Suppressed intrinsic fibrinolytic activity by monoclonal anti-beta-2 glycoprotein I autoantibodies: possible mechanism for thrombosis in patients with antiphospholipid syndrome.
beta2-glycoprotein I (beta2GPI) bears the epitope(s) for autoimmune anticardiolipin antibodies (aCL) frequently present in patients with antiphospholipid syndrome (APS). beta2GPI is involved in coagulation and fibrinolytic systems, including inhibition of contact activation. Coagulation factor XII is an initiator of intrinsic coagulation and also of intrinsic fibrinolysis. We investigated the effect of aCL (= anti-beta2GPI antibodies), regarding intrinsic fibrinolysis using autoimmune monoclonal anti-beta2GPI antibodies derived from a patient with APS or from an NZW/BXSB-F1 mouse. We developed a chromogenic assay system to determine intrinsic fibrinolytic activity. The reaction was activated by kaolin in the euglobulin fraction. Exogenous beta2GPI slightly suppressed intrinsic fibrinolytic activity of the euglobulin fraction from normal plasma. Human monoclonal anti-beta2GPI antibody (EY2C9) and mouse monoclonal anti-beta2GPI antibody (WBCAL-1) in the presence of beta2GPI decreased the activity. In this system, the suppression remained significant in the presence of an excess of exogenous activated factor XII. Euglobulin fractions from APS patients' plasma paralleled low activities of intrinsic fibrinolysis compared with those from healthy subjects. Our results suggest that beta2GPI and anti-beta2GPI antibodies suppress intrinsic fibrinolytic activities. This suppression was not only due to inhibition of factor XII activation but was also related to function of activated factor XII (XIIa). These phenomena partly explain the mechanisms of thrombosis in APS.
Takeuchi
Rie
R
Department of Medicine II, Hokkaido University School of Medicine, Kita-ku, Sapporo, Japan.
Atsumi
Tatsuya
T
Ieko
Masahiro
M
Amasaki
Yoshiharu
Y
Ichikawa
Kenji
K
Koike
Takao
T
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D016736:Antiphospholipid Syndrome / Q000097:blood*; D001323:Autoantibodies / Q000276:immunology / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005342:Fibrinolysis / Q000187:drug effects*; D006023:Glycoproteins / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D013927:Thrombosis / Q000209:etiology* / Q000276:immunology; D053482:beta 2-Glycoprotein I
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D006023:Glycoproteins; D053482:beta 2-Glycoprotein I