Beta2-glycoprotein I protects thrombin from inhibition by heparin cofactor II: Potentiation of this effect in the presence of anti-β2-glycoprotein I autoantibodies

Abstract

Objective. Beta2-glycoprotein I (β2GPI) is an important autoantigen in the antiphospholipid syndrome (APS). In vitro studies suggest that it may have multifaceted physiologic functions, since it displays both anticoagulant and procoagulant properties. We have previously reported that β2GPI can directly bind thrombin, a key serine protease in the coagulation pathway. The present study was undertaken to examine the influence of β2GPI on thrombin inactivation by the serpin heparin cofactor II (HCII). The effect of anti-β2GPI antibodies was also examined. Methods. HCII inactivation of thrombin was assessed using chromogenic and various platelet functional assays. The influence of intact and proteolytically cleaved β2GPI and anti-β2GPI antibodies was deter-mined in these systems. Results. β2GPI protected thrombin against inactivation by HCII/heparin. Cleavage of β2GPI at Lys317-Thr318 abrogated its protective effect. Patient polyclonal IgG and murine monoclonal anti-β2GPI antibodies potentiated the procoagulant influence of β2GPI in this system. Conclusion. These novel findings suggest that β2GPI may regulate thrombin inactivation by HCII/ heparin. The observation that anti-β2GPI antibodies potentiate the protective effect of β2GPI on thrombin in this system, thereby promoting a procoagulant response, may potentially delineate one of the pathophysiologic mechanisms contributing to the prothrombotic tendency in patients with APS. © 2008, American College of Rheumatology.