Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid syndrome

Cesarman‐Maus, Gabriela; Ríos-Luna, Nina Paola; Deora, Arunkumar B.; Huang, Bihui; Villa, Rosario; Cravioto, María del Carmen; Alarcón‐Segovia, Donato; Sánchez‐Guerrero, Jorge; Hajjar, Katherine A.

doi:10.1182/blood-2005-07-2636

Cited by 159 publications

(135 citation statements)

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“…Annexin II is directly involved in the pathogenesis of APS. Binding of ␤ 2 GPI to human umbilical vein endothelial cells is mediated by annexin II (23). By functioning as a receptor for ␤ 2 GPI, annexin II is a target not only for anti-annexin II antibodies but also for anti-␤ 2 GPI antibodies, which are direct inducers of TF overexpression and thus are significantly associated with thrombosis in the setting of APS (18).…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis in monocytes of antiphospholipid syndrome patients: Deregulation of proteins related to the development of thrombosis

López‐Pedrera¹,

Cuadrado²,

Herández³

et al. 2008

Arthritis & Rheumatism

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Objective. Antiphospholipid antibodies (aPL) are closely related to the development of thrombosis, but the exact mechanism(s) leading to thrombotic events remains unknown. In this study, using proteomic techniques, we evaluated changes in protein expression of monocytes from patients with antiphospholipid syndrome (APS) related to the pathophysiology of the syndrome.Methods. Fifty-one APS patients were included. They were divided into 2 groups: patients with previous thrombosis, and patients with recurrent spontaneous abortion. As controls, we studied patients with thrombosis but without aPL, and age-and sex-matched healthy subjects.Results. The proteins that were more significantly altered among monocytes from APS patients with thrombosis (annexin I, annexin II, protein disulfide isomerase, Nedd8, RhoA proteins, and Hsp60) were functionally related to the induction of a procoagulant state as well as to autoimmune-related responses. Proteins reported to be connected to recurrent spontaneous abortion (e.g., fibrinogen and hemoglobin) were also determined to be significantly deregulated in APS patients without thrombosis. In vitro treatment with IgG fractions purified from the plasma of APS patients with thrombosis changed the pattern of protein expression of normal monocytes in the same way that was observed in vivo for monocytes from APS patients with thrombosis.

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Section: Discussionmentioning

confidence: 99%

Proteomic analysis in monocytes of antiphospholipid syndrome patients: Deregulation of proteins related to the development of thrombosis

López‐Pedrera¹,

Cuadrado²,

Herández³

et al. 2008

Arthritis & Rheumatism

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“…Anti-annexin A2 antibodies as well as bivalent anti-annexin A2 (Fab') 2 fragments were able to activate EC whereas monomeric Fab fragments prevented the activation induced by antiannexin A2 or anti-β2GP1 antibodies [68]. Furthermore, anti-annexin A2 antibodies isolated from plasma of patients are equally efficient as anti-β2GP1 antibodies to induce TF expression by EC [69]. Antiannexin A2 antibodies increased also thrombosis extent in a mouse model of thrombosis [30].…”

Section: Annexin A2 As An Accessory Protein For Aplamentioning

confidence: 99%

Receptors involved in cell activation by antiphospholipid antibodies

Brandt

Kruithof

Moerloose

2013

Thrombosis Research

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The antiphospholipid syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). The plasma protein β2-glycoprotein 1 (β2GP1) has been identified as a major target of aPLA associated with APS. Cell activation by aPLA appears to be a major pathogenic cause in the pathogenesis of APS. Receptors, co-receptors and accessory molecules are known to assist the pathogenic effects of aPLA. Members of the TLR family and the platelet receptor apolipoprotein E receptor 2' (apoER2'), a receptor belonging to the low-density lipoprotein receptor (LDL-R) family, as well as GPIbα, were identified as putative candidates for aPLA recognition. CD14, a co-receptor for TLR2 and TLR4, and annexin A2, a ubiquitous Ca2+ -binding protein that is essential for actin-dependent vesicle transport, could serve as important accessory molecules in mediating the pathogenic effects of aPLA. Finally, complement activation has been reported in association with the pathogenicity of APS. The relative contribution of these different mechanisms in the pathogenesis of APS is controversial. Here, we review the various in vivo and in vitro models that have been used to investigate the pathogenic mechanisms of aPLA in APS

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“…Fifth, A2 is strikingly overexpressed in blast cells and is associated with hyperfibrinolytic hemorrhage in patients with acute promyelocytic leukemia (13). Sixth, autoantibodies directed against A2 are prevalent and associated with clinical thrombosis in patients with the anti-phospholipid syndrome (14). Finally, infusion of recombinant A2 can reverse microvascular fibrin accumulation and restore perivascular fibrinolysis in hyperhomocysteinemic mice, which are susceptible to arterial thrombosis (15).…”

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confidence: 99%

Feedback Regulation of Endothelial Cell Surface Plasmin Generation by PKC-dependent Phosphorylation of Annexin A2

He¹,

Sui

Xiong

et al. 2011

Journal of Biological Chemistry

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In response to blood vessel injury, hemostasis is initiated by platelet activation, advanced by thrombin generation, and tempered by fibrinolysis. The primary fibrinolytic protease, plasmin, can be activated either on a fibrin-containing thrombus or on cells. Annexin A2 (A2) heterotetramer (A2⅐p11) 2 is a key profibrinolytic complex that assembles plasminogen and tissue plasminogen activator and promotes plasmin generation. We now report that, in endothelial cells, plasmin specifically induces activation of conventional PKC, which phosphorylates serine 11 and serine 25 of A2, triggering dissociation of the (A2⅐p11) 2 tetramer. The resulting free p11 undergoes ubiquitinmediated proteasomal degradation, thus preventing further translocation of A2 to the cell surface. In vivo, pretreatment of A2 ؉/؉ but not A2 ؊/؊ mice with a conventional PKC inhibitor significantly reduced thrombosis in a carotid artery injury model. These results indicate that augmentation of fibrinolytic vascular surveillance by blockade of serine phosphorylation is A2-dependent. We also demonstrate that plasmin-induced phosphorylation of A2 requires both cleavage of A2 and activation of Toll-like receptor 4 on the cell surface. We propose that plasmin can limit its own generation by triggering a finely tuned "feedback" mechanism whereby A2 becomes serine-phosphorylated, dissociates from p11, and fails to translocate to the cell surface.The human hemostatic system represents a coordinated balance between procoagulant and anticoagulant/profibrinolytic activities. Together, these systems prevent blood loss while maintaining blood flow. Plasmin, the major protease of the fibrinolytic system, acts to digest insoluble fibrin into soluble fibrin degradation products. Plasmin generation is modulated by plasminogen activators and plasminogen activator inhibitors and is further regulated by binding of plasminogen and its activators to cell surface receptors (1). Membrane-associated annexin A2 (A2) 3 is part of a heterotetrameric complex in which the N termini of two copies of A2 bind to two copies of the S100 family protein, S100A10 (p11) (2). A2, a member of the annexin superfamily, consists of a highly conserved C-terminal phospholipid-binding core domain and an N-terminal ligandinteracting domain (3). Complex formation with p11 increases the affinity of A2 for calcium and phospholipids, thereby directing it to cellular membranes (4). Components of the (A2⅐p11) 2 tetramer, moreover, specifically bind tissue plasminogen activator (t-PA) and plasminogen and strongly enhance plasmin generation (5-8, 52).Several lines of evidence identify the (A2⅐p11) 2 complex as a significant regulator of fibrin balance in vivo. First, A2 Ϫ/Ϫ microvascular endothelial cells lack t-PA cofactor activity, and the fibrin content of highly perfused A2 Ϫ/Ϫ tissues is ϳ2-fold greater than that observed in wild type controls (9). In addition, arterial injury in A2 Ϫ/Ϫ mice is followed by a 2-fold increase in thrombotic vascular occlusion with an equivalent reduction in blood flo...

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Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid syndrome

Cited by 159 publications

References 53 publications

Proteomic analysis in monocytes of antiphospholipid syndrome patients: Deregulation of proteins related to the development of thrombosis

Proteomic analysis in monocytes of antiphospholipid syndrome patients: Deregulation of proteins related to the development of thrombosis

Receptors involved in cell activation by antiphospholipid antibodies

Feedback Regulation of Endothelial Cell Surface Plasmin Generation by PKC-dependent Phosphorylation of Annexin A2

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