IgG reactivity to phospholipid-bound beta(2)-glycoprotein I is the main determinant of the fraction of lupus anticoagulant activity quenched by addition of hexagonal (II) phase phospholipid in patients with the clinical suspicion of antiphospholipid-antibody syndrome

Background and Objective. Autoantibodies to beta(2)-glycoprotein I (beta(2) -GPI) and/or prothrombin (FII) have been involved in the expression of lupu s anticoagulant (LA) activity, an in vitro phenomenon associated with an in creased risk of arterial and/or venous thromboembolic events. However, LA a ctivity sustained by anti-FII antibodies has a much weaker association with thrombosis than LA activity sustained by anti-Pr GPI antibodies. Because a ssays aimed at detecting LA activity are now commercially available, we eva luated the relative sensitivity to anti-FII and anti-beta(2)-GPI antibodies of a commercial LA assay in a consecutive series of patients with the clin ical suspicion of anti-phospholipid antibody (APA) syndrome. Design and Methods. One hundred and ten consecutive patients with the clini cal suspicion of APA syndrome (primary in 39) and 36 healthy controls were evaluated for the presence of LA activity (LA, Staclot(R), Stago), anticard iolipin antibodies (Quanta Lite aCL IgG, IgM, Inova Diagnostics), and IgG b inding to solid-phase and/or phospholipid (PL)-bound beta(2)-GPI and FII by ELISA assays developed and optimized in our laboratory. Odds ratios for th e association of IgG binding activity with LA and the aCL IgG status were c alculated. In LA patients, dependency of LA potency (as assessed by clottin g time prolongation in absence or presence of hexagonal phospholipid) an au toantibody titers was analyzed by the generalized linear model. Total IgG f ractions were purified from selected patients to evaluate their ability to inhibit prothrombin activation at low FII concentration. Results. Anticardiolipin antibodies (aCL) of the IgG or IgM type were found in 64 and 23 patients and LA activity in 49 patients. Anti-beta(2)-GPI and anti-FII (solid-phase and PL-bound) IgG titers exceeding by more than 3 st andard deviations the mean values observed in control subjects were found i n 46 and 47 patients and in 56 and 30 patients respectively, with the highe st titers detected in the subgroup of patients with both LA and aCL IgG. Th e relative risk of LA for patients free of anti-FII and/or anti-beta(2)-GPI IgG was 0.03 after stratification for the aCL IgG status. Anti-beta(2)-GPI (solid-phase and PL-bound) IgG (RR 34.4 and 12.6) and anti-FII (solid-phas e) IgG (RR 6.33) were all associated with LA activity. However, when taking into account co-existence of anti-fit and anti-beta(2)-GPI IgG in the same patients, the relative risk of LA for patients with isolated anti-FII IgG (solid-phase and/or PL-bound) was 0.50, whereas it ranged from 4.24 to 8.70 for all the antibody combinations including anti-beta(2)-GPI IgG. Anti-bet a(2)-GPI (PL-bound) and aCL IgG titers were the only significant predictors of LA potency determined in the absence of phospholipid (anti-beta 2-GPI I gG) or presence of hexagonal phospholipid (aCL IgG). Total IgG fractions pu rified from 12 patients (6 with anti-FII IgG) did not significantly inhibit factor II activity up to a 150-fold molar excess. Interpretation and Conclusions. These results highlight the high prevalence of anti-FII and anti-beta(2)-GPI IgG in patients with the clinical suspici on of APA syndrome and particularly in the subgroup of patients with LA act ivity. The fraction of LB activity which can be quenched by addition of hex agonal phospholipid is, however, only dependent on IgG directed to PL-bound beta(2)-GPI. Other antibodies associated with anticardiolipin IgG may expl ain residual clotting time prolongation observed in the presence of hexagon al phospholipid. (C) 1999, Ferrata Storti Foundation.