Anti–Domain I β2-Glycoprotein I Antibodies and Activated Protein C Resistance Predict Thrombosis in Antiphospholipid Syndrome: TAC(I)T Study

Abstract

Background Antibodies binding to domain I of β2-glycoprotein I (aDI) and activated protein C (APC) resistance are associated with an increased risk of thrombosis in cross-sectional studies. The objective of this study was to assess their predictive value for future thromboembolic events in patients with antiphospholipid antibodies (aPL) or antiphospholipid syndrome. Methods This prospective multicenter cohort study included consecutive patients with aPL or systemic lupus erythematosus. We followed 137 patients (43.5 ± 15.4 year old; 107 women) for a mean duration of 43.1 ± 20.7 months. Results We detected aDI IgG antibodies by ELISA in 21 patients. An APC sensitivity ratio (APCsr) was determined using a thrombin generation–based test. The APCsr was higher in patients with anti–domain I antibodies demonstrating APC resistance (0.75 ± 0.13 vs 0.48 ± 0.20, P < 0.0001). In univariate analysis, the hazard ratio (HR) for thrombosis over time was higher in patients with aDI IgG (3.31 [95% CI, 1.15–9.52]; P = 0.03) and patients with higher APC resistance (APCsr >95th percentile; HR, 6.07 [95% CI, 1.69–21.87]; P = 0.006). A sensitivity analysis showed an increased risk of higher aDI IgG levels up to HR 5.61 (95% CI, 1.93–16.31; P = 0.01). In multivariate analysis, aDI IgG (HR, 3.90 [95% CI, 1.33–11.46]; P = 0.01) and APC resistance (HR, 4.98 [95% CI, 1.36–18.28]; P = 0.02) remained significant predictors of thrombosis over time. Conclusions Our study shows that novel tests for antibodies recognizing domain I of β2-glycoprotein I and functional tests identifying APC resistance are significant predictors of thrombosis over time and may be useful for risk stratification.

Insight into the hypercoagulable state of high‐risk thrombotic APS patients: Contribution of aβ2GPI and aPS/PT antibodies

“…Some studies have shown that aPC resistance is associated with thrombotic events in patients with APS. [31][32][33] aPC resistance is thought to be one of the ways through which LA is associated with a pro-thrombotic phenotype in APS. 17,19 Fluorogenic thrombin generation measurements have shown that the presence of LA is associated with a decreased aPC-induced inhibition of the ETP and peak thrombin.…”

“…Some studies have shown that aPC resistance is associated with thrombotic events in patients with APS 31‐33 . aPC resistance is thought to be one of the ways through which LA is associated with a pro‐thrombotic phenotype in APS 17,19 .…”

Recommendations for the measurement of thrombin generation: Communication from the ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies

“…62 Furthermore, depending on the research question, reference ranges can be measured on a specific patient population (e.g., APS patients) for appropriate between-group comparisons. 63 In other applications of TG, such as monitoring of antithrombotic drugs and assessment of bleeding and thrombotic risk levels of TG, TG parameters are compared between patient groups. 5,64,65 Each study should report what reference ranges they applied for interpretation of results.…”

“…These reference ranges may be acceptable if local measurements of 20 or more healthy subjects yield comparable results 62 . Furthermore, depending on the research question, reference ranges can be measured on a specific patient population (e.g., APS patients) for appropriate between‐group comparisons 63 . In other applications of TG, such as monitoring of antithrombotic drugs and assessment of bleeding and thrombotic risk levels of TG, TG parameters are compared between patient groups 5,64,65 .…”

A systematic review of the association between anti-β-2 glycoprotein I antibodies and APS manifestations

“…Indeed, 2 prospective studies identified in this review looked specifically at the clinical relevance of anti-B2GPI D1 positivity and reported a significant association with rates of thrombosis. 49,50 Further progress to standardize anti-B2GPI D1 testing and, ultimately, to clarify its clinical relevance is needed.…”