B2-glycoprotein I : Its role in the antiphospholipid syndrome

The association between the development of thrombosis in patients and the persistent presence of antiphospholipid antibodies in their plasma is called the antiphospholipid syndrome. These antiphospholipid antibodies are not directed against phospholipids directly, but against phospholipid-bound proteins. One of the most important proteins against which these antibodies are directed is B2-glycoproteine I (B2GPI). The antibodies can form a complex with B2GPI by two mechanisms: (1) one antibody binds one molecule of B2GPI, resulting in a conformational change in B2GPI and (2) one antibody binds two molecules of B2GPI, resulting in the formation of a bivalent complex. Both mechanisms result in an enormously increased affinity of B2GPI for negatively charged phospholipids. This is used for the detection of these antibodies: by the enormous increase in affinity for negatively charged phospholipids, the B2GPI-antibody complex competes with clotting factors to bind to these phospholipids in a coagulation assay. Therefore, the phospholipids, needed for coagulation, are not available. This results in a prolongation of the clotting time, which is named lupus anticoagulant (LAC) activity. In this study, fusion proteins between B2GPI and the dimerisation domain of factor XI were made. This dimeric B2GPI, which mimics the formation of a bivalent complex, binds with an enormously increased affinity to negatively charged phospholipids and possesses LAC activity. Thus, the contructs made mimic the in vitro effects of B2GPI-antibody complexes. The association between the thrombosis in patients and the LAC activity in vitro is paradoxal. Therefore, the effects of dimeric B2GPI on platelet adhesion in an in vitro thrombosis model were investigated. In this model, blood flows with a defined over a thrombogenic surface (e.g. collagen), resulting in the adhesion of platelets to the surface. This surface coverage is analysed afterwards. In this study, the flow rate of the blood resembles the flow rate in arteries. With this model, it was shown that in the presence of dimeric B2GPI or anti-B2GPI antibodies platelet deposition increased. Furthermore, it was shown that the increased adhesion disappeared in the presence of inhibitors of thromboxane formation. The increased platelet adhesion, observed in the presence of anti-B2GPI antibodies, was not affected when the Fc-receptor on platelets was blocked. An anti-B2GPI antibody, that did not increase platelet deposition, inhibited the increase in platelet adhesion observed in the presence of dimeric B2GPI, suggesting a role for a receptor specific for B2GPI. Taken these observations together, a model by which anti-B2GPI antibodies can cause arterial thrombosis was postulated. The B2GPI-antibody complex binds to negatively charged phospholipids exposed on the platelet surface. The exposition of these phospholipids is a result of the activation of the platelets by for example collagen. This is followed by the binding of the B2GPI-antibody complex to a receptor specific for B2GPI, which results in the activation of this receptor. Then, further activation of the platelets takes place, in which the formation of thromboxane is involved. Finally, this leads to sensitisation of the platelets, which are thereby more prone to form a thrombus. The described findings may lead to the development of new diagnostic tests and therapeutics in the future.