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 ϭ 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 Ͻ 0.05) and cellular crescents (P Ͻ 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.

Tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease

“…However, the incidence of VTE is not correlated with the prevalence of antiphospholipid antibodies or mutations in thrombosis associated factors 28. Even though the presence of antiplasminogen antibodies affecting in vitro fibrinolysis has been previously implicated in the hypercoagulability of AAV29 and an interplay between endothelial cells and ANCA or activated neutrophils in arterial vessels has been associated with disease pathogenesis,30 the involvement of the extrinsic coagulation system in AAV related thrombogenicity has not been completely elucidated.…”

Anti-Neutrophil Cytoplasmic Antibodies Stimulate Release of Neutrophil Microparticles

“…3,4 Recent studies from four different cohorts of patients with AAV strongly suggest an increased occurrence of thromboses associated with these types of vasculitis and that this risk is strongly associated with vasculitis disease activity. 3,36 Thrombin generated by excess NMPs or other MPs known to be increased in the circulation of patients with AAV 23,24 in conjunction with endothelial injury, 27,37 as well as anti-plasminogen antibodies, 18 could significantly contribute to this thrombotic propensity. Further prothrombotic potential of NMPs derived from ANCA stimulation could be mediated via interaction of active CD11b/CD18 on NMPs and platelets.…”

“…These include how ANCAs bind to endothelium independently of ANCA antigens to cause endothelial activation 15 even though endothelial cells have not been conclusively demonstrated to produce MPO or PR3, 16,17 and why patients with AAV have evidence of increased hypercoagulability. 3,18 Finally, ANCA levels do not always correlate with disease activity, 19 and it is unknown how therapeutic plasma exchange mediates its beneficial effects, 20,21 as this does not appear to be the result of ANCA removal from the circulation alone. Further understanding of the interaction between ANCAs, leukocytes, endothelium, and coagulation pathways could address some of these important but as yet unexplained observations.…”

Thrombosis in vasculitic disorders−clinical manifestations, pathogenesis and management

“…The higher frequency of VTE could be related to changes in the endothelial function (due to the chemokine release and cytokine production) and hypercoagulability [65]. Another explanation could be attributed to an increase in the number of antibodies, such as anti-plasminogen antibodies, at the time of a new/active disease, as demonstrated by Berden et al [16].…”

“…These disorders are associated with the presence of ANCA directed either against proteinase 3 (PR3) or myeloperoxidase (MPO). While patients with AAV are known to present with increased hypercoagulability, this observation is yet to be evaluated with respect to the underlying mechanisms of this phenomenon [16,17] (Table 1). A retrospective analysis has shown an increased incidence of cardiovascular events in patients with AAVs compared to a matched controlled group of patients with chronic kidney disease [18].…”