Mechanisms of antiphospholipid-induced thrombosis: effects on the protein C system.

An acquired resistance to activated protein C (APC) has been demonstrated in patients with antiphospholipid antibodies (aPL). Recent studies report interactions between beta2 glycoprotein I (beta2GPI) and prothrombin-binding antibodies and the protein C system. Some aPL in patients recognize one or more conformational epitopes shared by beta2GPI and catalytic domains of APC. Both beta2GPI and anti-prothrombin antibodies are associated with APC resistance. Several clinical studies have focused on an association between aPL and APC resistance, determined by classic activated partial thromboplastin time-based tests. It has been shown in most studies that APC resistance was associated with lupus anticoagulants. APC resistance is also associated with thrombosis, especially venous thromboembolism. Several recent studies have reported a novel integrated approach of coagulation using calibrated automated thrombography. This technique allows an approach of APC sensitivity without interference with lupus anticoagulants. Clinical associations between APC resistance and thromboembolic events have been demonstrated.

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

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 beta(2)-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 (ETP(0)) and the activated protein C concentration that reduced the ETP(0) by 50% (IC(50)-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 microg/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 IC(50)-APC, respectively, thus providing evidence for a procoagulant effect independent of platelet activation. The 84% decrease in ETP(0) indicated that 28F4 also displayed an anticoagulant effect. In platelet-rich plasma, this anticoagulant effect was significantly less (23% decrease in ETP(0)), 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 ETP(0)) was less than the inhibition of activated protein C activity (increased IC(50)-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.

Heparin-induced thrombocytopenia associated with interleukin-8-dependent platelet activation in a patient with antiphospholipid syndrome.

Platelet factor 4 heparin enzyme immunoassay, platelet aggregation test, and serotonin release assay are commonly used to diagnose and confirm heparin-induced thrombocytopenia. We describe a case of recurrent thrombocytopenia appearing in a few hours after each heparin administration and who tested negative for the three assays. Further analysis revealed anti-interleukin (IL)-8 antibodies and IL-8-dependent platelet activation facilitated by heparin, which may explain this unusual case of heparin-induced thrombocytopenia.