Effect of Glycoprotein IIb/IIIa Antagonist Abciximab on Monocyte-Platelet Aggregates and Tissue Factor Expression

Steiner, Sabine; Seidinger, Daniela; Huber, Kurt; Kaun, Christoph; Minar, Erich; Kopp, Christoph W.

doi:10.1161/01.atv.0000087035.46547.89

Cited by 44 publications

(37 citation statements)

References 23 publications

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“…This finding is consistent with those of Steiner et al 29 who also did not observe TFPI on the surface of platelets in whole blood stimulated with TRAP. Although platelets have previously been reported to secrete soluble TFPI following activation with either thrombin or calcium ionophore, 11 we did not observe secretion of TFPI following TRAP stimulation.…”

Section: Discussionsupporting

confidence: 94%

Active tissue factor pathway inhibitor is expressed on the surface of coated platelets

Maroney

Haberichter

Friese

et al. 2006

Blood

118

168

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The incorporation of blood-borne forms of tissue factor (TF) into a growing blood clot is necessary for normal fibrin generation and stabilization of the blood clot. Tissue factor pathway inhibitor (TFPI) is the primary physiologic inhibitor of tissue factor and is present within platelets. Expression of TFPI on the platelet surface may be the optimal location for it to abrogate blood-borne TF activity that incorporates within the blood clot, balancing the need for adequate hemostasis while preventing development of occlusive thrombosis. TFPI is produced by megakaryocytes but is not expressed on the platelet surface. Activation of platelets with thrombin receptor activation peptide does not cause release or surface expression of TFPI, demonstrating that TFPI is not stored within platelet ␣ granules. TFPI is expressed on the platelet surface following dual-agonist activation with convulxin plus thrombin to produce coated platelets. In association with its expression on the surface of coated platelets TFPI is also released in microvesicles or as a soluble protein. IntroductionVascular injury results in the exposure of collagen and tissue factor, present within the vessel wall, to flowing blood. Platelets rapidly adhere to the collagen within the subendothelial tissue of the injured vessel wall where they are activated; subsequently, platelet aggregation provides an initial barrier against blood loss. Tissue factor within the subendothelial tissue binds to factor VIIa, leading to the production of thrombin, which further activates platelets and generates fibrin. Platelets exposed to dual-agonist stimulation with collagen plus thrombin form a distinct subpopulation of platelets, called coated platelets, that express high levels of procoagulant proteins, including factor V, fibrinogen, fibronectin, and VWF, providing a procoagulant surface that supports further fibrin generation. [1][2][3] In this manner, collagen and tissue factor work synergistically at the site of vascular injury to produce a plateletfibrin plug that closes the wound and prevents severe hemorrhage.In addition to its presence within the subendothelial tissues of the vessel wall, tissue factor is also present on circulating microvesicles released from activated leukocytes or endothelial cells. Incorporation of these tissue factor-bearing microvesicles into the blood clot is thought to be necessary for effective stabilization within the vasculature. [4][5][6] The recruitment of tissue factor-bearing microvesicles into growing thrombi is mediated by interactions between P-selectin glycoprotein ligand-1 present on the microvesicles and P-selectin expressed on the surface of activated platelets within the blood clot. 7 It has been demonstrated that the tissue factor-bearing microvesicles can fuse with activated platelets. 8 In addition, splicing of tissue factor pre-mRNA within activated platelets is another potential mechanism for expression of tissue factor on the platelet surface. 9 However, overexpression of tissue factor or inadequate regulation o...

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Section: Discussionsupporting

confidence: 94%

Active tissue factor pathway inhibitor is expressed on the surface of coated platelets

Maroney

Haberichter

Friese

et al. 2006

Blood

118

168

View full text Add to dashboard Cite

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“…13 In brief, 100 L of citrateanticoagulated whole blood was stained with saturating concentrations of the following fluorochrome-conjugated monoclonal antibodies (mAbs): phycoerythrin (PE)-labeled mAb for human TF (Becton Dickinson), PE-Cy5-labeled mAb for monocyte CD14 (endotoxin receptor), PE-labeled mAb for the platelet activation marker CD62P (P-selectin), PE-labeled mAb for CD40L (CD40 ligand; all antibodies from Instrumentation Laboratories), APClabeled mAb for the constitutive platelet marker CD42b (glycoprotein Ib␣ of von Willebrand factor receptor complex; Becton Dickinson), and corresponding isotype controls (Becton Dickinson and Instrumentation Laboratories). After 10 minutes of preincubation with antibodies in the dark at room temperature, the samples were fixed and erythrolyzed with Optilyse B (Instrumentation Laboratories).…”

Section: Cell Count and Flow Cytometrymentioning

confidence: 99%

Simvastatin Blunts Endotoxin-Induced Tissue Factor In Vivo

et al. 2005

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Background-Beyond lipid lowering, various antiinflammatory properties have been ascribed to statins. Moreover, in vitro studies have suggested the presence of anticoagulant effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, as lipopolysaccharide (LPS)-induced monocyte tissue factor (TF) was suppressed. In this study, we examined the role of statins in experimental endotoxemia on inflammatory and procoagulant responses in vivo. Methods and Results-In this double-blind, placebo-controlled, parallel-group study, 20 healthy, male subjects were randomized to receive either simvastatin (80 mg/d) or placebo for 4 days before intravenous administration of LPS (20 IU/kg IV). Plasma high-sensitive C-reactive protein (hsCRP), monocyte chemoattractant protein (MCP-1), sCD40L, sCD40, and prothrombin fragment F1ϩ2 (F1.2) were determined by ELISAs at baseline and at 4 and 8 hours after LPS administration. Monocyte TF expression and monocyte-platelet aggregates were measured by whole-blood flow cytometry over the same time course. The increases in hsCRP and MCP-1, both known inducers of TF, were significantly suppressed by statin treatment after LPS challenge. Statin premedication blunted the increase of monocyte TF expression in response to LPS. In parallel, endotoxin-induced formation of F1.2 was significantly reduced by simvastatin after 4 and 8 hours. LPS infusion affected neither the formation and activation of monocyte-platelet aggregates nor plasma levels of sCD40 and sCD40L. Conclusions-Simvastatin

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“…Formation of platelet-monocyte aggregates is an established link between inflammation and thrombosis in acute coronary syndromes and related disorders (10). Interruption of signaling pathways that are triggered when platelets adhere to and activate monocytes may be a new target for molecular intervention (14,15). Signaling in platelet-monocyte aggregates and in related platelet-monocyte interactions can be characterized in informative in vitro model systems (5,(15)(16)(17)(18)(19), which also serve as models of human gene expression (19).…”

Section: Introductionmentioning

confidence: 99%

Expression of COX-2 in platelet-monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling

Dixon

2006

Journal of Clinical Investigation

101

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Tight regulation of COX-2 expression is a key feature controlling eicosanoid production in atherosclerosis and other inflammatory syndromes. Adhesive interactions between platelets and monocytes occur in these conditions and deliver specific signals that trigger inflammatory gene expression. Using a cellular model of monocyte signaling induced by activated human platelets, we identified the central posttranscriptional mechanisms that regulate timing and magnitude of COX-2 expression. Tethering of monocytes to platelets and to purified P-selectin, a key adhesion molecule displayed by activated platelets, induces NF-κB activation and COX-2 promoter activity. Nevertheless, COX-2 mRNA is rapidly degraded, leading to aborted protein synthesis. Timedependent signaling of monocytes induces a second phase of transcript accumulation accompanied by COX-2 enzyme synthesis and eicosanoid production. Here, generation of IL-1β, a proinflammatory cytokine, promoted stabilization of COX-2 mRNA by silencing of the AU-rich mRNA decay element (ARE) in the 3′-untranslated region (3'UTR) of the mRNA. Consistent with observed mRNA stabilization, activated platelets or IL-1β treatment induced cytoplasmic accumulation and enhanced ARE binding of the mRNA stability factor HuR in monocytes. These findings demonstrate that activated platelets induce COX-2 synthesis in monocytes by combinatorial signaling to transcriptional and posttranscriptional checkpoints. These checkpoints may be altered in disease and therefore useful as targets for antiinflammatory intervention.

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Effect of Glycoprotein IIb/IIIa Antagonist Abciximab on Monocyte-Platelet Aggregates and Tissue Factor Expression

Cited by 44 publications

References 23 publications

Active tissue factor pathway inhibitor is expressed on the surface of coated platelets

Active tissue factor pathway inhibitor is expressed on the surface of coated platelets

Simvastatin Blunts Endotoxin-Induced Tissue Factor In Vivo

Expression of COX-2 in platelet-monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling

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