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The effect of platelet activation on the hypercoagulability induced by murine monoclonal antiphospholipid antibodies

Antiphospholipid antibodies are associated with an increased risk of thrombosis. Findings of this study suggest that platelet activation reinforces the hypercoagulability induced by interference of antiphospholipid antibodies/target complexes with coagulation reactions on membrane surfaces. Background To identify the mechanisms of the hypercoagulability associated with antiphospholipid antibodies, we investigated antibody-mediated platelet activation and interference of antibodies with phospholipid-dependent reactions. Design and Methods We used two murine monoclonal antibodies, one against β2-glycoprotein I (7F6G), the other against prothrombin (28F4). Platelet activation was assessed by phospholipid-related platelet procoagulant activity. Endogenous thrombin potential without activated protein C (ETP0) and the activated protein C concentration that reduced the ETP0 by 50% (IC50-APC) were determined by calibrated automated thrombography. Results Both monoclonal antibodies mimicked the effect of IgG in 11 out of a series of 40 patients with antiphospholipid antibodies in thrombography. In the presence of their target, 7F6G and 28F4 at 200 μg/mL exhibited comparatively low and high binding to platelets and elicited low and high levels of procoagulant phospholipids on platelet surface, respectively. In platelet-poor plasma, these antibodies induced a 1.6 and >12-fold increase in IC50-APC, respectively, thus providing evidence for a procoagulant effect independent of platelet activation. The 84% decrease in ETP0 indicated that 28F4 also displayed an anticoagulant effect. In platelet-rich plasma, this anticoagulant effect was significantly less (23% decrease in ETP0), demonstrating that a high increase in procoagulant surfaces by platelet activation significantly antagonizes the anticoagulant effect of antiphospholipid antibodies. In both types of plasma, the inhibition of thrombin generation (reduced ETP0) was less than the inhibition of activated protein C activity (increased IC50-APC). Conclusions Our findings show that platelet activation reinforces the hypercoagulability induced by competition between antiphospholipid antibodies/target complexes and pro- and anticoagulant complexes for phospholipid surfaces.