Generation of potentially inhibitory autoantibodies to ADAMTS13 in coronavirus disease 2019

Abstract

It has recently been shown that von Willebrand factor (VWF) multimers contribute to immunothrombosis in Coronavirus disease 2019 (COVID-19). Since COVID-19 is associated with an increased risk of autoreactivity, the present study investigates, whether the generation of autoantibodies to ADAMTS13 contributes to this finding. In this observational prospective controlled multicenter study blood samples and clinical data of patients hospitalized for COVID-19 were collected from April to November 2020. The study included 156 individuals with 90 patients having confirmed COVID-19 of mild to critical severity. 30 healthy individuals and 36 critically ill ICU patients without COVID-19 served as controls. ADAMTS13 antibodies occurred in 31 (34.4%) COVID-19 patients. Antibodies occurred more often in critically ill COVID-19 patients (55.9%) than non-COVID-19 ICU patients and healthy controls (5.6% and 6.7%; p < 0.001), respectively. Generation of ADAMTS13 antibodies in COVID-19 was associated with lower ADAMTS13 activity (56.5%, interquartile range (IQR) 21.25 vs. 71.5%, IQR 24.25, p = 0.0041), increased disease severity (severe or critical in 90% vs. 62.3%, p = 0.019), and a trend to higher mortality (35.5% vs. 18.6%, p = 0.077). Median time to antibody development was 11 days after first positive SARS-CoV-2-PCR specimen. Gel analysis of VWF multimers resembled the constellation in patients with TTP. The present study demonstrates for the first time, that generation of ADAMTS13 antibodies is frequent in COVID-19, associated with lower ADAMTS13 activity and increased risk of an adverse disease course. These findings provide a rationale to include ADAMTS13 antibodies in the diagnostic workup of SARS-CoV-2 infections.

Figure 1

Baseline data of COVID-19 patients. (A) ADAMTS13 activity (%) in dependence on antibody (Ab) status. (B) Severity of disease in dependence on Ab status. (C) Ab concentration (U/mL) in dependence on disease severity and mortaliy. (D) % of critically ill COVID-19 and non-COVID-19 patients and healthy controls. (E) Ab concentration in critically ill COVID-19 vs. non-COVID-19 patients and healthy controls. Data are presented in % of patients with chi squared p-values, or median and interquartile range, respectively.

Figure 2

Von Willebrand factor multimers in a medium resolution gel (1.8% LGT-agarose, images taken from different gels) of (7-8) two patients with severe COVID-19, increased release of VWF and autoantibodies to ADAMTS13 and (1-3) three critically ill patients without COVID-19, (4 and 6) healthy controls, (5) pooled plasma of healthy controls, and (9-10) two patients with acute thrombotic thrombocytopenic purpura prior to initiation of treatment. The gel shows smear and a decrease of largest multimers predominantly in the patient lanes of both COVID-19 patients and those with thrombotic thrombocytopenic purpura.

Figure 3

(A) cumulative incidence of ADAMTS13 antibodies (Ab), (B) ADAMTS13 activity, (C) von Willebrand factor Antigen (VWF:Ag), (D) ADAMTS13/VWF:Ag ratio, and (E) mortality in dependence on ADAMTS13 antibody status in the course of Coronavirus disease. Data are presented in median and interquartile range.