The effects of phosphatidylserine-dependent antiprothrombin antibody on thrombin generation.
OBJECTIVE
Antibodies to prothrombin (APTs) and to beta2-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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Sakai
Yoshie
Y
Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Atsumi
Tatsuya
T
Ieko
Masahiro
M
Amengual
Olga
O
Furukawa
Shin
S
Furusaki
Akira
A
Bohgaki
Miyuki
M
Kataoka
Hiroshi
H
Horita
Tetsuya
T
Yasuda
Shinsuke
S
Koike
Takao
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000494:pharmacology; D016736:Antiphospholipid Syndrome / Q000097:blood* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005337:Fibrin / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D010718:Phosphatidylserines / Q000276:immunology*; D011516:Prothrombin / Q000276:immunology*; D013917:Thrombin / Q000378:metabolism*; D055815:Young Adult
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D015415:Biomarkers; D010718:Phosphatidylserines; D011516:Prothrombin; D005337:Fibrin; D013917:Thrombin