TY - JOUR
T1 - Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS
AU - Chaturvedi, Shruti
AU - Braunstein, Evan M.
AU - Yuan, Xuan
AU - Yu, Jia
AU - Alexander, Alice
AU - Chen, Hang
AU - Gavriilaki, Eleni
AU - Alluri, Ravi
AU - Streiff, Michael B.
AU - Petri, Michelle
AU - Crowther, Mark A.
AU - McCrae, Keith R.
AU - Brodsky, Robert A.
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH), Heart, Lung and Blood Institute grants R01HL133113 (R.A.B), R01HL123098 (K.R.M.), and K08HL138142 (E.M.B.); NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01AR069572 (M.P.); and a Hemostasis and Thrombosis Research Society (HTRS) Mentored Research Award (S.C.).
Publisher Copyright:
© 2020 American Society of Hematology. All rights reserved.
PY - 2020/1/23
Y1 - 2020/1/23
N2 - The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies, including anti-b2-glycoprotein-I (anti-b2GPI), 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 antib2GPI antibodies) and recurrent thrombosis. Patient-derived anti-b2GPI 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-b2GPI 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-b2GPI 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.
AB - The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies, including anti-b2-glycoprotein-I (anti-b2GPI), 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 antib2GPI antibodies) and recurrent thrombosis. Patient-derived anti-b2GPI 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-b2GPI 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-b2GPI 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.
UR - http://www.scopus.com/inward/record.url?scp=85078378512&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078378512&partnerID=8YFLogxK
U2 - 10.1182/blood.2019003863
DO - 10.1182/blood.2019003863
M3 - Article
C2 - 31812994
AN - SCOPUS:85078378512
VL - 135
SP - 239
EP - 251
JO - Blood
JF - Blood
SN - 0006-4971
IS - 4
ER -