Beta2-glycoprotein I protects thrombin from inhibition by heparin cofactor II: potentiation of this effect in the presence of anti-beta2-glycoprotein I autoantibodies.
OBJECTIVE
Beta2-glycoprotein I (beta2GPI) 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 beta2GPI can directly bind thrombin, a key serine protease in the coagulation pathway. The present study was undertaken to examine the influence of beta2GPI on thrombin inactivation by the serpin heparin cofactor II (HCII). The effect of anti-beta2GPI 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 beta2GPI and anti-beta2GPI antibodies was determined in these systems.


RESULTS
beta2GPI protected thrombin against inactivation by HCII/heparin. Cleavage of beta2GPI at Lys317-Thr318 abrogated its protective effect. Patient polyclonal IgG and murine monoclonal anti-beta2GPI antibodies potentiated the procoagulant influence of beta2GPI in this system.


CONCLUSIONS
These novel findings suggest that beta2GPI may regulate thrombin inactivation by HCII/heparin. The observation that anti-beta2GPI antibodies potentiate the protective effect of beta2GPI 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.
Rahgozar
Soheila
S
Department of Immunology, Allergy and Infectious Diseases, University of New South Wales, Sydney, New South Wales, Australia.
Giannakopoulos
Bill
B
Yan
Xiaokai
X
Wei
Jiewei
J
Cheng Qi
Jian
J
Gemmell
Rosalie
R
Krilis
Steven A
SA
D000328:Adult; D000925:Anticoagulants; D001323:Autoantibodies / Q000097:blood / Q000502:physiology*; D001777:Blood Coagulation / Q000276:immunology / Q000502:physiology*; D005260:Female; D006493:Heparin / Q000494:pharmacology; D015844:Heparin Cofactor II / Q000502:physiology*; D006801:Humans; D008297:Male; D013917:Thrombin / Q000502:physiology*; D053482:beta 2-Glycoprotein I / Q000097:blood* / Q000276:immunology
D000925:Anticoagulants; D001323:Autoantibodies; D053482:beta 2-Glycoprotein I; D015844:Heparin Cofactor II; D006493:Heparin; D013917:Thrombin