Renal damage and old age: risk factors for thrombosis in patients with ANCA-associated vasculitis

In this retrospective, observational large Asian cohort study, we illustrated that 11.3% of patients developed thrombosis out of 1203 patients with primary AAV who suffered from prolonged hospital stays. In the largest sample size of Asian patients, we concluded that age > 65 years, neurological or lung involvement, severe renal impairment, and elevated D-dimer were independent risk factors of thrombosis with satisfactory performance in the nomogram model. Furthermore, we first unveiled the causal effect between EGPA and DVT(PE) by integrating publicly available GWAS datasets.

Our results indicated that AAV patients in the Chinese population had similar incidences of VTE to Western countries, consistent with Europe (9.8%) [18], with similar VTE percentage to the data from Johns Hopkins Hospital (10.3% vs. 14%) [19]. The prospective study in the Netherlands showed that the VTE incidence of AAV patients was 1.8 per 100 person-years [2], mostly during active disease (3 months before and after diagnosis or relapse of AAV). However, the retrospective cohort in French showed no difference in VTE incidences among different AAV subtypes [3], inconsistent with our EGPA patients with the significantly highest rate of VTE (18.9%) than MPA or GPA patients.

The risk factors of thrombosis in AAV patients varied in different regions and races. Johns Hopkins Hospital reported that PR3-ANCA and hypoalbuminemia were risk factors for thrombosis in AAV patients, among which 65% were GPA [19]. In our study, among which half were MPA. Old age might increase risks for thrombosis, which was consistent with the retrospective study from France (OR = 1.29, 95%CI = 1.01–1.04, P = 0.002) [5]. In the previous report, the incidence of VTE was infrequent in young individuals (< 1 per 10,000 per year) but increased to about 2 per 1000 per year at the age of 65 years and continued rising in the older population [20]. The age-specific risk factors of thrombosis might be because of endothelial dysfunction and frailty exacerbated with aging [21]. In the context of AAV, older patients often present with comorbidities and physiological changes that contribute to an elevated risk of thrombosis. The aging process may affect the coagulation system, making patients more susceptible to clot formation [22].

Renal involvement is a common and severe manifestation of AAV, affecting many patients. Various studies suggested that baseline serum creatinine was associated with thrombosis [18, 23]. It might be caused by the loss of anti-thrombotic factors in the urine of patients with renal involvement and the generation of neutrophil extracellular traps (NETs) recognized as a key pathological feature in renal biopsies from patients with glomerulonephritis associated with AAV [7]. Our study suggested that the combination of severe renal damage and old age created a synergistic effect, significantly increasing the risk of thrombosis in patients with AAV. The European Vasculitis Study Group indicated other risk factors included cutaneous and gastrointestinal involvement [4]. Our study suggested that neurological and lung involvement might be associated with thrombosis. Neurologic involvement might be related to stroke events in AAV patients, which was listed as an indicator of systemic involvement in the BVAS score [14]. A nationwide cohort in Korea found that the risk of stroke was 2.3 times higher in AAV patients [24]. Lung involvement mainly manifested as interstitial lung lesions, pulmonary hemorrhage (PH), pulmonary nodules, etc. VTE and PH had a higher incidence with increasing disease activity [2]. Though rare, case reports suggested the coexistence of VTE and PH in patients with AAV [25], and VTE as an important clue for higher AAV disease activity. The mechanism might also involve severe lung involvement, and even a ventilator-assisted respiratory state led to the aggravation of the relative braking factor and caused thrombosis. More evidence should be obtained from different medical institutions.

We found a causal relationship between EGPA and VTE or PE in MR analysis. The nationwide study in Korea also found that the risks of VTE and PE were the highest in EGPA patients among AAV patients [24]. The mechanism of EGPA causing thrombosis involves multiple factors [26]. Primarily, eosinophils play a crucial role by storing and releasing tissue factors and other cationic proteins, such as major essential protein (MBP) and eosinophilic cationic protein (ECP). MBP disrupted the thrombin binding at the endothelial growth factor domain of thrombomodulin, leading to a deformed complex structure, causing a shift in thrombin’s substrate specificity from protein C to fibrinogen [27]. Additionally, ECP could prevent thrombin-dependent activation of protein C, thus blocking the anticoagulant effect of protein C [28]. Moreover, tissue factor released by eosinophil might activate factor X via factor VII [29]. The presence of ANCA also transforms the endothelium into a pro-adhesive surface, promoting thrombus formation. The combined impacts mentioned above would result in unimpeded fibrin and thrombin production, which would ultimately cause clot formation. In clinical practice, adequate and timely immunosuppression may contribute to preventing thrombosis. Patients who do not receive immunomodulatory therapy within the first two months after EGPA diagnosis are at a significantly higher risk of developing ATE or VTE compared to those treated with systemic corticosteroids (HR = 3.67(1.37–9.89), P = 0.010) [30]. Conversely, patients receiving immunosuppressive agents or corticosteroids as monotherapy exhibit a relatively balanced risk.

In our AAV patients, another solid indication of thrombosis is highly elevated D-dimer, which indicates both the activation of the coagulation pathway and the inflammatory state. It is associated with disease activity and inflammation in GPA patients [31] and predicted mortality and intensive care unit requirements among AAV patients in South Korea [32]. Our study suggested that the cut-off point of D-dimer (> 2 mg/L) might serve as an alerting biomarker to indicate disease activity, thrombosis, and adverse outcomes of AAV patients, which once observed in lupus patients [4].

The study has several limitations. Firstly, as a retrospective, single-center cohort study, the model’s external validity or generalized ability might need further evaluation. It’s challenging to distinguish the chronological relationship between AAV and thrombosis from the retrospective study. Secondly, in clinical practice, some thrombotic events were asymptomatic, and screening prevention was based on the physician’s judgment instead of regular tests on all patients, which may lead to underestimation of certain subclinical thrombotic events. Thirdly, the casual relationship proof from the MR analysis was from the European population’s genetic background. More prospective and Asian genome-wide association studies were needed to confirm the conclusion.