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

Antiphospholipid syndrome: laboratory detection, mechanisms of action and treatment

“…Therefore, it is unlikely that APS can be explained completely by a disturbance of the PC system. It was postulated that although the presence of aPL results in delayed thrombin formation in vitro, in vivo the same antibodies cause accelerated thrombin formation [34][35][36][37][38][39][40]. Increased plasma levels of thrombin-antithrombin complex have been measured in patients with APS [41].…”

Naturally occurring free thiols within β2-glycoprotein I in vivo: nitrosylation, redox modification by endothelial cells, and regulation of oxidative stress–induced cell injury

“…The function of ␤2GPI remains uncertain, although it is thought to play a role in apoptotic cell clearance and coagulation through multiple interactions with serine proteases, anionic phospholipid, and cell-surface receptors. [13][14][15][16][17][18][19][20] It is found in relatively high concentrations in circulating plasma (4M) and is also found within atherosclerotic plaque lesions, 21 although the function of ␤2GPI relating to atherosclerosis has not been elucidated. The antiphospholipid syndrome is an autoimmune condition characterized by pathogenic circulating anti-␤2GPI antibodies.…”

Autoimmunity and Recurrent Pregnancy Losses

“…In recurrent pregnancy losses, aPL, antiprothrombin, and antisaccharomycetes cerevisiae antibodies were more prevalent than in controls, with odd ratio of 4.8, 5.4, and 3.9 for each antibody, respectively. Therefore, although there is a general consensus to screen for aPL in patients with recurrent pregnancy losses, larger cohort studies are necessary to determine the true incidence of recurrent pregnancy losses in the presence of other autoantibody or combinations of autoantibodies [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66]. In addition, these cohort studies should either be corrected for the subsequent miscarriages caused by fetal chromosomal aberrations, or use multivariate analysis to corect for the effect of confounding factors such as maternal age.…”