Current concepts on the pathogenesis of the antiphospholipid syndrome

Abstract

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 ...

Ro 60 functions as a receptor for β2‐glycoprotein I on apoptotic cells

“…Extensive experimental evidence derived from in vivo murine models and in vitro analysis suggests that anti-␤ 2 GPI autoantibodies in complex with ␤ 2 GPI may directly mediate a pathogenic effect predisposing to thrombosis and fetal loss, via multiple distinct mechanisms (for review, see ref. 7). The physiologic role of the plasma protein ␤ 2 GPI appears to be multifaceted and complex, with evidence suggesting it may modulate the coagulation and fibrinolysis pathways, as well as mediate a role in murine placentation (for review, see ref.…”

Avascular necrosis of bone with hemiparesis: a rare presentation of primary antiphospholipid antibody syndrome

“…3 The aetiology of APS is multifactorial, and an exact, single cause cannot always be determined. 3,4 Pathophysiology includes the activation of endothelium, oxidized LDL mediated vascular injury, heparin induced thrombocytopenia and molecular mimicry. According to the largest survey of APS patients to date, deep vein thrombosis, sometimes accompanied by pulmonary embolism, is the most frequently reported manifestation of this syndrome (38.9%).…”

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

“…The interaction between oxidized b2GPI and DCs lead to IRAK phosphorylation and NF-jB activation that is triggered by TLR4 (Buttari et al, 2005). This raises one possible mechanism in that oxidized b2GPI alone or the anti-b2GPI/ b2GPI complex may be able to function as an endogenous immunological adjuvant by providing a costimulatory signal via binding and cross-talk with TLR4 on DCs and B cells, leading to the amplification of the production of autoantibodies (Buttari et al, 2005;Giannakopoulos et al, 2007).…”