Systemic Endothelial Cell Markers in Primary Antiphospholipid Syndrome

Williams, Frances; Parmar, Kiran; Hughes, G. R. V.; Hunt, Beverley J.

doi:10.1055/s-0037-1614108

Cited by 87 publications

(70 citation statements)

References 35 publications

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“…Furthermore, they are consistent with studies of human subjects showing evidence of activation of the endothelium in APS: endothelial cell microparticles, soluble VCAM1, soluble ICAM-1, von Willebrand factor, soluble thrombomodulin, and soluble P-selectin. [53][54][55][56] Our results confirm that endothelium activation is enhanced in the presence of aPL antibodies but demonstrate that enhancement is platelet thrombusdependent. By visualization of the targets of the anti-b2GP1 autoantibody/b2GP1 complex and the functional implications of anti-b2GP1 autoantibody/b2GP1 complex binding to that target, we establish important features of the pathogenesis of aPL autoantibodies.…”

supporting

confidence: 67%

Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS

Proulle

Furie

Merrill-Skoloff

et al. 2014

Blood

106

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• The anti-b2GP1 autoantibody/ b2GP1 complex binds to the platelet thrombus, amplifying platelet activation.• Platelets are required for enhanced activation of the endothelium and fibrin generation by the anti-b2GP1 autoantibody/b2GP1 complex.Antiphospholipid syndrome (APS) is defined by thrombosis, fetal loss, and the presence of antiphospholipid antibodies, including anti-b2-glycoprotein-1 autoantibodies (antib2GP1) that have a direct role in the pathogenesis of thrombosis in vivo. The cellular targets of the anti-b2GP1 autoantibody/b2GP1 complex in vivo were studied using a laserinduced thrombosis model of APS in a live mouse and human anti-b2GP1 autoantibodies affinity-purified from APS patients. Cell binding of fluorescently labeled b2GP1 and antib2GP1 autoantibodies revealed their colocalization on the platelet thrombus but not the endothelium. Anti-b2GP1 autoantibodies enhanced platelet activation, monitored by calcium mobilization, and endothelial activation, monitored by intercellular adhesion molecule-1 expression. When eptifibatide was infused to block platelet thrombus formation, enhanced fibrin generation and endothelial cell activation were eliminated. Thus, the anti-b2GP1 autoantibody/b2GP1 complex binds to the thrombus, enhancing platelet activation, and platelet secretion leads to enhanced endothelium activation and fibrin generation. These results lead to a paradigm shift away from the concept that binding of the anti-b2GP1 autoantibody/b2GP1 complex activates both endothelial cells and platelets toward one in which activation of platelets in response to anti-b2GP1 autoantibody/b2GP1 complex binding leads to subsequent enhanced endothelium activation and fibrin generation. (Blood. 2014;124(4):611-622) IntroductionAntiphospholipid syndrome (APS) is characterized by venous or arterial thrombosis and/or pregnancy morbidity and is associated with circulating antiphospholipid (aPL) autoantibodies.1-3 These antibodies, including anti-b2-glycoprotein-1 (anti-b2GP1) autoantibodies, recognize plasma proteins that bind to anionic phospholipids, among which b2GP1 is the major target. 4 Antibodies directed against b2GPI 5,6 are associated with thrombotic events in APS. Antib2GP1 autoantibodies from patients with APS and thrombosis enhance arterial thrombus formation after injury in a mouse model of APS, 7 with dramatic increases in platelet thrombus size and fibrin generation.The mechanisms leading to thrombosis in APS are unresolved. In vitro and in vivo studies using animal models demonstrated that aPL antibodies interact with endothelial cells and monocytes to increase tissue factor expression and complement activation and proinflammatory cytokines. 8,9 In vitro, platelet activation occurs after the binding of complexes of anti-b2GP1 antibodies and dimerized b2GP1 to GPIba and ApoER2. [10][11][12] Furthermore, APS patients exhibit markers of platelet activation. 13 The conventional understanding is that the antib2GP1/b2GP1 complex binds to receptors on both the endothelial cell and the platelet, lea...

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supporting

confidence: 67%

Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS

Proulle

Furie

Merrill-Skoloff

et al. 2014

Blood

106

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“…Utilizing ICAM-1, E-selectin, and P-selectin knock-out mice and specific anti-VCAM-1 monoclonal antibodies, we demonstrated that EC-activating properties of aPL are mediated by these CAMs [13,14]. Accordingly, some investigators have shown increased levels of soluble adhesion molecules such as VCAM-1 and P-selectin in patients with aPL and thrombosis [15,16].…”

Section: Effects Of Apl On Ecsmentioning

confidence: 85%

Mechanisms of aPL-mediated thrombosis: Effects of aPL on endothelium and platelets

Vega-Ostertag¹,

Pierangeli²

2007

Curr Rheumatol Rep

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Antiphospholipid antibodies (aPL) are associated with thrombosis and pregnancy loss in patients with systemic lupus erythematosus and antiphospholipid syndrome. Strong evidence demonstrates that aPL are pathogenic in vivo from studies that utilized animal models of thrombosis, endothelial cell activation, and pregnancy loss. However, the mechanisms by which aPL mediate disease are only partially understood, and our knowledge is limited by the polyspecificity of the antibodies, the multiple potential end-organ targets, and the variability of the clinical context in which the disease may present. This review discusses and summarizes the most current data available on molecular interactions and pathogenic mechanisms in antiphospholipid syndrome.

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“…Different indirect parameters of EC perturbation ex-vivo have been investigated with no definite conclusions. While some studies reported increased plasma levels of single soluble ADM or endothelial derived microparticles in APS patients, others did not confirm these findings [36][37][38][39]. Additional confounding variables-such as a concomitant associated immune-mediated systemic inflammatory disorder-did weaken the comparison.…”

Section: Do Apl Induce An Endothelial Perturbation In Vivo Too?mentioning

confidence: 91%

Inflammatory response and the endothelium

Meroni

Borghi

Raschi

et al. 2004

Thrombosis Research

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Antiphospholipid-mediated endothelium perturbation plays a role in antiphospholipid syndrome (APS)-associated vasculopathy. Antiphospholipid antibodies activate endothelium both in vitro and in vivo experimental models by inducing a pro-inflammatory/-coagulant phenotype; the antibodies recognize h2 glycoprotein I (h2GPI) on human endothelial cells (EC) from different parts of the vasculature.In spite of such large in vitro evidence, few studies have addressed the issue whether or not a comparable endothelial perturbation might be detectable in vivo.We investigated several indirect ex vivo parameters of endothelial dysfunction: plasma levels of soluble adhesion molecules (sADM), soluble thrombomodulin (sTM), von Willebrand factor (vWF) and tissue plasminogen activator (t-PA) by solid-phase assays. The study included: patients with primary antiphospholipid syndrome (n=32), with the syndrome secondary to non-active systemic lupus erythematosus (SLE, n=10), six patients with persistent antiphospholipid positivity at medium/high titre without any clinical manifestation of the syndrome. Fifty-two age and sex matched healthy subjects have been enrolled as controls. In addition, circulating endothelial cells identified by flow cytometry and the brachial artery flow-mediated vasodilation (FMV) were evaluated in 26 patients (20 primary and 6 lupus syndromes) and 30 healthy controls.

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Systemic Endothelial Cell Markers in Primary Antiphospholipid Syndrome

Cited by 87 publications

References 35 publications

Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS

Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS

Mechanisms of aPL-mediated thrombosis: Effects of aPL on endothelium and platelets

Inflammatory response and the endothelium

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