Novel Risk Factors for Thromboembolism in ANCA-Associated Vasculitis

Researchers conducted a study to examine the frequency of VTEs in ANCA-associated vasculitis, and to identify its novel risk factors.

Several novel factors, including heart involvement and the presence of red blood cell casts, increase the risk for venous thromboembolic events (VTEs) in patients with anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, according to research published in Arthritis and Rheumatology.

Researchers conducted a double-blind, placebo-controlled trial to examine the frequency of VTEs among patients in the Rituximab (RTX) in the ANCA-Associated Vasculitis (RAVE) clinical trial. The researchers also aimed to identify novel potential risk factors. The RAVE trial randomly assigned 197 patients to receive either 375 mg/m² RTX weekly for 4 weeks or 2 mg/kg body weight cyclophosphamide for 3 to 6 months, followed by maintenance treatment with 2 mg/kg body weight azathioprine. Patients were classified according to their diagnosis (granulomatosis with polyangiitis or microscopic polyangiitis), and vasculitis activity was assessed via the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) and the Vasculitis Damage Index.

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VTEs occurred in 16 (8.1%) patients; 11 patients had deep vein thrombosis, 4 had pulmonary embolism, and 1 had concomitant deep vein thrombosis and pulmonary embolism. Time from baseline to VTE was 1.5 (range 1.0-2.75) months. Patients who experienced VTEs had a higher BVAS/WG score at baseline (10 vs 8; P =.017) and a higher frequency of proteinase 3 vs myeloperoxidase positivity (15 vs 1; P =.016). In total, 7 VTEs were noted in the RTX group (P =.558). Univariate analyses identified several variables associated with VTEs. In particular, the investigators identified heart involvement (hazard ratio [HR] 17.408; 95% CI, 2.247-134.842; P =.006), proteinase 3 positivity (HR 7.731; 95% CI, 1.021-58.545; P =.048), pulmonary hemorrhage (HR 3.889; 95% CI, 1.448-10.448; P =.008), and the presence of red blood cell casts (HR 15.617; 95% CI, 3.491-69.854; P <.001) as positive associations with VTEs.

Multivariate models, adjusted for age and sex, confirmed the associations made by the univariate analyses. After adjusting for demographic variables, associations between VTEs and heart involvement (HR 21.836; 95% CI, 2.566-185.805), pulmonary hemorrhage (HR 3.91; 95% CI, 1.453-10.522, P =.007), proteinase 3 positivity (HR 9.120; 95% CI 1.158-71.839, P=.036), and the presence of red blood cell casts (HR 16.455; 95% CI, 3.607-75.075) remained significant. VTE frequency was similar in both treatment groups (HR 0.747; 95% CI, 0.278-2.006; P =.563), with no difference between newly diagnosed and relapsing patients (HR 1.067; 95% CI,0.400-2.844; P =.896).

Study limitations included the inclusion of only clinically apparent VTEs and potential variations in the definition of alveolar hemorrhage, which was left to the site investigators to determine. Some variables, including serum albumin and proteinuria, were not available for all participants.

The study researchers concluded, “The associations between heart involvement and presence of [red blood cell casts] [have] not been previously described and may reflect the contribution of overall disease burden to the risk of thrombotic complications. Further studies are needed to confirm and expand these findings.”


Kronbichler A, Leierer J, Shin JI, et al; for the RAVE–ITN Research Group. The association of pulmonary haemorrhage, positive PR3-ANCA and urinary red blood cell casts with venous thromboembolism in ANCA-associated vasculitis [published online June 19, 2019]. Arthritis Rheumatol. doi: 10.1002/art.41017