title: Anti-plasminogen antibodies compromise fibrinolysis and associate with renal histology in ANCA-associated vasculitis.
abstract: Antibodies recognizing plasminogen, a key component of the fibrinolytic system, associate with venous thrombotic events in PR3-ANCA vasculitis. Here, we investigated the prevalence and function of anti-plasminogen antibodies in independent UK and Dutch cohorts of patients with ANCA-associated vasculitis (AAV). We screened Ig isolated from patients (AAV-IgG) and healthy controls by ELISA. Eighteen of 74 (24%) UK and 10/38 (26%) Dutch patients with AAV had anti-plasminogen antibodies compared with 0/50 and 1/61 (2%) of controls. We detected anti-plasminogen antibodies in both PR3-ANCA- and MPO-ANCA-positive patients. In addition, we identified anti-tissue plasminogen activator (tPA) antibodies in 13/74 (18%) patients, and these antibodies were more common among patients with anti-plasminogen antibodies (P = 0.011). Eighteen of 74 AAV-IgG (but no control IgG) retarded fibrinolysis in vitro, and this associated with anti-plasminogen and/or anti-tPA antibody positivity. Only 4/18 AAV-IgG retarded fibrinolysis without harboring these antibodies; dual-positive samples retarded fibrinolysis to the greatest extent. Patients with anti-plasminogen antibodies had significantly higher percentages of glomeruli with fibrinoid necrosis (P < 0.05) and cellular crescents (P < 0.001) and had more severely reduced renal function than patients without these antibodies. In conclusion, anti-plasminogen and anti-tPA antibodies occur in AAV and associate with functional inhibition of fibrinolysis in vitro. Seropositivity for anti-plasminogen antibodies correlates with hallmark renal histologic lesions and reduced renal function. Conceivably, therapies that enhance fibrinolysis might benefit a subset of AAV patients.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Annelies E
authors.initials: AE
authors.lastname: Berden
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Nolan
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Morris
authors.forename: Rogier M
authors.initials: RM
authors.lastname: Bertina
authors.forename: Dianhdra D
authors.initials: DD
authors.lastname: Erasmus
authors.forename: E Christiaan
authors.initials: EC
authors.lastname: Hagen
authors.forename: Donal P
authors.initials: DP
authors.lastname: Hayes
authors.forename: Nico H
authors.initials: NH
authors.lastname: van Tilburg
authors.forename: Jan A
authors.initials: JA
authors.lastname: Bruijn
authors.forename: Caroline O S
authors.initials: CO
authors.lastname: Savage
authors.forename: Ingeborg M
authors.initials: IM
authors.lastname: Bajema
authors.forename: Peter
authors.initials: P
authors.lastname: Hewins
mesh_terms: D000704:Analysis of Variance; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000276:immunology* / Q000378:metabolism; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology* / Q000378:metabolism; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005342:Fibrinolysis / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D007674:Kidney Diseases / Q000276:immunology / Q000473:pathology*; D007677:Kidney Function Tests; D008297:Male; D009426:Netherlands; D010958:Plasminogen / Q000276:immunology* / Q000378:metabolism; D012016:Reference Values; D018709:Statistics, Nonparametric; D006113:United Kingdom
chemical_list: D000888:Antibodies, Anti-Idiotypic; D019268:Antibodies, Antineutrophil Cytoplasmic; D007074:Immunoglobulin G; D010958:Plasminogen