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

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.

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 (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 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 <11 ng/mL and D‐dimer <1.0 mg/L had a 3.6% probability of incident VTE during a COVID‐19 hospitalization. This subgroup represented 41% of the total study population. No other suPAR and D‐dimer cutoff combinations yielded a <5% probability of the outcome. The red color indicates lower probabilities, and the blue color indicates higher probabilities. Units for suPAR and D‐dimer as shown in the figure are ng/mL and mg/L, respectively.