Novel autoantibodies against the activated coagulation factor IX (FIXa) in the antiphospholipid syndrome that interpose the FIXa regulation by antithrombin.
We previously reported that some human antiphospholipid Abs (aPL) in patients with the antiphospholipid syndrome (APS) bind to the homologous enzymatic domains of thrombin and the activated coagulation factor X (FXa). Moreover, some of the reactive Abs are prothrombotic and interfere with inactivation of thrombin and FXa by antithrombin (AT). Considering the enzymatic domain of activated coagulation factor IX (FIXa) is homologous to those of thrombin and FXa, we hypothesized that some aPLs in APS bind to FIXa and hinder AT inactivation of FIXa. To test this hypothesis, we searched for IgG anti-FIXa Abs in APS patients. Once the concerned Abs were found, we studied the effects of the Ab on FIXa inactivation by AT. We found that 10 of 12 patient-derived monoclonal IgG aPLs bound to FIXa and that IgG anti-FIXa Abs in APS patients were significantly higher than those in normal controls (p < 0.0001). Using the mean + 3 SD of 30 normal controls as the cutoff, the IgG anti-FIXa Abs were present in 11 of 38 (28.9%) APS patients. Importantly, 4 of 10 FIXa-reactive monoclonal aPLs (including the B2 mAb generated against beta(2)-glycoprotein I significantly hindered AT inactivation of FIXa. More importantly, IgG from two positive plasma samples were found to interfere with AT inactivation of FIXa. In conclusion, IgG anti-FIXa Ab occurred in approximately 30% of APS patients and could interfere with AT inactivation of FIXa. Because FIXa is an upstream procoagulant factor, impaired AT regulation of FIXa might contribute more toward thrombosis than the dysregulation of the downstream FXa and thrombin.
Yang
Yao-Hsu
YH
Division of Rheumatology, Department of Medicine, University of California, Los Angeles, CA 90095, USA.
Chien
Daniel
D
Wu
Meifang
M
FitzGerald
John
J
Grossman
Jennifer M
JM
Hahn
Bevra H
BH
Hwang
Kwan-Ki
KK
Chen
Pojen P
PP
D000293:Adolescent; D000328:Adult; D000368:Aged; D017152:Antibodies, Antiphospholipid / Q000097:blood / Q000502:physiology*; D000911:Antibodies, Monoclonal / Q000097:blood / Q000378:metabolism / Q000502:physiology; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000276:immunology*; D000991:Antithrombins / Q000378:metabolism / Q000502:physiology*; D001666:Binding Sites, Antibody; D015949:Factor IXa / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000502:physiology; D008297:Male; D008875:Middle Aged; D011485:Protein Binding / Q000276:immunology
D017152:Antibodies, Antiphospholipid; D000911:Antibodies, Monoclonal; D000991:Antithrombins; D007074:Immunoglobulin G; D015949:Factor IXa