TFPI and FXIII negatively and S100A8/A9 and Cystatin C positively correlate with D-dimer in COVID-19

D-dimer is an established biomarker of thromboembolism and severity in COVID-19. We and others have recently reported the dysregulation of tissue factor pathway inhibitor (TFPI), FXIII, fibrinolytic pathway, inflammatory markers, and tissue injury markers, particularly in severe COVID-19. However, association of these markers with thromboembolism in COVID-19 remains elusive. The correlation analyses between these markers in patients with moderate (non-ICU) and severe COVID-19 (ICU) were performed to delineate the potential pathomechanisms and impact of thromboembolism. We observe a negative correlation of plasma TFPI (r(2) = 0.148, P = 0.035), FXIII (r(2) = 0.242, P = 0.006), and plasminogen (r(2) = 0.27, P = 0.003) with D-dimer, a biomarker of thromboembolism, levels in these patients. Further analysis revealed a strong positive correlation between fibrinolytic markers tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) (r(2) = 0.584, P < 0.0001). Interestingly, a significant positive correlation of PAI-1, but not tPA, was observed with platelets and endothelial cells dysfunction markers P-selectin (r(2) = 0.184, P = 0.01) and soluble CD40 ligand (sCD40 L) (r(2) = 0.163, P = 0.02). Moreover, calprotectin (S100A8/A9) and cystatin C (CST3), previously linked with thromboembolism, exhibited positive correlations with each other (r(2) = 0.339, P = 0.0007) and with the level of D-dimer independently in COVID-19. Finally, the tissue injury marker myoglobin demonstrated a strong positive correlation with D-dimer (r(2) = 0.408, P = 0.0001). Taken together, inverse correlations of TFPI and FXIII with D-dimer suggest the TF pathway activation and aberrant fibrin polymerization in COVID-19 patients. The elevated level of PAI-1 is potentially contributed by activated platelets and endothelial cells. S100A8/A9 may also play roles in impaired fibrinolysis and thromboembolism, in part, through regulating the CST3. These findings strengthen the understanding of thromboembolism and tissue injury and may help in better management of thromboembolic complications in COVID-19 patients.

Automated summary

This study investigates the correlation between various biomarkers and thromboembolism in COVID-19 patients. The results show a negative correlation between plasma TFPI, FXIII, and plasminogen and the thromboembolism biomarker D-dimer. Additionally, a strong positive correlation is observed between fibrinolytic markers tPA and PAI-1. PAI-1 is also found to be positively correlated with platelets and endothelial cells dysfunction markers. Furthermore, calprotectin and cystatin C exhibit positive correlations with each other and with the level of D-dimer. Finally, the tissue injury marker myoglobin demonstrates a strong positive correlation with D-dimer. These findings enhance our understanding of thromboembolism and tissue injury in COVID-19 and may contribute to better management of thromboembolic complications in COVID-19 patients.