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.
© 2020 by The American Society of Hematology.
Conflict of interest statement
Conflict-of-interest disclosure: M.A.C. has served on data safety monitoring boards supported by Bayer and on advisory bodies for Servier Canada and Asahi Kasei; has prepared educational materials and/or presented such materials for Pfizer, CSL Behring, and Diagnostica Stago; and owns stock in Alnylam. S.C. has served on advisory boards for Alexion and Sanofi. R.A.B. has served on the scientific advisory boards of Alexion and Achillion. The remaining authors declare no competing financial interests.
Anti-beta2-glycoprotein I, anti-prothrombin and anticardiolipin antibodies in a longitudinal study of patients with systemic lupus erythematosus and the antiphospholipid syndrome.Br J Rheumatol. 1998 Oct;37(10):1089-94. Br J Rheumatol. 1998. PMID: 9825748
Antiphospholipid syndrome: 30 years and our contribution.Int J Rheum Dis. 2015 Feb;18(2):233-41. doi: 10.1111/1756-185X.12438. Epub 2014 Dec 19. Int J Rheum Dis. 2015. PMID: 25524556 Review.
Anti-beta2-glycoprotein I antibodies in pediatric systemic lupus erythematosus and antiphospholipid syndrome.Arthritis Rheum. 2002 Aug;47(4):414-20. doi: 10.1002/art.10510. Arthritis Rheum. 2002. PMID: 12209489
The value of IgA antiphospholipid testing for diagnosis of antiphospholipid (Hughes) syndrome in systemic lupus erythematosus.J Rheumatol. 2001 Dec;28(12):2637-43. J Rheumatol. 2001. PMID: 11764209
Prevalence and Thrombotic Risk Assessment of Anti-β2 Glycoprotein I Domain I Antibodies: A Systematic Review.Semin Thromb Hemost. 2018 Jul;44(5):466-474. doi: 10.1055/s-0037-1603936. Epub 2017 Aug 4. Semin Thromb Hemost. 2018. PMID: 28778105 Review.