Urokinase-type plasminogen activator and plasminogen activator inhibitor-1 complex as a serum biomarker for COVID-19

Front Immunol. 2024 Jan 11:14:1299792. doi: 10.3389/fimmu.2023.1299792. eCollection 2023.

Abstract

Patients with coronavirus disease-2019 (COVID-19) have an increased risk of thrombosis and acute respiratory distress syndrome (ARDS). Thrombosis is often attributed to increases in plasminogen activator inhibitor-1 (PAI-1) and a shut-down of fibrinolysis (blood clot dissolution). Decreased urokinase-type plasminogen activator (uPA), a protease necessary for cell-associated plasmin generation, and increased tissue-type plasminogen activator (tPA) and PAI-1 levels have been reported in COVID-19 patients. Because these factors can occur in free and complexed forms with differences in their biological functions, we examined the predictive impact of uPA, tPA, and PAI-1 in their free forms and complexes as a biomarker for COVID-19 severity and the development of ARDS. In this retrospective study of 69 Japanese adults hospitalized with COVID-19 and 20 healthy donors, we found elevated free, non-complexed PAI-1 antigen, low circulating uPA, and uPA/PAI-1 but not tPA/PAI-1 complex levels to be associated with COVID-19 severity and ARDS development. This biomarker profile was typical for patients in the complicated phase. Lack of PAI-1 activity in circulation despite free, non-complexed PAI-1 protein and plasmin/α2anti-plasmin complex correlated with suPAR and sVCAM levels, markers indicating endothelial dysfunction. Furthermore, uPA/PAI-1 complex levels positively correlated with TNFα, a cytokine reported to trigger inflammatory cell death and tissue damage. Those levels also positively correlated with lymphopenia and the pro-inflammatory factors interleukin1β (IL1β), IL6, and C-reactive protein, markers associated with the anti-viral inflammatory response. These findings argue for using uPA and uPA/PAI-1 as novel biomarkers to detect patients at risk of developing severe COVID-19, including ARDS.

Keywords: C-reactive protein; COVID-19; fibrinolysis; interleukin-6; plasminogen activator inhibitor-1; respiratory distress syndrome; thrombosis; urokinase-type plasminogen activator.

Publication types

  • Research Support, Non-U.S. Gov't
  • Comment

MeSH terms

  • Adult
  • Biomarkers
  • COVID-19*
  • Fibrinolysin
  • Humans
  • Plasminogen Activator Inhibitor 1
  • Respiratory Distress Syndrome*
  • Retrospective Studies
  • Thrombosis*
  • Urokinase-Type Plasminogen Activator / metabolism

Substances

  • Urokinase-Type Plasminogen Activator
  • Plasminogen Activator Inhibitor 1
  • Fibrinolysin
  • Biomarkers

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported partly by JSPS KAKENHI Grant Numbers JP22F21773(BH), JP22KF0337(BH), JP17K09941(KH), JP22K07206(ST), a grant from The Japanese Society of Hematology Research Grant (KH), Nakatani Foundation (KH), Terumo Life Science Foundation (KH), Okinaka Memorial Institute for Medical Research (KH), Grants from the Society of iodine science (KH), Radiation effects association (KH) and International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo (KH, BH), Heiwa Nakajima Foundation (BH), Institute for Environmental & Gender-specific Medicine, Juntendo University (BH).