Resistance to Annexin A5 Anticoagulant Activity and Specificity for Anti-B2GPI Domain I Antibodies in Obstetric Antiphospholipid Syndrome

Background Obstetric antiphospholipid (aPL) syndrome (APS) is defined by the presence of persisting aPL with previous unexplained recurrent first trimester pregnancy loss, &/or intrauterine death, &/or placental dysfunction (severe pre-eclampsia, intrauterine growth retardation or placental abruption). The placental anticoagulant protein Annexin A5 (AnxA5) is expressed on the surfaces of placental syncytiotrophoblasts where it has been postulated to play a thrombomodulatory role. aPL antibodies have been demonstrated to reduce the quantity of AnxA5 on these cells and accelerate plasma coagulation. Resistance to AnxA5 anticoagulant activity has previously been demonstrated in APS patients with thrombotic histories. We have investigated whether plasma samples from patients with the obstetric APS also interfere with AnxA5 anticoagulant activity and also whether this correlated with antibody recognition of domain I on β2GPI.

Methods Plasmas were obtained from 30 healthy non-pregnant donors (median age 34, range 18–55) and 70 healthy non-pregnant women with previous obstetric APS (median age 39, range 24–58), and assayed for AnxA5 resistance and anti-β2GPI domain I antibodies, using previously published assays.

Results Women with obstetric APS had significant reduction of AnxA5 anticoagulant ratios compared to controls (median 216%, range 130–282% vs 247%, range 217–283%, p<0.0001) and also elevated levels of antidomain I IgG (median optical density: 0.056, range 0.021–0.498 vs 0.042, range 0.020–0.323, p=0.002). Patients in the lowest tertile of AnxA5 anticoagulant ratios had an odds ratio for obstetric APS of 121.1 (95% confidence interval of 6.5–2240.2) and patients in the highest tertile of antidomain I IgG had an odds ratio for obstetric APS of 3.4 (95% confidence interval of 1.2–9.7). There was a significant correlation between reduction of AnxA5 anticoagulant activity and elevation of antidomain I IgG (r=−0.49, p<0.0001).

Conclusions. Women with obstetric APS are more likely to have AnxA5 resistance and also anti-domain I IgG antibodies than the control groups. These results are consistent with the hypothesis that aPL antibody-mediated disruption of AnxA5, via recognition of domain I of β2GPI is a mechanism for pregnancy morbidity & mortality in obstetric APS.