In a recent article published within the journal Scientific Reports, researchers performed a prospective observational study in three healthcare centers in Germany to grasp the impact of ADAMTS13 activity during coronavirus disease 2019 (COVID-19).

Study: Generation of doubtless inhibitory autoantibodies to ADAMTS13 in coronavirus disease 2019. Image Credit: peterschreiber.media / Shutterstock.com

Background

ADAMTS13, also generally known as von Willibrand factor (VWF)-cleaving protease, cleaves VWF to forestall the formation of ultra-large VWF multimers. ADAMTS13 deficiency can result in a condition generally known as thrombocytic thrombocytopenic purpura (TTP), a rare and life-threatening blood disorder often treated with plasmapheresis.

Recent studies have demonstrated that COVID-19 markedly increases VWF antigen levels which, in turn, exceeds ADAMTS13 processing capability. Eventually, this results in the formation of enormous VWF multimers much like what occurs in TTP. Thus, the ADAMTS13/VWF antigen (VWF:Ag) ratio could be used as an independent predictor of COVID-19 severity and mortality. 

Nevertheless, there stays an absence of research on ADAMTS13 autoantibodies and their role in COVID-19. Recently, two small case series have examined severe COVID-19 patients, by which just one out of the 13 patients exhibited detectable ADAMTS13 antibodies.

In regards to the study

COVID-19 is related to an increased risk of autoreactivity. In the current study, researchers investigated whether the generation of autoantibodies to ADAMTS13 contributes to the reduced ADAMTS13/VWF:Ag ratio observed in COVID-19. 

A complete of 156 patients at Ruhr-University Bochum, University of Duisburg-Essen, and Asklepios Klinikum Hamburg Harburg hospitals were included in the present study, 90 of whom were hospitalized as a result of COVID-19.

Each study participant’s blood samples were obtained to measure ADAMTS13 activity, in addition to ADAMTS13 autoantibodies exceeding 16 U/mL. A sandwich enzyme-linked immunosorbent assay (ELISA) was used to measure the VWF:Ag ratio, which was calculated as ADAMTS13 (IU/ml)/VWF:Ag (IU/ml) × 100. Sodium dodecyl sulfate (SDS) agarose gel electrophoresis was used for the VWF multimer evaluation.

ADAMTS13 autoantibodies during severe COVID-19

ADAMTS13 autoantibodies were observed in nearly one-third of hospitalized COVID-19 patients. ADAMTS13 autoantibody activity was low, thus indicating an inhibitory effect on the protease. Notably, this phenomenon was not observed in intensive care unit (ICU) patients not diagnosed with COVID-19. These findings indicate the potential utility of using ADAMTS13 autoantibody levels to predict COVID-19 severity.

Together with increased VWF release, increased ADAMTS13 autoantibody levels contributed to a decreased ADAMTS13/VWF:Ag ratio. Notably, within the diagnosis of TTP, reduced ADAMTS13 activity and ADAMTS13 autoantibodies in serum are well-established criteria.

Not one of the patients within the study developed severe thrombopenia, defined as a platelet count of fifty,000/µl or less. This means that the potential inhibitory effect of apathogenic ADAMTS13 autoantibodies was weaker in COVID-19 than in TTP.

Large VWF multimers accumulate in microthrombi; thus, their reduced concentrations within the blood likely contributed to COVID-19-induced immunothrombosis. SDS agarose gel analyses on samples from patients with COVID-19 confirmed these results. 

Other studies have shown that COVID-19 patients exhibit lupus- and rheumatoid arthritis-like antibody patterns. Accordingly, critically sick COVID-19 patients also exhibit hallmarks of B-cell activation and B-cell repertoire (BCR) observed in autoimmune settings.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection increases the chance of thrombotic microangiopathy by two synergistic mechanisms. Resulting from the excessive release of VWF, the protease activity of ADAMTS13 exceeded the conventional limit.

The COVID-19-induced autoreactive inflammatory environment results in the formation of autoantibodies to ADAMTS13. The circulation of those autoantibodies subsequently reduced ADAMTS13 activity and contributed to the event of immunothrombosis. Each of those mechanisms may increase the chance of ultra-large VWF multimers formation in COVID-19, resembling those formed in TTP.

Conclusions

In the present study, plasma exchange therapy in 25 severe COVID-19 patients with acute respiratory distress syndrome markedly decreased their VWF:Ag ratio and increased ADAMTS13 activity, thereby re-establishing the physiological balance between VWF and its protease. 

Thus, the study findings provide evidence of an extra good thing about plasma exchange therapy beyond the attenuation or elimination of circulating cytokines and inflammation for the treatment of COVID-19. Moreover, considering VWF, ADAMTS13 activity, and ADAMTS13 autoantibodies levels throughout the diagnostic workup of COVID-19 may provide essential insights into disease severity.

Journal reference:

• Doevelaar, A. A. N., Bachmann, M., Hölzer, B. et al. (2023). Generation of doubtless inhibitory autoantibodies to ADAMTS13 in coronavirus disease 2019. Scientific Reports 13(10501). doi:10.1038/s41598-023-37405-5