{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Chaturvedi S"],"funding":["NHLBI NIH HHS","European Hematology Association","NIAMS NIH HHS"],"pagination":["239-251"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6978159"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["135(4)"],"pubmed_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."],"journal":["Blood"],"pubmed_title":["Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS."],"pmcid":["PMC6978159"],"funding_grant_id":["K99 HL150594","RG32","R01 HL133113","R01 AR069572","K08 HL138142"],"pubmed_authors":["Brodsky RA","Alluri R","Streiff MB","Petri M","McCrae KR","Crowther MA","Chen H","Yu J","Gavriilaki E","Braunstein EM","Chaturvedi S","Alexander A","Yuan X"],"additional_accession":[]},"is_claimable":false,"name":"Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS.","description":"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.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Jan","modification":"2022-07-19T16:34:09.427Z","creation":"2021-02-21T01:07:07Z"},"accession":"S-EPMC6978159","cross_references":{"pubmed":["31812994"],"doi":["10.1182/blood.2019003863"]}}