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The antiphospholipid syndrome (APS) is an important cause of acquired thrombophilia. It is characterized by the core clinical manifestations of thrombosis, either venous or arterial, and in women it can also be associated with recurrent fetal loss. The detection of persistently elevated levels of antiphospholipid antibodies (aPL Abs) is a requisite laboratory feature for the diagnosis to be made. The dominant antigenic targets in APS are beta 2-glycoprotein I (␤ 2 -GPI) and prothrombin. There is an accumulating body of experimental evidence that suggests that specific subgroups of aPL Abs may directly contribute to disease pathogenesis. This review critically examines the experimental evidence underlying the various propositions made to explain how these antibodies may predispose to disease in humans. Furthermore, it also examines the evidence relating to the immunologic mechanisms that may contribute to the breakage of peripheral tolerance in IntroductionThe antiphospholipid syndrome (APS) is characterized by the core clinical manifestations of thrombosis, venous or arterial, and recurrent fetal loss. 1 The detection of persistently elevated levels of antiphospholipid antibodies (aPL Abs) is a requisite laboratory feature for the diagnosis to be made. 2 APS can occur in isolation or in association with other autoimmune conditions, particularly systemic lupus erythematosus (SLE). 1 The predominant antibodies in this disorder are directed against protein antigens that bind to anionic phospholipids, such as beta 2-glycoprotein I (␤ 2 -GPI) 3 and prothrombin. 4 The physiological function of prothrombin has been well described. 5 It is a proenzyme that upon cleavage by the prothrombinase complex leads to the generation of thrombin. 5 ␤ 2 -GPI is a 54-kDa protein, with a plasma concentration of 4 M, composed of 5 complement control protein modules, which are termed domains I through to V. 5 Domain V is responsible for binding anionic phospholipids. 5 The in vivo function of ␤ 2 -GPI is not definitively known. As discussed in this review, in vitro it interacts with diverse cell types, receptors, and enzymes. In vivo significance of these interactions needs to be established.Antibodies directed against phospholipids per se, such as cardiolipin (CL) and phosphatidylserine (PS), are also detected in patients with APS. 1 They appear to be part of the natural antibody repertoire and increase during certain infections. 1 In this latter context they do not tend to be associated with the clinical manifestations of APS. 6 Antigenic targets other than ␤ 2 -GPI and prothrombin have been identified in APS patients, including tissue plasminogen activator (tPA), 7 plasmin, 8 annexin A2, 9 and thrombin 10 to name a few. ␤ 2 -GPI 3 and prothrombin 4 are the main antigenic targets in APS, and it would seem reasonable to assert that the dominant pathopsychological mechanisms are likely to involve antibodies directed against these antigens.The generic term "aPL Abs" encompasses antibodies that target protein antigens that bind ...

Objective.Results of previous studies suggest that anti-␤ 2 -glycoprotein I (anti-␤ 2 GPI) antibodies in complex with ␤ 2 GPI activate platelets in a dysregulated manner, potentially contributing to the prothrombotic tendency associated with the antiphospholipid syndrome (APS). We undertook this study to investigate the possible contribution of the GPIb-IX-V receptor to platelet activation mediated by the anti-␤ 2 GPI antibody-␤ 2 GPI complex.Methods. In vitro methods were used in the present study. The interaction between ␤ 2 GPI and the GPIb␣ subunit of the GPIb-IX-V receptor was delineated using direct binding and competitive inhibition assays. The interaction between the anti-␤ 2 GPI antibody-␤ 2 GPI complex and platelets was studied using a novel method in which the Fc portion of the antibody was immobilized using protein A coated onto a microtiter plate. Platelet activation was assessed by two methods; one involved measuring thromboxane B 2 production and the other involved assessment of the activation of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3␤ intracellular signaling pathway. The contribution of the GPIb␣ receptor to platelet activation induced by the anti-␤ 2 GPI antibody-␤ 2 GPI complex was assessed by observing the influence of 2 anti-GPIb␣ antibodies (AK2 and SZ2) directed against distinct epitopes.Results. This study showed that ␤ 2 GPI could bind to the GPIb␣ receptor. The anti-␤ 2 GPI antibody-␤ 2 GPI complex was able to activate platelets, and this effect was inhibited by anti-GPIb␣ antibody directed against epitope Leu-36-Gln-59, but not by anti-GPIb␣ antibody directed against residues Tyr-276-Glu-282.Conclusion. Our findings show that inappropriate platelet activation by the anti-␤ 2 GPI antibody-␤ 2 GPI complex via the GPIb␣ receptor may contribute to the prothrombotic tendency associated with APS.