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. Author summary An infection with SARS-CoV-2 affects patients differently. While some individuals do not develop any symptoms at all, others become seriously ill, displaying signs of hypercoagulation with involvement of different organ systems. The immune response triggered upon infection may comprise both protective as well as detrimental elements. Among the latter, antibodies targeting a wide range of self-proteins have been evidenced. 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. Using a linear mixed-effects model, we further established that anti-prothrombin IgM autoantibodies emerge in proportion to the strength of the antibody response elicited against SARS-CoV-2 proteins, with disease severity and sex as additional contributors. Further research is warranted to investigate the relation between infection with SARS-CoV-2, hypercoagulation, and the presence of autoantibodies directed against prothrombin.
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