Low-grade endotoxemia, oxidative stress and thrombotic events in patients with primary antiphospholipid syndrome

Abstract

Abstract Introduction The persistence of antiphospholipid antibodies (aPL) is associated with a procoagulant state that could precipitate thrombotic events in the presence of a second pro-inflammatory stimulus, realizing thus the antiphosholipid syndrome (APS). Circulating lipopolysaccharide (LPS) is associated with systemic inflammation, enhanced oxidative stress and cardiovascular events in different clinical conditions, however, its presence and significance has not been evaluated in APS. Purpose To investigate the relationship between LPS, oxidative stress markers and risk of thrombotic events in the prospective multicenter ATHERO-APS study. Methods Baseline serum levels comparison of LPS, soluble NADPH oxidase 2-derived peptide (sNOX-dp), H2O2 production, hydrogen peroxide breakdown activity (HBA), and nitric oxide (NO) bioavailability in 97 primary APS (PAPS), 20 aPL carriers and 20 healthy controls (CTRL) matched for age, sex and BMI. In patients with high LPS levels, Cox-regression analysis was performed to assess the risk for a composite outcome of cardiovascular death, venous (VTE) and arterial thromboembolism (ATE). Results In the whole population (median age 51 (IQR: 45-61) years, 72% female), LPS levels were inversely correlated with HBA (Rs: -0.231, p=0.009) and NO (rS: -0.286, p=0.001) and directly correlated with sNOX-dp (rS:0.423, p<0.001) and H202 (rS: 0.211, p=0.017) (Table 1). Patients with PAPS showed a significant increased levels of LPS, sNOX-dp and H2O2 and a significant lower level of NO and HBA compared to aPL carriers and healthy CTRL. No correlation was found between LPS levels and anti-cardiolipin (aCL) IgG/IgM, anti-beta-2-Glycoprotein-I (aβ2GPI) IgG/IgM and lupus anticoagulant (LAC). After a median follow-up of 4.7 (4.1-5.6) years, 11 composite outcomes were reported: 1 cardiovascular death (stroke related), 3 ischemic strokes, 2 myocardial infarctions, 3 peripheral ATE and 2 VTE. Patients with basal LPS levels above the median value (>20.1 pg/ml) showed a higher annual incidence of composite outcome compared to those with LPS levels below the median value (4.0% vs 0.7%, p=0.013). On Cox-regression analysis, PAPS patients with LPS above the median value showed a 5-fold increased risk of composite outcome compared to patients with LPS below the median value, after adjustment for age, sex, aCL IgG, aβ2GPI IgG and LAC (Figure 1). Conclusion These preliminary data suggest that in PAPS, LPS is associated with a higher risk for a composite outcome of cardiovascular death, ATE and VTE. Further studies are needed to know which pharmacological approach may counteract the prothrombotic effect of LPS.