Thrombomodulin Resistance: a Novel Prothrombotic Pathway in Covid-19

Hypercoagulability and endothelial dysfunction are strongly involved in the worsening of the clinical condition in COVID-19 patients. In severe cases, the inflammatory process triggers the release of angiopoietin 2, which could decrease circulating thrombomodulin (TM), a major regulatory mechanism in thrombin generation. Although some studies have described an increased TM resistance, further data are needed to obtain robust results. The objective of our study was to evaluate TM resistance in hospitalized COVID-19 patients using the thrombin generation test and its correlation with clinical events. Forty-seven hospitalized COVID-19 patients were included (mean age was 59 years (15–90) and 42.6% were women). Measurement of endogenous thrombin potential (ETP) revealed that 39.4% of patients had a % of ETP inhibition < 40%, suggesting TM resistance. Twenty-three% of patients (n = 11/47) presented at least one severe clinical event (SCE). Significant resistance to TM was observed in patients with SCE: % of ETP inhibition was 20.8% vs 48.3% in the non-SCE group. Higher resistance to TM and higher ETP values significantly correlated with increased clot stiffness (r = 0.339/r = 0.322). The ETP (in presence of TM) and the resistance to TM proved to be good predictors of SCE with an AUC of 0.756 and 0.803, To conclude, thrombin generation can be a powerful tool for risk stratification in hospitalized COVID-19 patients. In addition, increased resistance to TM is associated with the development of SCE and can be considered as a new independent marker of poor prognosis.