Inhibition of APC anticoagulant activity on oxidized phospholipid by anti–β2-glycoprotein I monoclonal antibodies

Safa, Omid; Esmon, Charles T.; Esmon, Naomi L.

doi:10.1182/blood-2005-01-0404

Cited by 32 publications

(27 citation statements)

References 49 publications

(60 reference statements)

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“…6 It should, however, be realized that our results cannot be generalized since we cannot infer that differences mainly rely on the target, its conformation/orientation and the kinetics of the antigen/antibody interaction. The previously reported mechanism based on a similar phosphatidylethanolamine requirement for APC and aPL/target complexes 15 is unlikely to explain our results since APC-resistance is not restricted to anti-β2GPI antibodies, and prothrombin is known to interact with phosphatidylserine.…”

Section: Discussioncontrasting

confidence: 49%

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

Membré¹,

Wahl²,

Latger‐Cannard³

et al. 2008

Haematologica

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Section: Discussioncontrasting

confidence: 49%

“…13,14 Arguments have been made in favor of selective inhibition of APC activity. 15 Using thrombography, we demonstrated that APC resistance of thrombin generation is partially offset by an anticoagulant effect in aPL patients. The net result of these opposite effects is hypercoagulability associated with an increased risk of thrombosis.…”

Section: Introductionmentioning

confidence: 99%

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

Membré¹,

Wahl²,

Latger‐Cannard³

et al. 2008

Haematologica

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“…43 A number of murine monoclonal anti-␤ 2 -GPI Abs in the presence of ␤ 2 -GPI have been shown to be able to inhibit APC anticoagulant activity in vitro. 44 It is hypothesized that the anti-␤ 2 -GPI Ab/␤ 2 -GPI complex may either compete with components of the APC complex for limited phospholipid binding sites or disrupt an interaction within the APC complex. 44 The presence of oxidized phosphatidylethanolamine (PE) containing phospholipids allowed the anti-␤ 2 -GPI Ab/␤ 2 -GPI complex to selectively disturb APC function.…”

Section: Other Receptors and Cell Surfaces That Interact With ␤ 2 -Gpimentioning

confidence: 99%

“…44 It is hypothesized that the anti-␤ 2 -GPI Ab/␤ 2 -GPI complex may either compete with components of the APC complex for limited phospholipid binding sites or disrupt an interaction within the APC complex. 44 The presence of oxidized phosphatidylethanolamine (PE) containing phospholipids allowed the anti-␤ 2 -GPI Ab/␤ 2 -GPI complex to selectively disturb APC function. 44 This, it is hypothesized, may explain why the APC complex may be disturbed relative to the PS-dependent procoagulant pathways in vivo.…”

Section: Other Receptors and Cell Surfaces That Interact With ␤ 2 -Gpimentioning

confidence: 99%

Current concepts on the pathogenesis of the antiphospholipid syndrome

Giannakopoulos

Passam

Rahgozar

et al. 2006

Blood

208

189

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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 ...

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“…Hypotheses include platelet activation via the ␤ 2 -GP1 antibody/␤ 2 -GP1 complex binding to the apolipoprotein E 2 receptor, 6 interaction of anti-␤ 2 -GP1 antibodydimerized ␤ 2 -GP1 and GPIb, leading to platelet adhesion, 7 endothelium activation via the targeting of anti-␤ 2 -GP1 antibodies to the ␤ 2 -GP1-annexin 2 complex, 8 the inhibition of activated protein C by ␤ 2 -GP1/anti-␤ 2 -GP1 antibody complex, 9 disruption of the potential role of annexin V as an anticoagulant by antiphospholipid antibodies, 10 impairment of fibrinolysis by antiphospholipid antibodies associated with endothelial cells, 11 and exposure of a cryptic epitope on domain I of ␤ 2 -GP1 to allow formation of the ␤ 2 -GP1/anti-␤ 2 -GP1 antibody complex. 12 These concepts derive from in vitro studies.…”

Section: Introductionmentioning

confidence: 99%

β2-glycoprotein-1 autoantibodies from patients with antiphospholipid syndrome are sufficient to potentiate arterial thrombus formation in a mouse model

Arad

Proulle

Furie

et al. 2011

Blood

126

101

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Antiphospholipid syndrome is characterized by thrombosis, recurrent fetal loss, and the presence of the lupus anticoagulant, anticardiolipin antibodies, or anti–β2-glycoprotein-1 (anti–β2-GP1) antibodies. Although anti–β2-GP1 antibodies have been documented as a biomarker for diagnosis of antiphospholipid syndrome, their direct role in the pathogenesis of thrombosis is unknown. We have demonstrated using intravital microscopy that anti–β2-GP1 autoantibodies purified from the sera of patients with antiphospholipid syndrome complicated by thrombosis greatly amplify thrombus size after laser-induced vessel wall injury in live mice. Anti–β2-GP1 autoantibodies from 3 patients with antiphospholipid syndrome were affinity-purified using human β2-GP1 bound to agarose. The effects of purified anti–β2-GP1 IgG autoantibodies, of anti–β2-GP1–depleted IgG, and of IgG from normal human sera on thrombus formation were measured in mice after arterial injury in the cremaster muscle. Before injury, purified anti–β2-GP1 IgG autoantibodies, anti–β2-GP1 antibody–depleted IgG, or IgG from normal human sera were infused. Increasing amounts of purified anti–β2-GP1 autoantibodies increased thrombus size in a dose-dependent manner, whereas neither anti–β2-GP1 antibody-depleted IgG nor IgG from normal serum affected thrombus size. These results indicate that anti–β2-GP1 IgG autoantibodies in antiphospholipid syndrome patient sera are not only a marker of antiphospholipid syndrome but are directly involved in the pathogenesis of thrombosis.

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Inhibition of APC anticoagulant activity on oxidized phospholipid by anti–β2-glycoprotein I monoclonal antibodies

Cited by 32 publications

References 49 publications

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

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

Current concepts on the pathogenesis of the antiphospholipid syndrome

β2-glycoprotein-1 autoantibodies from patients with antiphospholipid syndrome are sufficient to potentiate arterial thrombus formation in a mouse model

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