Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS

Abstract

The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies, including anti-β2-glycoprotein-I (anti-β2GPI), that are considered central to APS pathogenesis. Based on animal studies showing a role of complement in APS-related clinical events, we used the modified Ham (mHam) assay (complement-dependent cell killing) and cell-surface deposition of C5b-9 to test the hypothesis that complement activation is associated with thrombotic events in APS. A positive mHam (and corresponding C5b-9 deposition) were present in 85.7% of catastrophic APS (CAPS), 35.6% of APS (and 68.5% of samples collected within 1 year of thrombosis), and only 6.8% of systemic lupus erythematosus (SLE) sera. A positive mHam assay was associated with triple positivity (for lupus anticoagulant, anticardiolipin, and anti-β2GPI antibodies) and recurrent thrombosis. Patient-derived anti-β2GPI antibodies also induced C5b-9 deposition, which was blocked completely by an anti-C5 monoclonal antibody, but not by a factor D inhibitor, indicating that complement activation by anti-β2GPI antibodies occurs primarily through the classical complement pathway. Finally, patients with CAPS have high rates of rare germline variants in complement regulatory genes (60%), compared with patients with APS (21.8%) or SLE (28.6%) or normal controls (23.3%), and have mutations at a rate similar to that of patients with atypical hemolytic uremic syndrome (51.5%). Taken together, our data suggest that anti-β2GPI antibodies activate complement and contribute to thrombosis in APS, whereas patients with CAPS have underlying mutations in complement regulatory genes that serve as a “second hit,” leading to uncontrolled complement activation and a more severe thrombotic phenotype.

Severe COVID‐19 infection and thrombotic microangiopathy: success does not come easily

“…Catastrophic antiphospholid syndrome (CAPS) is a plausible diagnosis that could not be confirmed, because of the requirement to repeat testing in 12 weeks. Even in this case, the clinical presentation, pathophysiology, and management that will be described below, would also match those of complement‐mediated TMA 4 …”

Coagulopathy and thromboembolic events in patients with SARS-CoV-2 infection: pathogenesis and management strategies

“…In a different murine model of MERS-CoV infection, augmented levels of C5a and C5b-9 were reported in pulmonary tissues. Stopping C5a with a murine antibody reduced pulmonary injury with diminished cytokine response and viral proliferation [80,81].…”

Venous Thromboembolism in COVID-19: Towards an Ideal Approach to Thromboprophylaxis, Screening, and Treatment

“…However, the association between COVID-19 and antiphospholipid syndrome (APS) remains speculative at this point given that the definitive diagnosis of APS requires persistence of IgG antibodies (rather than IgA antibodies as reported) at 12 weeks along with thrombotic events meeting the Sapporo criteria. In patients that harbor rare germline mutations in complement regulatory genes, complement activation can lead to antiphospholipid antibody-induced thrombotic events [8], suggesting a possible role for complement blockade in managing complement-mediated APS [6].…”