Anti-prothrombin autoantibodies enriched after infection with SARS-CoV-2 and influenced by strength of antibody response against SARS-CoV-2 proteins.

Marc Emmenegger,Dirk Roggenbuck,Peter Schierack,Sreedhar Saseendran Kumar,Laura Rose,Karl J Lackner,Martin F Sprinzl,Adriano Aguzzi,Clemens J Sommer,Tomas Malinauskas,Thomas Buettner,Katrin B M Frauenknecht,Vishalini Emmenegger,Ali Ellebedy

doi:10.1371/journal.ppat.1010118

Abstract

Antiphospholipid antibodies (aPL), assumed to cause antiphospholipid syndrome (APS), are notorious for their heterogeneity in targeting phospholipids and phospholipid-binding proteins. The persistent presence of Lupus anticoagulant and/or aPL against cardiolipin and/or β2-glycoprotein I have been shown to be independent risk factors for vascular thrombosis and pregnancy morbidity in APS. aPL production is thought to be triggered by-among other factors-viral infections, though infection-associated aPL have mostly been considered non-pathogenic. Recently, the potential pathogenicity of infection-associated aPL has gained momentum since an increasing number of patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been described with coagulation abnormalities and hyperinflammation, together with the presence of aPL. Here, we present data from a multicentric, mixed-severity study including three cohorts of individuals who contracted SARS-CoV-2 as well as non-infected blood donors. We simultaneously measured 10 different criteria and non-criteria aPL (IgM and IgG) by using a line immunoassay. Further, IgG antibody response against three SARS-CoV-2 proteins was investigated using tripartite automated blood immunoassay technology. Our analyses revealed that selected non-criteria aPL were enriched concomitant to or after an infection with SARS-CoV-2. Linear mixed-effects models suggest an association of aPL with prothrombin (PT). The strength of the antibody response against SARS-CoV-2 was further influenced by SARS-CoV-2 disease severity and sex of the individuals. In conclusion, our study is the first to report an association between disease severity, anti-SARS-CoV-2 immunoreactivity, and aPL against PT in patients with SARS-CoV-2.

Highlights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was found to elicit a spectrum of autoimmune reactions [1–4], similar to other viral infections [5–7]
Our research has focused on autoantibodies targeting phospholipids and phospholipid-binding proteins, held responsible for an increased tendency to thrombosis in an autoimmune disease called antiphospholipid syndrome
Using cohorts from different centres, including patients of mixed disease severities, we found that IgM antibodies targeting prothrombin and β2-glycoprotein I are enriched upon infection

Summary

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was found to elicit a spectrum of autoimmune reactions [1–4], similar to other viral infections [5–7]. Patients with severe SARS-CoV-2 infection, some of whom require mechanical ventilation in specialised hospitals wards, have been shown to be at a high risk of developing thrombotic vessel occlusion [8]. Ischemic events such as stroke have been generally linked with infection, in particular infections affecting the respiratory tract [9]. APL extracted from SARS-CoV-2 infected patients were reported to induce an accelerated hypercoagulation via activation of neutrophils and release of neutrophil extracellular traps (NETs) that points to a pathogenic role of aPL in SARS-CoV-2 infected individuals [15]. The hypercoagulable state [16] with platelet activation, endothelial dysfunction, increased circulating leukocytes, as well as cytokines and fibrinogen in these patients might be the result of an acquired thrombophilia, as described for patients with APS [17]

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