Abstract
Objective
Beta~2~‐glycoprotein I (β~2~GPI) 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 β~2~GPI can directly bind thrombin, a key serine protease in the coagulation pathway. The present study was undertaken to examine the influence of β~2~GPI on thrombin inactivation by the serpin heparin cofactor II (HCII). The effect of anti‐β~2~GPI 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 β~2~GPI and anti‐β~2~GPI antibodies was determined in these systems.
Results
β~2~GPI protected thrombin against inactivation by HCII/heparin. Cleavage of β~2~GPI at Lys^317^–Thr^318^ abrogated its protective effect. Patient polyclonal IgG and murine monoclonal anti‐β~2~GPI antibodies potentiated the procoagulant influence of β~2~GPI in this system.
Conclusion
These novel findings suggest that β~2~GPI may regulate thrombin inactivation by HCII/heparin. The observation that anti‐β~2~GPI antibodies potentiate the protective effect of β~2~GPI 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.