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

ISIC (International Study of Inflammation in COVID‐19) Group, Jens Tingleff (Member of study group), Marius Ahm Stauning (Member of study group), Morten Baltzer Houlind (Member of study group), Mette Bendtz Lindstrøm (Member of study group), Ove Andersen (Member of study group), Hejdi Gamst-Jensen (Member of study group), Line Jee Hartmann Rasmussen (Member of study group), Jan Nehlin (Member of study group), Thomas Kallemose (Member of study group)

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.

Original languageEnglish
Article numbere025198
JournalJournal of the American Heart Association
Volume11
Issue number18
Pages (from-to)1-15
Number of pages15
ISSN2047-9980
DOIs
Publication statusPublished - 20 Sep 2022

Keywords

  • Biomarkers
  • COVID-19/complications
  • Female
  • Humans
  • Male
  • Middle Aged
  • Receptors, Urokinase Plasminogen Activator
  • Urokinase-Type Plasminogen Activator
  • Venous Thromboembolism/diagnosis
  • COVID-19
  • soluble urokinase plasminogen activator receptor
  • thromboembolism

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