Dynamic Assessment of Plasma von Willebrand Factor and ADAMTS13 Predicts Mortality in Hospitalized Patients with SARS-CoV-2 Infection

Abstract

Background: Plasma levels of von Willebrand factor (VWF) are significantly elevated in patients with coronavirus disease 2019 (COVID-19). However, dynamic changes and prognostic value of this biomarker in hospitalized patients with COVID-19 have not been determined.

Methods: A total of 124 patients infected with SARS-CoV-2 were prospectively recruited for the study. Serial blood samples were obtained at the time of admission (D1), 3-4 days following standard-care treatments (D2), and 1-2 days prior to discharge or any time collected prior to death (D3). Plasma VWF antigen, ADAMTS13 antigen, and ADAMTS13 proteolytic activity, as well as the ratio of VWF/ADAMTS13 were determined, followed by various statistical analyses.

Results: On admission, plasma levels of VWF in COVID-19 patients were significantly elevated compared with those in the healthy controls, but no statistical significance was detected among patients with different disease severity. Plasma ADAMTS13 activity but not its antigen levels were significantly lower in patients with severe or critical COVID-19 compared with that in other patient groups. Interestingly, the ratios of plasma VWF antigen to ADAMTS13 antigen were significantly higher in patients with severe or critical COVID-19 than in those with mild to moderate disease. More importantly, plasma levels of VWF and the ratios of VWF/ADAMTS13 were persistently elevated in patients with COVID-19 throughout hospitalization. Kaplan-Meier and Cox proportional hazard regression analyses demonstrated that an increased plasma level of VWF or ratio of VWF/ADAMTS13 at D2 and D3 was associated with an increased mortality rate.

Conclusions: Persistent endotheliopathy, marked by the elevated levels of plasma VWF or VWF/ADAMTS13 ratio, is present in all hospitalized patients following SARS-CoV-2 infection, which is strongly associated with mortality.

Keywords: ADAMTS13; COVID-19; endothelial dysfunction; mortality; von Willebrand factor.

Figure 1

Plasma levels of biomarkers in hospitalized patients with SARS-CoV-2 infection and healthy controls. Admission plasma VWF antigen (A), ADAMTS13 activity (B), ADAMTS13 antigen (C), and the ratio of VWF/ADAMTS13 antigen in healthy controls, hospitalized patients with SARS-CoV-2 infection on admission (D1) with various disease severities (e.g., asymptomatic, moderate, severe, and critical) (D). The data shown are the median (bar) and interquartile range (IQR) (horizontal lines), as well as individual values [55]. Kruskal–Willis test was performed to determine the statistical significance of the difference among various groups. Here, n.s., *, **, *** and **** indicate a p-value >0.05, <0.05, <0.01, <0.005, and <0.001, respectively.

Figure 2

Longitudinal changes in plasma biomarkers in patients who survived and died of COVID-19. Each solid line depicts the change in plasma levels of VWF antigen (A), ADAMTS13 antigen (B), and the ratio of VWF/ADAMTS13 antigen (C) in patients who survived (survivors on the left) or died (non-survivors on the right) in each panel on admission (D1), 3–4 days following therapy (D2), and before discharge or death (D3). Data were analyzed by Wilcoxon test between two groups. Here, n.s., *, **, and **** indicate p > 0.05, <0.05, <0.01, and <0.001, respectively.

Figure 3

Kaplan–Meier survival analysis in patients with COVID-19 based on plasma levels of VWF or the VWF/ADAMTS13 ratio at different time points. The 60-day survival probabilities in patients with high (>75th percentile) and low (≤75th percentile) levels of plasma VWF antigen on admission (D1) (A), 3 to 4 days following therapy (D2) (B), and prior to being discharged or death (D3) (C) are shown. Similarly, the 60-day survival probabilities in patients with high (>75th percentile) and low (≤75th percentile) ratios of plasma VWF/ADAMTS13 antigen at D1 (D), D2 (E), and D3 (F) are also shown. Here, p < 0.05 and <0.01 are statistically significant and highly significant, respectively.

Figure 4

Cox proportional hazard regression analysis. The hazard ratios (HRs) for death were determined in patients with high VWF antigen (>75th percentile) 3–4 days following therapy (D2) (A) and prior to discharge or death (D3) (B). Additionally, the HRs were also determined in patients with high ratios of VWF/ADAMTS13 antigen (>75th percentile) at D2 (C) and D3 (D). The HRs were adjusted for covariates (age; sex; and body mass index, BMI), as indicated in each panel. Here, p < 0.05 and 0.01 are statistically significant and highly significant, respectively.