A monoclonal antibody against rabbit tissue factor inhibits thrombus formation in stenotic injured rabbit carotid arteries.

Pawashe, Aruna B.; Golino, Paolo; Ambrosio, Giuseppe; Migliaccio, Fernando; Ragni, Maurizio; Pascucci, I; Chiariello, Massimo; Bach, Ronald R.; Garen, Alan; Konigsberg, William

doi:10.1161/01.res.74.1.56

Cited by 127 publications

(115 citation statements)

References 30 publications

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“…36 TF activity has been shown in rabbit subendothelium, 24 and an antibody against rabbit TF, AP-1, has shown to inhibit thrombus formation in rabbit carotid. 37 Additionally, inhibition of TF activity may serve as adjunctive therapy to tissue plasminogen activator-induced thrombolysis by shortening the time needed for the lysis of thrombus and preventing reocclusion in the carotid rabbit model. 38 Our study demonstrates that TF pathway inhibition by local administration of TFPI or antibodies to TF is highly effective in reducing arterial thrombosis in human atherosclerotic lesions.…”

Section: Discussionmentioning

confidence: 99%

Local Inhibition of Tissue Factor Reduces the Thrombogenicity of Disrupted Human Atherosclerotic Plaques

Badimón¹,

Lettino²,

Toschi³

et al. 1999

Circulation

227

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Background-Plaque disruption and subsequent thrombus formation lead to acute coronary syndromes and progression of atherosclerotic disease. Tissue factor (TF) appears to mediate plaque thrombogenicity. Tissue factor pathway inhibitor (TFPI) is the major physiological inhibitor of TF. This study analyzes the role of TF on thrombogenicity of disrupted human atherosclerotic plaques and the therapeutic possibilities of its specific inhibition. Methods and Results-Human atherosclerotic and normal arterial segments were exposed to heparinized blood at flow conditions modeling medium-grade coronary stenosis in the Badimon perfusion chamber. The antithrombotic effects of the specific inhibition of plaque TF was assessed by reduction in the deposition of radiolabeled platelets and fibrin(ogen) and immunohistochemical analysis of perfused arteries. TF activity was inhibited by both recombinant TFPI and a polyclonal antibody against human TF. Human lipid-rich plaques were more thrombogenic than less advanced atherosclerotic plaques. Specific inhibition of TF activity reduced plaque thrombogenicity, inhibiting both platelet and fibrin(ogen) deposition (580 versus 194 plateletsϫ10 6 /cm 2 ; PϽ0.01, and 652 versus 172ϫ10 12 molecules of Fg/cm 2 ; PϽ0.05, respectively) and thrombosis (immunohistochemistry). Conclusions-This study documents the key role of TF activity in acute arterial thrombosis after atherosclerotic plaque disruption and provides evidence of the benefit of blocking plaque TF activity. Therefore the inhibition of the TF pathway opens a new therapeutic strategy in the prevention of acute coronary thrombosis after plaque disruption.

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Section: Discussionmentioning

confidence: 99%

Local Inhibition of Tissue Factor Reduces the Thrombogenicity of Disrupted Human Atherosclerotic Plaques

Badimón¹,

Lettino²,

Toschi³

et al. 1999

Circulation

227

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“…To determine whether FVIIa requires binding to TF to induce proliferation, SMCs were pretreated, 15 minutes before FVIIa was added to the medium, with AP-1 (100 g/mL), a monoclonal antibody against rabbit TF. 13 This concentration exceeds 10 times that necessary to double prothrombin time in rabbit plasma. 13 In addition, to determine whether FVIIa enzymatic activity is also required to promote SMC proliferation, cells were incubated with 100 nmol/L of FVIIai.…”

Section: Fviia Induces Smc Proliferationmentioning

confidence: 95%

“…13 This concentration exceeds 10 times that necessary to double prothrombin time in rabbit plasma. 13 In addition, to determine whether FVIIa enzymatic activity is also required to promote SMC proliferation, cells were incubated with 100 nmol/L of FVIIai. Results are expressed as percent increase in […”

Section: Fviia Induces Smc Proliferationmentioning

confidence: 95%

Tissue Factor Binding of Activated Factor VII Triggers Smooth Muscle Cell Proliferation via Extracellular Signal–Regulated Kinase Activation

et al. 2004

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Background-Tissue factor (TF) is the main initiator of coagulation in vivo. Recently, however, a role for TF as a cell receptor involved in signal transduction has been suggested. The aim of the present study was to assess whether activated factor VII (FVIIa) binding to TF could induce smooth muscle cell (SMC) proliferation and to clarify the possible intracellular mechanism(s) responsible for this proliferation. Methods and Results-Cell proliferation was induced by FVIIa in a dose-dependent manner, as assessed by [3 H]thymidine incorporation and direct cell counting, whereas no response was observed with active site-inhibited FVIIa (FVIIai), which is identical to FVIIa but is devoid of enzymatic activity. Similarly, no proliferation was observed when binding of FVIIa to TF was prevented by the monoclonal anti-TF antibody AP-1. Activation of the p44/42 mitogen-activated protein (MAP) kinase (extracellular signal-regulated kinases 1 and 2 [ERK 1/2]) pathway on binding of FVIIa to TF was demonstrated by transient ERK phosphorylation in Western blots and by suppression of proliferation with the specific MEK (MAP kinase/ERK kinase) inhibitor UO126. ERK phosphorylation was not observed with FVIIai or when cells were pretreated with AP-1. Conclusions-These data indicate a specific effect by which binding of FVIIa to TF on the surface of SMCs induces proliferation via a coagulation-independent mechanism and possibly indicate a new link between coagulation, inflammation, and atherosclerosis. Key Words: coagulants Ⅲ signal transduction Ⅲ cell division T issue factor (TF) is a cell surface-anchored glycoprotein that binds both the zymogen factor VII (FVII) and the active serine protease factor VIIa (FVIIa). 1 TF/FVIIa complex activates coagulation by cleaving its natural substrates, factors IX and X, ultimately leading to thrombin generation, fibrin deposition, and platelet activation. 1,2 On these grounds, TF has been considered to function as a major initiator of blood coagulation in vivo. Recently, however, some evidence has suggested that TF may mediate important coagulationindependent biological phenomena, including embryonic and oncogenic angiogenesis, 3,4 and inflammation. 5 In addition, recent data indicate that TF/FVIIa interaction may activate different intracellular signals, culminating in a variety of cell responses, thus suggesting a role for TF as a "true" cell membrane receptor. For example, TF/FVIIa interaction has been shown to be a strong chemotactic stimulus for smooth muscle cells (SMCs), mediating their migration in vitro. 6 FVIIa has been also shown to induce phosphorylation of the extracellular signalregulated kinases 1 and 2 (ERK 1/2) 7 and to upregulate poly(A) polymerase, 8 urokinase-type plasminogen activator receptor, 9 and a host of genes identified with the use of cDNA microarrays. 10 However, despite evidence suggesting close links between TF, activation of coagulation, and intracellular signaling, no direct effects of TF/FVIIa on SMC proliferation have yet been demonstrated. Thus, in the pr...

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“…17 Immunohistology for TF antigen was performed, as recently described in detail, 12 with the murine monoclonal rabbit TF antibody AP-1 (0.375 g/mL, kindly provided by Dr Michael D. Ezekowitz, Yale University, New Haven, Conn), the production, purification, and characterization of which are reported elsewhere. 18 Negative controls were performed with mouse anti-rabbit immunoglobulin (clone MR 12/53, 0.425 g/mL, DAKO). Sections were counterstained with hematoxylin and mounted in gelatin.…”

Section: Immunostainingmentioning

confidence: 99%

Hirudin Reduces Tissue Factor Expression and Attenuates Graft Arteriosclerosis in Rat Cardiac Allografts

et al. 2000

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Background-Intravascular clotting has been implicated in the pathogenesis of cardiac allograft vasculopathy (CAV). We previously identified the expression of tissue factor (TF), the primary cellular initiator of blood coagulation, within the coronary intima, which was associated with neointimal thickening. In the present study, the effect of recombinant hirudin on CAV was assessed in Lewis to Fisher rat heterotopic cardiac allografts. Methods and Results-Transplant recipients were randomized to a control group (nϭ10) and a hirudin-treated group (nϭ12; 2 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 SC). Histological evaluations of rejection, CAV, and TF staining were performed 120 days after transplantation. No significant differences were observed between the 2 groups with respect to the degree of rejection. Hirudin significantly (PϽ0.05) suppressed the development of CAV in the graft microvessels, but it was less effective in large coronary arteries. Graft intimal cells, isolated by laser-assisted cell picking, showed a marked upregulation of TF gene transcription, which was prevented by hirudin (PϽ0.01). As demonstrated by immunohistochemistry and quantitative analyses of TF mRNA levels by real-time polymerase chain reaction, hirudin treatment resulted in a significant reduction of TF protein and mRNA expression (PϽ0.001). Conclusions-Treatment with hirudin in this rat cardiac transplant model inhibited TF expression and decreased neointimal hyperplasia. These results suggest that TF inhibition by hirudin, in addition to its direct effect on thrombin, may attenuate the hypercoagulable state and prevent the development of CAV at least in restricted sites of the graft coronary vasculature.

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A monoclonal antibody against rabbit tissue factor inhibits thrombus formation in stenotic injured rabbit carotid arteries.

Cited by 127 publications

References 30 publications

Local Inhibition of Tissue Factor Reduces the Thrombogenicity of Disrupted Human Atherosclerotic Plaques

Local Inhibition of Tissue Factor Reduces the Thrombogenicity of Disrupted Human Atherosclerotic Plaques

Tissue Factor Binding of Activated Factor VII Triggers Smooth Muscle Cell Proliferation via Extracellular Signal–Regulated Kinase Activation

Hirudin Reduces Tissue Factor Expression and Attenuates Graft Arteriosclerosis in Rat Cardiac Allografts

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