Monoclonal Antibody Against Tissue Factor Shortens Tissue Plasminogen Activator Lysis Time and Prevents Reocclusion in a Rabbit Model of Carotid Artery Thrombosis

Ragni, Maurizio; Cirillo, Plinio; Pascucci, I; Scognamiglio, Annalisa; D’Andrea, Davide; Eramo, Nicola; Ezekowitz, Michael D.; Pawashe, Aruna B.; Chiariello, Massimo; Golino, Paolo

doi:10.1161/01.cir.93.10.1913

Cited by 74 publications

(56 citation statements)

References 29 publications

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“…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. In conclusion, our results clearly establish the causal role of TF activity in thrombus formation after atherosclerotic plaque disruption.…”

Section: Discussionmentioning

confidence: 64%

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: 64%

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

Badimón¹,

Lettino²,

Toschi³

et al. 1999

Circulation

227

View full text Add to dashboard Cite

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“…22 Because of the dual function of TFPI as a direct inhibitor of factor Xa and as an inhibitor of the catalytic tissue factor/VIIa complex, we are unable to distinguish between the relative role of factor Xa and tissue factor/factor VIIa as a target of TFPI gene therapy. Nonetheless, studies of specific factor Xa inhibitors 23 and tissue factor-blocking antibodies 24 have demonstrated that both factor Xa and tissue factor play essential roles in arterial thrombogenesis.…”

Section: Discussionmentioning

confidence: 99%

Thromboresistance of Balloon-Injured Porcine Carotid Arteries After Local Gene Transfer of Human Tissue Factor Pathway Inhibitor

et al. 2000

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Background-Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of factor Xa and the coagulant initiator complex tissue factor/factor VIIa. Methods and Results-To study the effects of TFPI gene transfer on thrombus formation, balloon-injured porcine carotid arteries were treated locally with an adenovirus encoding human TFPI (Ad-TFPI) or control virus. Gene transfer of TFPI was confirmed by detection of human TFPI in the conditioned medium of porcine carotid arteries kept in culture after in vivo transduction. When carotid flow was measured with Doppler probe 5 days after surgery, cyclic flow variations (CFVs) developed in 7 of 8 control pigs after constriction of the injured carotid artery by 40%, and all control-treated arteries occluded after 70% constriction. In contrast, CFVs were observed in only 1 of 8 Ad-TFPI-treated pigs after 40% constriction, and only 3 of 8 occluded after constriction by 70% (Pϭ0.0027 and Pϭ0.007, respectively).

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“…4,5 Finally, previous studies from our own group have demonstrated that inhibition of formation of TF/FVII complex results in marked antithrombotic effects. [7][8][9] TFPI is a Kunitz-type serine protease inhibitor of Ϸ34 kDa. 11 TFPI is a potent inhibitor of the factor VIIa/TF complex in the presence of factor Xa and is also a direct inhibitor of factor Xa.…”

Section: Discussionmentioning

confidence: 99%

Endogenous Tissue Factor Pathway Inhibitor Modulates Thrombus Formation in an In Vivo Model of Rabbit Carotid Artery Stenosis and Endothelial Injury

et al. 2000

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Background —Tissue factor pathway inhibitor (TFPI) is the sole known inhibitor of the extrinsic coagulation pathway of physiological importance; however, its role in modulating thrombosis in vivo is still unclear. Methods and Results —Intravascular thrombosis was initiated by placing an external constrictor around endothelially injured rabbit carotid arteries (n=10). Carotid blood flow velocity was measured by a Doppler flow probe. After placement of the constrictor, cyclic flow reductions (CFRs), due to recurrent thrombosis, developed at the site of stenosis. Transstenotic TFPI plasma activity was measured in blood samples before induction of CFRs and after 30, 60, and 180 minutes of CFRs. TFPI plasma activity distal to the site of thrombosis was significantly lower than the corresponding proximal values at 30, 60, and 180 minutes of CFRs. In addition, a progressive decrease in TFPI plasma activity was observed in both the proximal and the distal samples, indicating consumption of TFPI during thrombus formation. In 10 additional rabbits, CFRs were abolished by administration of aspirin (10 mg/kg). In the animals in which aspirin abolished CFRs, endogenous TFPI was depleted by a bolus of a polyclonal antibody against rabbit TFPI, and the effects on restoration of CFRs were monitored. In 5 of 6 animals in which aspirin abolished CFRs, depletion of endogenous TFPI activity caused full restoration of CFRs. Conclusions —The data of the present study support the involvement of endogenous TFPI in the process of thrombus formation in vivo and its active role in modulating arterial thrombosis .

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Monoclonal Antibody Against Tissue Factor Shortens Tissue Plasminogen Activator Lysis Time and Prevents Reocclusion in a Rabbit Model of Carotid Artery Thrombosis

Abstract: TF exposure and activation of the extrinsic coagulation pathway play an important role in prolonging lysis time and mediating reocclusion after thrombolysis in this model. AP-1, a monoclonal antibody against TF, might be suitable as adjunctive therapy to TPA.

Cited by 74 publications

References 29 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

Thromboresistance of Balloon-Injured Porcine Carotid Arteries After Local Gene Transfer of Human Tissue Factor Pathway Inhibitor

Endogenous Tissue Factor Pathway Inhibitor Modulates Thrombus Formation in an In Vivo Model of Rabbit Carotid Artery Stenosis and Endothelial Injury

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