Cardiovascular Research Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, UAE.
Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, UAE.
Exp Biol Med (Maywood). 2022 Sep;247(17):1570-1576. doi: 10.1177/15353702221102117. Epub 2022 Jun 20.
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 ( = 0.148, = 0.035), FXIII ( = 0.242, = 0.006), and plasminogen ( = 0.27, = 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) ( = 0.584, < 0.0001). Interestingly, a significant positive correlation of PAI-1, but not tPA, was observed with platelets and endothelial cells dysfunction markers P-selectin ( = 0.184, = 0.01) and soluble CD40 ligand (sCD40 L) ( = 0.163, = 0.02). Moreover, calprotectin (S100A8/A9) and cystatin C (CST3), previously linked with thromboembolism, exhibited positive correlations with each other ( = 0.339, = 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 ( = 0.408, = 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.
D-二聚体是 COVID-19 血栓栓塞和严重程度的既定生物标志物。我们和其他人最近报道了组织因子途径抑制剂 (TFPI)、FXIII、纤维蛋白溶解途径、炎症标志物和组织损伤标志物的失调，尤其是在严重 COVID-19 中。然而，这些标志物与 COVID-19 中的血栓栓塞之间的关联仍不清楚。对中度（非 ICU）和重度 COVID-19（ICU）患者这些标志物之间的相关性进行了分析，以阐明潜在的病理机制和血栓栓塞的影响。我们观察到血浆 TFPI（ = 0.148， = 0.035）、FXIII（ = 0.242， = 0.006）和纤溶酶原（ = 0.27， = 0.003）与 D-二聚体呈负相关，D-二聚体是血栓栓塞的生物标志物，这些患者的水平。进一步分析显示，纤维蛋白溶解标志物组织型纤溶酶原激活物 (tPA) 和纤溶酶原激活物抑制剂-1 (PAI-1) 之间存在很强的正相关（ = 0.584， < 0.0001）。有趣的是，PAI-1 而不是 tPA 与血小板和内皮细胞功能障碍标志物 P-选择素 ( = 0.184， = 0.01) 和可溶性 CD40 配体 (sCD40L) ( = 0.163， = 0.02) 呈显著正相关。此外，先前与血栓栓塞相关的钙卫蛋白 (S100A8/A9) 和胱抑素 C (CST3) 相互之间呈正相关（ = 0.339， = 0.0007），并且在 COVID-19 中与 D-二聚体水平呈独立正相关。最后，组织损伤标志物肌红蛋白与 D-二聚体呈强正相关（ = 0.408， = 0.0001）。总之，TFPI 和 FXIII 与 D-二聚体呈负相关表明 COVID-19 患者 TF 途径激活和异常纤维蛋白聚合。PAI-1 水平升高可能是由活化的血小板和内皮细胞引起的。S100A8/A9 也可能通过调节 CST3 在一定程度上参与纤溶和血栓栓塞受损。这些发现加深了对血栓栓塞和组织损伤的理解，并可能有助于更好地管理 COVID-19 患者的血栓栓塞并发症。
