Abstract P357: Induction Of Soluble P-selectin And CD40 Ligand And, FXIII Deficiency Promote Aberrant Coagulation And Thromboembolism In Severe COVID-19

Abstract

Coagulation dysfunction and thromboembolism emerge as strong comorbidity factors in severe COVID-19. However, the underlying pathomechanisms are largely undefined. Here, we sought to identify the potential underlying molecular mechanisms of SARS-CoV-2 mediated coagulopathy and thromboembolism. In this series, 30 hospitalized COVID-19 patients presenting elevated D-dimer with (severe cases that required intensive care) or without pneumonia (moderate cases) were included in the study. Patients with anticoagulant/ antiplatelet therapy or with a history of cardiovascular diseases were excluded. Phenotypic and molecular characterizations were carried out employing basic coagulation tests, flow cytometry-based multiplex assays, and ELISA. The findings revealed slightly higher prothrombin and activated partial thromboplastin times (aPTT) with normal platelet counts. Elevated levels of plasma P-selectin and CD40 ligand (CD40L), markers of platelet activation, were observed in the moderate COVID-19 cases which were significantly abolished with the progression of COVID-19 severity. Moreover, analysis of the coagulation pathways revealed comparable FIX, prothrombin, and anti-thrombin levels, and a significantly higher level of fibrinogen was observed in both the moderate and severe patients vs. control group. Interestingly, the levels of plasma tissue factor pathway inhibitor (TFPI) and FXIII, a regulator of stable thrombus formation, were significantly lower particularly in the severe COVID-19 cases. Moreover, a dysregulated fibrinolysis was indicated by elevated tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI), and D-dimer levels in COVID-19 cases. In summary, SARS-CoV-2 infection-mediated endothelial cell lining damage potentially enhances soluble P-selectin and CD40L levels inducing platelet activation. Furthermore, in severe COVID-19, a decreased level of TFPI possibly contributes to additional thrombin generation through activation of the TF pathway and provides positive feedback to platelet activation and thrombus formation. FXIII deficiency plays a key role in thrombus instability which most likely promotes thromboembolism in the severe COVID-19.

SARS-CoV-2 infection- induced growth factors play differential roles in COVID-19 pathogenesis

“…We found higher levels of both PDGF isoforms in COVID-19, which comply with our recent finding of elevated sCD40L in these patients [45] . These molecules are released by activated platelets and play a role in immune modulation and cell survival [46] , [47] .…”

Lipocalin-2, S100A8/A9, and cystatin C: Potential predictive biomarkers of cardiovascular complications in COVID-19

“…9,10 The precise mechanism of VTE is largely undefined though the induction of platelet activation markers at early moderate stage of infection, inflammatory mediator (cytokine storm), and acquired FXIII deficiency seem to play critical roles in VTE. 2,11 Vascular inflammation induces endothelial activation, which promotes the prothrombotic state of the endothelial layer. 12 The endothelial dysfunction occurs not only due to SARS-CoV-2 invasion but also through inflammatory markers secreted from activated endothelial cells.…”

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

“…Several coagulation parameters such as activated partial thromboplastin time (APTT), prothrombin time (PT), platelet count and fibrinogen, fibrin split products (FSP), and D-dimer formation are deranged in patients with severe COVID-19. 4,5 It is evident that severe SARS-CoV-2 infection induces chemokine production and cytokine storm, which cause pulmonary intravascular coagulopathy and microvascular thrombosis. 6 The viral invasion induces procoagulant changes in endothelium and platelet activation through the secretion of numerous biologically active molecules.…”