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  • Title: The role of beta 2-glycoprotein I-dependent lupus anticoagulants in the pathogenesis of the antiphospholipid syndrome.
    Author: Arnout J.
    Journal: Verh K Acad Geneeskd Belg; 2000; 62(5):353-72. PubMed ID: 11144685.
    Abstract:
    The antiphospholipid syndrome (APS) is defined as the association of antiphospholipid antibodies (aPL) with arterial or venous thrombosis, recurrent fetal loss, thrombocytopenia or neurologic disorders. Some aPL can be detected via phospholipid dependent coagulation assays where they present as an aspecific coagulation inhibitor termed the lupus anticoagulant (LA). Other antibodies can be measured via immunological assays mostly via their capability to bind to immobilised cardiolipin and are therefore called anticardiolipin antibodies (aCL). Affinity purification of aCL led to the discovery that, in contrast to what the term antiphospholipid antibody could suggest, these autoimmune antibodies do not bind to negatively charged phospholipids per se but to beta-2-glycoprotein I (beta 2GPI), a phospholipid-binding protein eventually bound to phospholipid surfaces. LAs have been found to be directed towards either prothrombin or beta 2GPI bound to anionic phospholipids. Whereas clinical and animal experimental data clearly suggest a role for beta 2GPI-dependent aPL in the development of the APS, the pathogenic mechanism is not known. Interferences with several phospholipid dependent anticoagulant pathways have been proposed but none of these has received general acceptance. Based on clinical and experimental similarities with heparin-induced thrombocytopenia, another syndrome of antibody mediated thrombosis, we proposed a model of prothrombotic cellular activation. This model, although supported by a number of experimental observations, does not provide a direct explanation for the recent observation that LA are more strongly associated with thrombosis than aCL. In order to study this, we raised murine monoclonal antibodies (moab) against human beta 2GPI. These antibodies, of which some had LA activities and others not, enabled us to study the interaction between beta 2GPI, antibody and phospholipids. In contrast to what was generally accepted, beta 2GPI appeared to have only low affinity for coagulation promoting phospholipids. In the presence of LA positive anti-beta 2GPI moabs, the affinity of beta 2GPI for phospholipids increased significantly. This appeared to be dependent on the formation of bivalent beta 2GPI-antibody complexes on the phospholipid surface. It is conceivable that such bivalent complexes also remain tightly attached to membranes of activated cells enabling further thrombosis promoting activation via Fc receptor interaction or the complement system, a hypothesis that is currently being investigated. Further studies also showed that our LA positive anti-beta 2GPI moabs have a potential for the production of LA control specimens, that could be made available to routine hemostasis laboratories to assess intra-laboratory precision of LA testing, to manufacturers to produce highly sensitive assay systems and to control batch-to-batch variability of their reagents and to organizations involved in external quality assessment. In conclusion this work has enabled us to understand the molecular mechanism by which certain autoimmune antibodies found in patients with APS prolong coagulation assays in vitro. The antibodies generated are an important tool to improve the laboratory diagnosis of the lupus anticoagulant and may help us clarify the pathogenic role of autoimmune anti-beta 2GPI antibodies.
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