PB0057 - SARS-CoV-2 infection results in upregulation of PAI-1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity

Background: SARS-CoV-2 infection results in coagulation activation although it is usually not associated with consumption coagulopathy. D-dimers are also commonly elevated despite systemic hypofibrinolysis.

Aims: To understand these unusual features of COVID-19 coagulopathy, 64 adult patients with SARS-CoV-2 infection (36 moderate, 28 severe) and 16 controls were studied. To determine pulmonary expression of PAI-1 and Neuroserpin in the lungs.

Methods: We evaluated the repertoire of plasma protease inhibitors (Serpins, Kunitz, Kazal, Cystatin-like) targeting the fibrinolytic system: PAI-1, t-PA/PAI-1, A2AP, PAP, TAFI/TAFIa, PN-1 and Neuroserpin (the main t-PA inhibitor of the CNS). Inhibitors of the common (AT, TAT, PZ/PZI, HCII, A2M), protein C (PCI, PC, PS), contact (Kallistatin, PN2/ABPP, A1AT) and complement (C1-INH) pathways, in addition to FXIII, Histidine-rich glycoprotein/HRG and Vaspin were also investigated by ELISA. The association of these markers with disease severity was evaluated by logistic regression. Pulmonary expression of PAI-1 and Neuroserpin in the lungs from 8 post-mortem cases was assessed by immunohistochemistry.

Results: Results show that 6 patients (10%) developed thrombotic events, and mortality was 11%. There was no significant reduction in plasma anticoagulants, in keeping with a compensated state. However, an increase in fibrinolysis inhibitors (PAI-1, Neuroserpin, PN-1, PAP, t-PA/PAI-1) was consistently observed, while HRG was reduced. Furthermore, these markers were associated with moderate and/or severe disease. Notably, immunostains demonstrated overexpression of PAI-1 in epithelial cells, macrophages and endothelial cells of fatal COVID-19, while Neuroserpin was found in intraalveolar macrophages only.

Conclusion(s): These results imply that the lungs in SARS-Cov-2 infection provide anti-fibrinolytic activity resulting in a shift towards a local and systemic hypofibrinolytic state predisposing to (immuno)thrombosis, often in a background of compensated DIC.