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.