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

Abstract

ObjectiveTo 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.ConclusionPatients 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.

Venous Thrombotic Events in ANCA-Associated Vasculitis: Incidence and Risk Factors

“…Our study confirms a strong relationship between PR3 ANCA and VTE risk, as seen in prior studies (6,8). In contrast, VTE incidence was higher in MPO ANCA patients in a retrospective study by Stassen et al The reason for this discrepancy is unclear (1).…”

“…Importantly, we were able to confirm the association of PR3 ANCA andhypoalbuminemiawith VTE incidence in our dataset (6,17). We were unable to confirm a previously seen association between alveolar hemorrhage and VTE in our dataset, likely due to the limited number of cases with alveolar hemorrhage in our dataset (8).…”

“…Several studies have sought to uncover molecular determinants of active vasculitis. There is increased recognition that antibodies against proteinase-3 (PR3) correlates well with the incidence of VTE (6,8). A slightly older study, however did note a protective effect of PR3 ANCA (1).…”

Nierenbeteiligung bei ANCA-assoziierten Vaskulitiden

“…Schließlich haben Patienten mit aktiver Vaskulitis ein deutlich erhöhtes Thromboserisiko (8-10 %) [52,53], sodass bei langer Hospitalisierung und bei geringem Blutungsrisiko an eine prophylaktische Antikoagulation jedenfalls gedacht werden sollte. Während der initialen Phase der Erkrankung (hohe Steroiddosis, additive Immunsuppression und Aktivität der Grunderkrankung) ist eine antibiotische Prophylaxe mit Trimethoprim-Sulfamethoxazol sinnvoll [24,54].…”

Immunopathogenesis of ANCA-Associated Vasculitis

“…Cases with double seropositivity for both PR3- and MPO-ANCA are rarely seen, and are mainly associated with secondary forms of ANCA-associated vasculitis (i.e., in cocaine-induced forms or drug-induced vasculitis) [ 8 , 9 ]. Recent research found that the ANCA serotype better discriminates between genetic associations, therapeutic response, relapse risk, prognosis and co-morbidities (venous thromboembolic events and cardiovascular death) than a classification based on the clinical phenotype [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. In addition, the respective ANCA serotype more closely relates to biomarkers of disease activity [ 17 ] and may help to identify novel therapeutic targets and predict response to current treatment regimens.…”