Antibodies to beta(2)-glycoprotein I associated with antiphospholipid syndrome suppress the inhibitory activity of tissue factor pathway inhibitor

Anionic phospholipid membranes have a dual role in blood coagulation: they are essential for the initiation and propagation as well as for the limitat ion and termination of the blood coagulation process. Patients with the ant i-phospholipid syndrome (APS) carrying antibodies against complexes of anio nic phospholipids and plasma proteins, show in vitro inhibited phospholipid dependent coagulation reactions, whereas in vivo the presence of these ant ibodies is associated with an increased risk of thrombosis. In this study w e focussed on the effects of these anti-phospholipid antibodies on the regu lation of TF-mediated factor Xa (FXa) generation in plasma. We hypothesized that anti-phospholipid antibodies interfere with the phospholipid-dependen t inhibition by tissue factor pathway inhibitor (TFPI) of TF-induced coagul ation. Indeed, total-IgG, anti-cardiolipin-IgG (aCL) and anti-beta(2)GPI-Ig G, isolated from patient plasmas, all stimulated TF-induced FXa generation in normal plasma. This enhanced FXa generation was not observed when the pa tient's IgG was depleted of anti-beta(2)GPI-IgG or when normal plasma was d epleted of beta(2)GPI or TFPI. Taken together, these data indicate that ant ibodies to beta(2)GPI, circulaiing in patients with APS, suppress TFPI-depe ndent inhibition of TF-induced coagulation, which results in an increased F Xa generation.