Enhanced prediction of thrombotic events in hospitalized COVID-19 patients with soluble thrombomodulin

Abstract

We aimed to determine the predictive accuracy of elevated soluble thrombomodulin (sTM) and angiopoietin-2 (Ang2) for thrombotic events (TE) in hospitalized COVID-19 patients. We conducted a nested case-control study within a cohort of people admitted to hospital with COVID-19 from March 2020 to August 2022. The cases (people with TE within 28 days after hospital admission) were matched by propensity score to comparable patients without TE. We determined plasma levels of sTM and Ang2 in all available frozen samples, prioritizing the earliest post-admission samples, using an automated immunoassay technique. Among 2,524 hospitalized COVID-19 patients (43% females; median age 67 years), 73 had TE (incidence 1.15 events per 1000 patient-days of follow-up). Frozen plasma samples were available for 43 cases and 176 controls. Elevated plasma concentration of sTM was significantly associated with TE (2.8 [1.8, 4] vs. 1.52 [1.1, 2.65] ng/mL; p =  0.001) and mortality (median [Q1, Q3], 3.32 [2.16, 4.65] vs. 1.58 [1.11, 2.73] ng/mL; p =  0.001), while D-dimer showed a specific association with TE (2.3 [0.8, 7.4] vs. 0.75 [0.4, 1.6] mcg/mL; p =  0.001). In contrast, Ang2 was not associated with any of these events. The association with thrombotic events remained in adjusted models (HR [95%CI] per unit increase, 1.24 [1.04-1.47] for sTM; 1.07 [1.03-1.10] for D-dimer). The adjusted regression model that included both biomarkers, sTM and D-dimer, improved (AUC 73%, sensitivity 77% and specificity 65% for TE diagnosis; p =  0.007) the predictive capacity of the same model without sTM. In conclusion, determination of soluble thrombomodulin along with D-dimer enhances thrombotic risk assessment in hospitalized COVID-19 patients.