Association of Pulmonary Hemorrhage, Positive Proteinase 3, and Urinary Red Blood Cell Casts With Venous Thromboembolism in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Andreas Kronbichler, Johannes Leierer, Jae Il Shin, Peter A Merkel, Robert Spiera, Philip Seo, Carol A Langford, Gary S Hoffman, Cees G M Kallenberg, E William St Clair, Paul Brunetta, Fernando C Fervenza, Duvuru Geetha, Karina A Keogh, Paul A Monach, Steven R Ytterberg, Gert Mayer, Ulrich Specks, John H Stone, RAVE−ITN Research Group, Andreas Kronbichler, Johannes Leierer, Jae Il Shin, Peter A Merkel, Robert Spiera, Philip Seo, Carol A Langford, Gary S Hoffman, Cees G M Kallenberg, E William St Clair, Paul Brunetta, Fernando C Fervenza, Duvuru Geetha, Karina A Keogh, Paul A Monach, Steven R Ytterberg, Gert Mayer, Ulrich Specks, John H Stone, RAVE−ITN Research Group

Abstract

Objective: To assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (RAVE) trial and identify novel potential risk factors.

Methods: VTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA-associated vasculitis (AAV).

Results: VTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0-2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247-134.842]; P = 0.006), positive proteinase 3 (PR3)-ANCA (HR 7.731 [95% CI 1.021-58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448-10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491-69.854]; P < 0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566-185.805]; P = 0.005), PR3-ANCA (HR 9.12 [95% CI 1.158-71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453-10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607-75.075]; P < 0.001) remained.

Conclusion: Patients diagnosed as having AAV with pulmonary hemorrhage, positive PR3-ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention.

Trial registration: ClinicalTrials.gov NCT00104299.

© 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Figures

Figure 1
Figure 1
Kaplan‐Meier analysis of the association between venous thromboembolism (VTE) and pulmonary hemorrhage, proteinase 3 (PR3) positivity, and the presence of red blood cell (RBC) casts. A, Event‐free survival of patients with and patients without pulmonary hemorrhage (P < 0.003). B, Time to VTE event according to the specific antigen (PR3 versus myeloperoxidase [MPO]) (P < 0.018). C, Time to VTE event in patients with RBC casts compared to those without significant RBC casts (P < 0.001). All analyses were calculated from trial entry.

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