Details

Autor(en) / Beteiligte

• Rahgozar, Soheila
• Yang, Qiuxia
• Giannakopoulos, Bill
• Yan, Xiaokai
• Miyakis, Spiros
• Krilis, Steven A

Titel

Beta2-glycoprotein I binds thrombin via exosite I and exosite II: Anti- phi 2-glycoprotein I antibodies potentiate the inhibitory effect of phi 2-glycoprotein I on thrombin-mediated factor XIa generation

Ist Teil von

• Arthritis and rheumatism, 2007-02, Vol.56 (2), p.605-613

Erscheinungsjahr

2007

Link zum Volltext

Quelle

Wiley Blackwell Single Titles

Beschreibungen/Notizen

• Objective Beta2-glycoprotein I (2GPI) is a dominant antigenic target in antiphospholipid syndrome (APS). Beta2-glycoprotein I may bind to factor XI and serve a physiologic function as a regulator of factor XI activation by thrombin. We undertook this study to investigate the possible interactions of 2GPI with thrombin in 2GPI-regulated factor XI activation by thrombin and to evaluate the effect of anti-2GPI antibodies on this system. Methods The 2GPI interaction with thrombin was investigated in direct and competitive assays using 2GPI domain mutants and thrombin-binding exosite oligonucleotides. Beta2-glycoprotein I inhibition of thrombin-mediated factor XI activation was assessed in the presence of 8 anti-2GPI monoclonal antibodies (mAb) directed against domain I. Results Domain V of 2GPI was involved in direct binding to thrombin, and exosite I and exosite II on thrombin took part in this interaction. Anti-2GPI mAb produced a >70% inhibition of thrombin-mediated factor XI activation in the presence of 2GPI. Conclusion We demonstrate that 2GPI interacts with thrombin exosites I and II. This novel finding necessitates a reinterpretation of previous studies from which the detection of anti-human thrombin antibodies in APS has been reported. We also show that anti-2GPI antibodies potentiate the inhibitory effect of 2GPI on thrombin-mediated factor XIa generation.