tetano
Editor, Senior Moderator
Front Immunol
. 2024 Jan 11:14:1299792.
doi: 10.3389/fimmu.2023.1299792. eCollection 2023. Urokinase-type plasminogen activator and plasminogen activator inhibitor-1 complex as a serum biomarker for COVID-19
Tetiana Yatsenko[SUP] 1 2 [/SUP], Ricardo Rios[SUP] 3 [/SUP], Tatiane Nogueira[SUP] 3 [/SUP], Satoshi Takahashi[SUP] 4 [/SUP], Yoko Tabe[SUP] 1 [/SUP], Toshio Naito[SUP] 1 [/SUP], Kazuhisa Takahashi[SUP] 1 5 [/SUP], Koichi Hattori[SUP] 6 7 [/SUP], Beate Heissig[SUP] 1 [/SUP]
Affiliations
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.
. 2024 Jan 11:14:1299792.
doi: 10.3389/fimmu.2023.1299792. eCollection 2023. Urokinase-type plasminogen activator and plasminogen activator inhibitor-1 complex as a serum biomarker for COVID-19
Tetiana Yatsenko[SUP] 1 2 [/SUP], Ricardo Rios[SUP] 3 [/SUP], Tatiane Nogueira[SUP] 3 [/SUP], Satoshi Takahashi[SUP] 4 [/SUP], Yoko Tabe[SUP] 1 [/SUP], Toshio Naito[SUP] 1 [/SUP], Kazuhisa Takahashi[SUP] 1 5 [/SUP], Koichi Hattori[SUP] 6 7 [/SUP], Beate Heissig[SUP] 1 [/SUP]
Affiliations
- PMID: 38313435
- PMCID: PMC10835145
- DOI: 10.3389/fimmu.2023.1299792
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.