin resistance as a novel pathway involved in the hypercoagulable state of COVID-19 patients

Background: Hypercoagulability and endothelial dysfunction are strongly involved in the worsening of the clinical condition of COVID-19 patients. In the most severe cases, it has been shown that the inflammatory process triggers the release of angiopoietin-2 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.

Aims: To analyze the resistance to TM in hospitalized COVID-19 patients by thrombin generation test (TGT) and its correlation with clinical events.

Methods: 120 hospitalized COVID-19 patients (47 with clinical data) were included at admission. TGT 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. Resistance to TM was defined as a %ETP (endogenous thrombin potential) inhibition < 40% compared to non-TM ETP.

Results: Measurement of ETP with/without TM revealed that 39% of patients had % ETP inhibition < 40%, suggesting TM resistance. 23.4% of patients (n=11/47) presented any SAE. Significant resistance to TM was observed in the SAE group: ETP (% inhibition) was 24.3% vs 47.6% in non-SAE group, p< 0.001. Higher resistance to TM and higher values of ETP were significantly correlated with increased clot stiffness (r=0.339/r=0.322). No differences in TM levels were observed, although higher TM levels correlated with a higher von Willebrand Factor/ADAMTS13 ratio (r=0.681). The ETP (in presence of TM) and the resistance to TM (% ETP inhibition) proved to be good predictors of SAE at admission with an AUC of 0.756 and 0.803, respectively.

Conclusion(s): Thrombin generation 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 poor prognosis.