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

• Published in: Blood 2020-01, Vol.135 (4), p.239-251
• Main Authors: Chaturvedi, Shruti, Braunstein, Evan M., Yuan, Xuan, Yu, Jia, Alexander, Alice, Chen, Hang, Gavriilaki, Eleni, Alluri, Ravi, Streiff, Michael B., Petri, Michelle, Crowther, Mark A., McCrae, Keith R., Brodsky, Robert A.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antibodies, Antiphospholipid - immunology; Antiphospholipid Syndrome - complications; Antiphospholipid Syndrome - genetics; Antiphospholipid Syndrome - immunology; beta 2-Glycoprotein I - immunology; Complement Activation; Female; Gene Expression Regulation; Germ-Line Mutation; Humans; Male; Middle Aged; Plenary Paper; Thrombosis - etiology; Thrombosis - genetics; Thrombosis - immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2019003863

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. •Complement activation is associated with antiphospholipid antibody–induced thrombotic events.•Patients with catastrophic APS harbor rare germline mutations in complement regulatory genes. [Display omitted]