Rahgozar Soheila, Giannakopoulos Bill, Yan Xiaokai, Wei Jiewei, Cheng Qi Jian, Gemmell Rosalie, Krilis Steven A
Department of Immunology, Allergy and Infectious Diseases, University of New South Wales, Sydney, New South Wales, Australia.
Arthritis Rheum. 2008 Apr;58(4):1146-55. doi: 10.1002/art.23387.
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.
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.
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.
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.
β2糖蛋白I（β2GPI）是抗磷脂综合征（APS）中的一种重要自身抗原。体外研究表明，它可能具有多方面的生理功能，因为它兼具抗凝和促凝特性。我们之前报道过β2GPI能直接结合凝血酶，凝血酶是凝血途径中的一种关键丝氨酸蛋白酶。本研究旨在探讨β2GPI对丝氨酸蛋白酶抑制因子肝素辅因子II（HCII）使凝血酶失活的影响。同时也研究了抗β2GPI抗体的作用。
使用发色底物法和多种血小板功能检测方法评估HCII对凝血酶的失活作用。在这些系统中确定完整的和经蛋白水解切割的β2GPI以及抗β2GPI抗体的影响。
β2GPI可保护凝血酶不被HCII/肝素失活。在Lys317 - Thr318处切割β2GPI可消除其保护作用。患者的多克隆IgG和鼠单克隆抗β2GPI抗体在该系统中增强了β2GPI的促凝作用。
这些新发现表明β2GPI可能调节HCII/肝素对凝血酶的失活作用。抗β2GPI抗体在该系统中增强β2GPI对凝血酶的保护作用从而促进促凝反应，这一观察结果可能揭示了导致APS患者血栓形成倾向的病理生理机制之一。
