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

Arad, Ariela; Proulle, Valérie; Furie, Richard; Furie, Barbara C.; Furie, Bruce

doi:10.1182/blood-2010-08-300715

Cited by 128 publications

(106 citation statements)

References 33 publications

Supporting

Mentioning

103

Contrasting

Order By: Relevance

“…36 However, the mechanisms underlying APLA/anti-␤ 2 GPImediated thrombosis remain incompletely understood. These antibodies inhibit key components of several naturally occurring anticoagulant pathways, including the thrombomodulin-mediated activation of protein C, 37 the activity of activated protein C, 28 and the assembly of the annexin V crystal shield on exposed phospholipid surfaces, among others.…”

Section: Discussionmentioning

confidence: 99%

Endothelial cell activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors

Allen

Hamik

Jain

et al. 2011

Blood

View full text Add to dashboard Cite

IntroductionThe antiphospholipid syndrome (APS) is characterized by arterial or venous thrombosis and/or recurrent fetal loss in the presence of antiphospholipid antibodies (APLAs). [1][2][3] It is now widely accepted that the majority of pathologic antibodies in patients with this disorder are actually directed against phospholipid-binding proteins, the most common of which is ␤ 2 -glycoprotein I (␤ 2 GPI).The pathogenesis of APS-associated thrombosis is multifactorial, and a number of mechanisms have been proposed. 4 These include inhibition of protein C activation and activity, 5,6 inhibition of annexin V assembly on exposed phospholipid surfaces, 7 and prevention of appropriate interactions of antithrombin with glycosaminoglycans, 8 among others. 4,9 Studies from our laboratory and others suggest that ␤ 2 GPI-dependent activation of vascular cells by APLA/anti-␤ 2 GPI antibodies plays a central role in disease pathogenesis 10,11 and may initiate the cascade of events that leads to thrombus development. For example, ␤ 2 GPI binds to endothelial cell annexin A2, and subsequent cross-linking of annexin A2-bound ␤ 2 GPI initiates endothelial cell activation through a pathway that may involve Toll-like receptor 4 (TLR-4) [11][12][13] and leads to activation of NF-B. 14 A similar pathway may be functional in monocytes, activation of which also contributes to the development of thrombosis in patients with APLA. 15 In addition, APLA may promote platelet activation in the presence of subthreshold concentrations of agonists, 16 although whether this is a receptor-mediated process, and if so, its relationship to platelet ␤ 2 GPI binding sites, such as GP1b 17 and apoER2, 18 requires further study.In endothelial cells, activation of NF-B stimulates an inflammatory and procoagulant response 19 and plays a critical role in the ability of APLA to promote thrombosis. 20 Thus, modulation of NF-B activity may provide an opportunity to reverse the pathologic vascular response in APS. The Krüppel-like factors (KLFs), 21 particularly KLF2 and KLF4, inhibit inflammatory cytokinemediated responses in endothelial cells, 22,23 at least in part through inhibition of NF-B activity. 23 However, expression of KLF2 itself may be inhibited by inflammatory cytokines and/or vascular injury, [23][24][25] although the expression of KLF4 appears to be increased under these conditions. 26 In considering the importance of NF-B in endothelial cell activation mediated by APLA/anti-␤ 2 GPI antibodies 14 and the potentially opposing effects of KLF2 and KLF4, we hypothesized that changes in expression of these transcription factors might influence the endothelial cell response to APLA/anti-␤ 2 GPI antibodies. Here, we report that, unlike responses to inflammatory cytokines, the expression of both KLF2 and KLF4 is decreased in response to APLA/anti-␤ 2 GPI antibodies. Moreover, restoring the expression of these KLFs blocks endothelial cell activation in response to APLA/anti-␤ 2 GPI antibodies. These activities result from inhibition of NF-B transcrip...

show abstract

Section: Discussionmentioning

confidence: 99%

Endothelial cell activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors

Allen

Hamik

Jain

et al. 2011

Blood

View full text Add to dashboard Cite

show abstract

“…Similarly, mice producing aCL antibodies after immunization with Subsequently, Jankowski et al and Fischetti et al demonstrated the thrombogenic effects of monoclonal and polyclonal anti- 2 GPI in hamsters and rats respectively [88,89]. More recently, Arad and colleagues showed in an animal model that affinity purified anti- 2 GPI antibodies induce thrombosis in mice in a dose-dependent manner [90]. Hence, several investigators have underscored and confirmed the causal relationship between the presence of these autoantibodies and thrombo-embolic complications.…”

Section: A Animal Models Of Thrombosis and Endothelial Cell Activationmentioning

confidence: 97%

Antiphospholipid Syndrome - An Evolving Story of a Multisystemic Disease

Pierangeli¹,

Harper²,

Harris³

2012

Antiphospholipid Syndrome

View full text Add to dashboard Cite

“…Autoantibodies from patients with APS potentiate thrombus formation when infused into mice with injured vessels. If the fraction of anti-β2-GPI is removed, the clotting tendency disappears [23,24].…”

Section: Considering Possible Mechanismsmentioning

confidence: 99%