Antibodies against the Activated Coagulation Factor X (FXa) in the Antiphospholipid Syndrome That Interfere with the FXa Inactivation by Antithrombin

Abstract

Antiphospholipid Ab have been shown to promote thrombosis and fetal loss in the antiphospholipid syndrome (APS). Previously, we found IgG anti-thrombin Ab in some APS patients that could interfere with inactivation of thrombin by antithrombin (AT). Considering that activated coagulation factor X (FXa) is homologous to thrombin in the catalytic domains and is also regulated primarily by AT, we hypothesized that some thrombin-reactive Ab may bind to FXa and interfere with AT inactivation of FXa. To test these hypotheses, we studied reactivity of eight patient-derived monoclonal IgG antiphospholipid Ab with FXa and the presence of IgG anti-FXa Ab in APS patients and investigated the effects of FXa-reactive mAb on AT inactivation of FXa. The results revealed that six of six thrombin-reactive IgG mAb bound to FXa and that the levels of plasma IgG anti-FXa Ab in 38 APS patients were significantly higher than those in 30 normal controls (p < 0.001). When the mean plus 3 SDs of the 30 normal controls was used as the cutoff, 5 of 38 APS patients (13.2%) had IgG anti-FXa Ab. Importantly, three of six FXa-reactive mAb significantly inhibited AT inactivation of FXa. Combined, these results indicate that anti-FXa Ab may contribute to thrombosis by interfering with the anticoagulant function of AT on FXa in some APS patients.

Anti-prothrombin antibodies in type 1 diabetes mellitus

“…Although, some studies [19,20] have reported that there was no significant correlation between aPT IgG/IgM antibodies and thrombosis in lupus anticoagulant positive patients, the presence of anti-phosphatidylserine/anti-prothrombin was correlated with increased thrombin formation in patients with APS [21]. Antiphospholipid antibodies are known to bind to plasma proteins with an affinity for phospholipids' surfaces [22][23][24][25]. Prothrombin is another important autoantigen recognized by anti-phospholipid antibodies [26,27].…”

Antiphospholipid Antibodies and APS Nephropathy

“…Several aPT also display thrombin-binding activity and in their interaction with thrombin, prevent its inactivation by antithrombin (AT), promoting thrombosis by unchecked fibrinogen and platelet activation by thrombin [34,35]. The presence of aPL with binding activity for activated factor IX (FIXa) and FXa in APS patients has also been reported, and several of these antibodies prevent the inactivation of FIXa and FXa by antithrombin [36,37].…”

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 Abs derived from APS patients bind to the homologous enzymatic domains of several serine proteases (SP) involved in coagulation, such as thrombin, activated PC, plasmin, tissue plasminogen activator, and FXa (10,12,14,15,17). Moreover, some of these autoantibodies are prothrombotic and interfere with different anticoagulation pathways and/or fibrinolytic process (10,12,14,15,17,32).…”

“…Moreover, some of these autoantibodies are prothrombotic and interfere with different anticoagulation pathways and/or fibrinolytic process (10,12,14,15,17,32). FIXa also belongs to the SP family and its enzymatic domain is homologous to those of thrombin and FXa (33).…”

“…The hallmark aPLs recognize a variety of Ags including various phospholipids (PL), PL-binding proteins, and protein-PL complexes, as well as other factors related to hemostasis (4 -7). The involved proteins include ␤ 2 -glycoprotein I (␤ 2 GPI), prothrombin (PT), protein C (PC), protein S, annexin V, thrombomodulin, thrombin, tissue factor pathway inhibitor, activated PC, endothelial PC/activated PC receptor, plasmin, tissue plasminogen activator, annexin 2, and the activated coagulation factor X (FXa) (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Functional studies of aPLs have shown that different aPLs may promote thrombosis through different pathways (4,18,19).…”