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Updated: Sep 7, 2025
Author Spotlight: High-Sensitivity Tissue Factor Activity Assay for Plasma Diagnosis
Published on: December 29, 2023
TFPI and FXIII negatively and S100A8/A9 and Cystatin C positively correlate with D-dimer in COVID-19
Anamika Gupta1, Rizwan Qaisar1, Rabih Halwani2
1Cardiovascular Research Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, UAE.
Insights
COVID-19 thromboembolism involves complex interactions. Decreased tissue factor pathway inhibitor (TFPI) and FXIII correlate with increased D-dimer, suggesting TF pathway activation and fibrin issues in severe cases.
Area of Science:
- Biochemistry
- Hematology
- Infectious Diseases
Background:
- D-dimer is a key marker for thromboembolism and COVID-19 severity.
- Previous studies noted dysregulation of TFPI, FXIII, fibrinolysis, inflammation, and tissue injury markers in severe COVID-19.
- The precise association of these markers with COVID-19-related thromboembolism requires further elucidation.
Purpose of the Study:
- To investigate the correlations between various biomarkers and D-dimer in moderate and severe COVID-19.
- To explore potential pathomechanisms underlying thromboembolism in COVID-19.
- To understand the impact of these markers on thromboembolic complications.
Main Methods:
- Correlation analyses were performed on plasma samples from moderate (non-ICU) and severe (ICU) COVID-19 patients.
- Key markers analyzed included TFPI, FXIII, plasminogen, tPA, PAI-1, P-selectin, sCD40 L, calprotectin (S100A8/A9), cystatin C (CST3), and myoglobin.
- Statistical correlations (r^2 and P-values) were calculated to assess relationships between markers and D-dimer levels.
Main Results:
- Negative correlations were observed between D-dimer and 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).
- A strong positive correlation existed between tPA and PAI-1 (r^2=0.584, P<0.0001). PAI-1 correlated positively with platelet/endothelial dysfunction markers P-selectin (r^2=0.184, P=0.01) and sCD40 L (r^2=0.163, P=0.02).
- Calprotectin (S100A8/A9) and cystatin C (CST3) correlated positively with each other (r^2=0.339, P=0.0007) and independently with D-dimer. Myoglobin showed a strong positive correlation with D-dimer (r^2=0.408, P=0.0001).
Conclusions:
- Inverse correlations of TFPI and FXIII with D-dimer suggest TF pathway activation and aberrant fibrin polymerization in COVID-19.
- Elevated PAI-1 may be linked to activated platelets and endothelial cells.
- S100A8/A9 and CST3 may contribute to impaired fibrinolysis and thromboembolism in COVID-19, enhancing understanding and management of complications.
Abstract:
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 (r2 = 0.148, P = 0.035), FXIII (r2 = 0.242, P = 0.006), and plasminogen (r2 = 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) (r2 = 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 (r2 = 0.184, P = 0.01) and soluble CD40 ligand (sCD40 L) (r2 = 0.163, P = 0.02). Moreover, calprotectin (S100A8/A9) and cystatin C (CST3), previously linked with thromboembolism, exhibited positive correlations with each other (r2 = 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 (r2 = 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.
