COVID-19 severity linked to autoantibodies against blood clotting protein

In a recent article published in the journal scientific reportsresearchers conducted a prospective observational study at three healthcare centers in Germany to understand the impact of ADAMTS13 activity during coronavirus disease 2019 (COVID-19).

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

Background

ADAMTS13, also known as von Willibrand factor (vWF)-cleaving protease, cleaves vWF to prevent the formation of ultra-large vWF multimers. ADAMTS13 deficiency can lead to a condition known as thrombocytic thrombocytopenic purpura (PTT), a rare and life-threatening blood disorder that is often treated with plasmapheresis.

Recent studies have shown that COVID-19 markedly increases VWF antigen levels that, in turn, exceed the processing capacity of ADAMTS13. Eventually, this leads to the formation of large VWF multimers similar to what occurs in TTP. Therefore, the ADAMTS13/VWF antigen (VWF:Ag) ratio can be used as an independent predictor of COVID-19 severity and mortality.

However, there remains a lack of research on ADAMTS13 autoantibodies and its role in COVID-19. Recently, two small case series have examined severely ill patients with COVID-19, in which only one of 13 patients exhibited detectable ADAMTS13 antibodies.

About the study

COVID-19 is associated with an increased risk of self-reactivity. In the present study, the investigators investigated whether the generation of autoantibodies against ADAMTS13 contributes to the reduced ADAMTS13/VWF:Ag ratio observed in COVID-19.

A total of 156 patients at the hospitals Ruhr-University Bochum, University of Duisburg-Essen and Asklepios Klinikum Hamburg Harburg were included in the current study, 90 of whom were hospitalized due to COVID-19.

Blood samples were obtained from each study participant to measure ADAMTS13 activity, as well as ADAMTS13 autoantibodies greater than 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. Dodecyl sulfate agarose gel. sodium (SDS) electrophoresis was used for analysis of VWF multimers.

ADAMTS13 autoantibodies during severe COVID-19

ADAMTS13 autoantibodies were observed in almost a third of hospitalized patients with COVID-19. ADAMTS13 autoantibody activity was low, indicating an inhibitory effect on 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 the severity of COVID-19.

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

None of the study patients developed severe thrombocytopenia, defined as a platelet count of 50,000/µL or less. This indicates that the potential inhibitory effect of nonpathogenic ADAMTS13 autoantibodies was weaker in COVID-19 than in TTP.

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

Other studies have shown that patients with COVID-19 exhibit antibody patterns similar to those in lupus and rheumatoid arthritis. Consequently, critically ill patients with COVID-19 also exhibit characteristics of B cell activation and B cell repertoire (BCR) observed in autoimmune settings.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) increases the risk of thrombotic microangiopathy by two synergistic mechanisms. Due to the excessive release of VWF, the ADAMTS13 protease activity exceeded the normal limit.

The autoreactive inflammatory environment induced by COVID-19 leads to the formation of autoantibodies against ADAMTS13. Circulating these autoantibodies subsequently reduced ADAMTS13 activity and contributed to the development of immunothrombosis. Both mechanisms may increase the risk of formation of ultralarge VWF multimers in COVID-19, similar to those formed in TTP.

conclusions

In the current 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 restoring the physiological balance between VWF and its protease.

Therefore, the study findings provide evidence of additional benefit of plasma exchange therapy beyond attenuation or elimination of circulating cytokines and inflammation for the treatment of COVID-19. In addition, considering VWF levels, ADAMTS13 activity, and ADAMTS13 autoantibodies during the diagnosis of COVID-19 may also provide important information about disease severity.