Platelet Activation by Antiphospholipid Antibodies through the IgG Receptor FcγRIIa: Possible Role in Thrombosis Associated with Antiphospholipid Syndrome?

Abstract

Background: Antiphospholipid antibodies (aPLAbs) targeting beta-2glycoprotein I (B2GPI) are of primary importance in thrombosis associated with antiphospholipid syndrome (APS). The predominance of the IgG isotype in APS is conspicuously linked with increased risk of thrombosis, raising the question whether the platelet IgG receptor,FcγRIIa, may play a role in thrombosis caused by aPLAbs, as is the case in heparin-induced thrombocytopenia in which heparin Abs directly activate platelets through FcγRIIa. We have previously shown that:(1) goat anti-human B2GPI-Abs ± human B2GPI strongly activate human platelets in vitro, and that this activity is abolished by the anti-FcγRIIa antibody IV.3;(2) anti-B2GPI immune complexes are thrombotic in mice transgenic for human FcγRIIa but not in wild type mice. Aims: We sought to investigate if IgG from patients with aPLAbs can activate platelets in a manner dependent on FcγRIIa.Methods: IgG was purified from plasma of 46 patients with aPLAbs and/or lupus anticoagulant. The capacity of the IgG to activate plate-lets (±B2GPI) was evaluated by serotonin release assay (SRA) and washed platelet aggregation (WPA). With WPA, platelets ± IV.3 were either: (a) primed with ADP followed by IgG introduction or (b) incubated with IgG (30 min) followed by introduction of low thrombin concentrations. Results: With or without B2GPI, IgG from 10 of 46 (22%) patients caused platelet dense granule release. In all cases this was abolished by IV.3, indicating the dependence of FcγRIIa. Aggregation of ADP-primed platelets was observed with 1 of 2 of the above10 IgGs. Preincubation of platelets with aPL IgG from 2 patients, sensitized platelets to aggregate in response to otherwise subaggregetory thrombin stimuli. This effect was also abolished by IV.3.Conclusions: These findings suggest that aPLAbs from patients can directly activate and/or sensitize platelets in a FcγRIIa-dependent manner. This mechanism may contribute to thrombosis in patients with aPLAbs.