Soluble Urokinase Plasminogen Activator Receptor and Venous Thromboembolism in COVID-19

Shengyuan Luo, Alexi Vasbinder, Jeanne M Du-Fay-de-Lavallaz, Joanne Michelle D Gomez, Tisha Suboc, Elizabeth Anderson, Annika Tekumulla, Husam Shadid, Hanna Berlin, Michael Pan, Tariq U Azam, Ibrahim Khaleel, Kishan Padalia, Chelsea Meloche, Patrick O'Hayer, Tonimarie Catalan, Pennelope Blakely, Christopher Launius, Kingsley-Michael Amadi, Rodica Pop-Busui, Sven H Loosen, Athanasios Chalkias, Frank Tacke, Evangelos J Giamarellos-Bourboulis, Izzet Altintas, Jesper Eugen-Olsen, Kim A Williams, Annabelle Santos Volgman, Jochen Reiser, Salim S Hayek, ISIC (International Study of Inflammation in COVID‐19) Group, Salim S Hayek, Pennelope Blakely, Christopher Launius, Hanna Berlin, Kingsley Amadi, Tariq U Azam, Husam Shadid, Michael Pan, Patrick O'Hayer, Chelsea Meloche, Rafey Feroze, Kishan J Padalia, Elizabeth Anderson, Danny Perry, Abbas Bitar, Rayan Kaakati, Lili Zhao, Peiyao Zhao, Erinleigh Michaud, Yiyuan Huang, Toniemarie Catalan, Ibrahim Khaleel, Jochen Reiser, Beata Samelko, Alexander Hlepas, Xuexiang Wang, Priya Patel, Jesper Eugen-Olsen, Izzet Altintas, Jens Tingleff, Marius Stauning, Morten Baltzer Houlind, Mette B Lindstrøm, Ove Andersen, Hejdi Gamst-Jensen, Line Jee Hartmann Rasmussen, Christian Rasmussen, Jan O Nehlin, Thomas Kallemose, Imran Parvaiz, Evangelos J Giamarellos-Bourboulis, Maria-Evangelia Adami, Nicky Solomonidi, Maria Tsilika, Maria Saridaki, Vasileios Lekakis, Sven Loosen, Tom Luedde, Verena Keitel, Athanasios Chalkias, Ioannis Pantazopoulos, Eleni Laou, Anargyros Skoulakis, Frank Tacke, Pinkus Tober-Lau, Raphael Mohr, Florian Kurth, Leif Erik Sander, Christoph Jochum, Philipp Koehler, Shengyuan Luo, Alexi Vasbinder, Jeanne M Du-Fay-de-Lavallaz, Joanne Michelle D Gomez, Tisha Suboc, Elizabeth Anderson, Annika Tekumulla, Husam Shadid, Hanna Berlin, Michael Pan, Tariq U Azam, Ibrahim Khaleel, Kishan Padalia, Chelsea Meloche, Patrick O'Hayer, Tonimarie Catalan, Pennelope Blakely, Christopher Launius, Kingsley-Michael Amadi, Rodica Pop-Busui, Sven H Loosen, Athanasios Chalkias, Frank Tacke, Evangelos J Giamarellos-Bourboulis, Izzet Altintas, Jesper Eugen-Olsen, Kim A Williams, Annabelle Santos Volgman, Jochen Reiser, Salim S Hayek, ISIC (International Study of Inflammation in COVID‐19) Group, Salim S Hayek, Pennelope Blakely, Christopher Launius, Hanna Berlin, Kingsley Amadi, Tariq U Azam, Husam Shadid, Michael Pan, Patrick O'Hayer, Chelsea Meloche, Rafey Feroze, Kishan J Padalia, Elizabeth Anderson, Danny Perry, Abbas Bitar, Rayan Kaakati, Lili Zhao, Peiyao Zhao, Erinleigh Michaud, Yiyuan Huang, Toniemarie Catalan, Ibrahim Khaleel, Jochen Reiser, Beata Samelko, Alexander Hlepas, Xuexiang Wang, Priya Patel, Jesper Eugen-Olsen, Izzet Altintas, Jens Tingleff, Marius Stauning, Morten Baltzer Houlind, Mette B Lindstrøm, Ove Andersen, Hejdi Gamst-Jensen, Line Jee Hartmann Rasmussen, Christian Rasmussen, Jan O Nehlin, Thomas Kallemose, Imran Parvaiz, Evangelos J Giamarellos-Bourboulis, Maria-Evangelia Adami, Nicky Solomonidi, Maria Tsilika, Maria Saridaki, Vasileios Lekakis, Sven Loosen, Tom Luedde, Verena Keitel, Athanasios Chalkias, Ioannis Pantazopoulos, Eleni Laou, Anargyros Skoulakis, Frank Tacke, Pinkus Tober-Lau, Raphael Mohr, Florian Kurth, Leif Erik Sander, Christoph Jochum, Philipp Koehler

Abstract

Background Venous thromboembolism (VTE) contributes significantly to COVID-19 morbidity and mortality. The urokinase receptor system is involved in the regulation of coagulation. Levels of soluble urokinase plasminogen activator receptor (suPAR) reflect hyperinflammation and are strongly predictive of outcomes in COVID-19. Whether suPAR levels identify patients with COVID-19 at risk for VTE is unclear. Methods and Results We leveraged a multinational observational study of patients hospitalized for COVID-19 with suPAR and D-dimer levels measured on admission. In 1960 patients (mean age, 58 years; 57% men; 20% Black race), we assessed the association between suPAR and incident VTE (defined as pulmonary embolism or deep vein thrombosis) using logistic regression and Fine-Gray modeling, accounting for the competing risk of death. VTE occurred in 163 (8%) patients and was associated with higher suPAR and D-dimer levels. There was a positive association between suPAR and D-dimer (β=7.34; P=0.002). Adjusted for clinical covariables, including D-dimer, the odds of VTE were 168% higher comparing the third with first suPAR tertiles (adjusted odds ratio, 2.68 [95% CI, 1.51-4.75]; P<0.001). Findings were consistent when stratified by D-dimer levels and in survival analysis accounting for death as a competing risk. On the basis of predicted probabilities from random forest, a decision tree found the combined D-dimer <1 mg/L and suPAR <11 ng/mL cutoffs, identifying 41% of patients with only 3.6% VTE probability. Conclusions Higher suPAR was associated with incident VTE independently of D-dimer in patients hospitalized for COVID-19. Combining suPAR and D-dimer identified patients at low VTE risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.

Keywords: COVID‐19; soluble urokinase plasminogen activator receptor; thromboembolism.

Figures

Figure 1. Odds ratios and 95% CIs…
Figure 1. Odds ratios and 95% CIs for venous thromboembolism per soluble urokinase plasminogen activator receptor (suPAR) tertile in patients hospitalized with COVID‐19, with and without adjustments for baseline covariables and D‐dimer level.
Baseline clinical characteristics included in model 1: age, sex, Black race, body mass index, history of diabetes, history of hypertension, history of congestive heart failure, history of atrial fibrillation or flutter, history of stroke, history of chronic obstructive pulmonary disease, history of malignancy, before admission anticoagulation therapy, and estimated glomerular filtration rate.
Figure 2. Cumulative incidence of venous thromboembolism…
Figure 2. Cumulative incidence of venous thromboembolism (VTE) within 30 days of hospitalization by soluble urokinase plasminogen activator receptor (suPAR) tertile.
suPAR categories are defined as follows: first tertile, 0 to 5.2 ng/mL; second tertile, 5.3 to 8.7 ng/mL; and third tertile, 8.8 to 62.7 ng/mL
Figure 3. A decision tree based on…
Figure 3. A decision tree based on predicted probabilities from random forest exploring soluble urokinase plasminogen activator receptor (suPAR) and D‐dimer cutoff combinations for the stratification of patients by probability of venous thromboembolism (VTE).
The subgroup of patients with suPAR

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