The effects of phosphatidylserine-dependent antiprothrombin antibody on thrombin generation
Version of Record online: 30 JUL 2009
Copyright © 2009 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 60, Issue 8, pages 2457–2467, August 2009
How to Cite
Sakai, Y., Atsumi, T., Ieko, M., Amengual, O., Furukawa, S., Furusaki, A., Bohgaki, M., Kataoka, H., Horita, T., Yasuda, S. and Koike, T. (2009), The effects of phosphatidylserine-dependent antiprothrombin antibody on thrombin generation. Arthritis & Rheumatism, 60: 2457–2467. doi: 10.1002/art.24708
- Issue online: 30 JUL 2009
- Version of Record online: 30 JUL 2009
- Manuscript Accepted: 1 MAY 2009
- Manuscript Received: 18 JUL 2008
- Japanese Ministry of Health, Labor and Welfare
- Japanese Ministry of Education, Culture, Sports, Science and Technology
Antibodies to prothrombin (APTs) and to β2-glycoprotein I are the major autoantibodies responsible for lupus anticoagulant (LAC) activity. APTs comprise antibodies against prothrombin alone as well as antibodies against phosphatidylserine/prothrombin complex (anti-PS/PT), the latter being highly associated with the antiphospholipid syndrome (APS). The effect of anti-PS/PT on thrombin generation has not been elucidated, and the paradoxical effect of LAC (an anticoagulant in vitro, but a procoagulant in vivo) remains an enigma. The purpose of this study was to investigate the effects of anti-PS/PT on thrombin generation and to examine the LAC paradox.
We evaluated 36 anti-PS/PT–positive APS patients and 127 healthy subjects. Markers of in vivo thrombin/fibrin generation, including prothrombin fragment F1+2, thrombin–antithrombin III complex, soluble fibrin monomer, D-dimer, and fibrin degradation products, were measured. Mouse monoclonal anti-PS/PT antibody 231D was established, and its effects on in vitro thrombin generation were investigated by chromogenic assay.
Significantly elevated levels of markers of thrombin/fibrin generation were observed in anti-PS/PT–positive patients, regardless of the presence or absence of anticardiolipin antibodies, as compared with healthy subjects. In the presence of low concentrations of human activated factor V (FVa), monoclonal antibody 231D increased thrombin generation in a dose-dependent manner. In contrast, when high concentrations of FVa were added, monoclonal antibody 231D decreased thrombin generation. Under a constant concentration of FVa, a high concentration of human FXa enhanced the effect of 231D.
The presence of anti-PS/PT greatly correlated with increased thrombin generation in APS patients. The in vitro effects of monoclonal antibody 231D on thrombin generation are “biaxial” according to the FVa/FXa balance. These data may serve as a clue to understanding the LAC paradox and the thrombogenic properties of anti-PS/PT.