High activity of factor XI and C1 inhibitor in patients with ANCA-associated vasculitis: clinical and laboratory correlations with follow-up analysis of thrombotic events

Abstract Antineutrophil cytoplasmic antibody(ANCA)-associated vasculitis (AAV) is a rare, systemic autoimmune disease that can lead to thrombosis and vascular damage. Previous studies demonstrated prothrombotic changes in peripheral blood in AAV patients. We evaluated activity and levels of coagulation contact system factors, including factor(F)XI, FXII, and C1 inhibitor (C1inh), in patients with AAV compared with healthy controls. In this case-control study, 42 patients diagnosed with AAV and 42 age- and sex-matched healthy controls were enrolled. At baseline, most patients were in remission or had low disease activity (median BVAS: 0, Q1-Q3: 0–2). The activities of FXI and FXII were measured by coagulometric methods (FXI: C and FXII: C), and the antigen levels of FXI and FXII were evaluated using an immunoenzymatic method (FXI: Ag and FXII: Ag). The activity of C1inh was assessed by the chromogenic method (C1inh: Ac). Thrombin generation was assessed using the Calibrated Automated Thrombogram (CAT) assay, including thrombin peak, endogenous thrombin potential, lag time, and time to peak. The diagnosis of AAV was based on the ACR/EULAR 2022 classification criteria. Patients with AAV had 16.43% higher FXI activity (FXI: C) as compared to controls (median: 128.65% vs. 110.50%, p < 0.001). No differences were observed for FXI: Ag, FXII: C and FXII: Ag between the analyzed groups. Notably, C1inh: Ac was 16.43% higher in AAV patients than in controls (median: 129.00% vs. 110.80%, p < 0.001). Among the AAV group, the age of patients showed a significant positive correlation with FXI: C (R S = 0.37, p = 0.015), FXI: C was positively correlated with FXII: C (R S = 0.33, p = 0.035), and FXI: C also showed a positive correlation with C1inh: Ac (R S = 0.47, p = 0.002). Next, patients with AAV also showed altered thrombin generation dynamics, with higher ETP ( p = 0.017), longer lag time ( p < 0.001), and longer time to thrombin peak ( p = 0.021), while thrombin peak remained comparable to controls ( p = 0.32). During a median follow-up of 3 years, thromboembolic complications occurred in 10 patients (23.8%), including 7 patients with venous and 6 with arterial events, with 3 patients experiencing both types. Patients who developed thromboembolic complications had lower baseline FXI antigen concentrations (by 52.66%, p = 0.02) and lower peak thrombin generation (by 19.21%, p = 0.026). There were no significant differences in the other analyzed coagulometric parameters ( p > 0.05 for all). Our findings indicate alterations in FXI-related coagulation parameters and C1 inhibitor activity in patients with predominantly inactive or low-activity AAV. These observations suggest that abnormalities in hemostatic regulation may persist despite clinical disease control, although their underlying mechanisms and clinical significance require further investigation.