Antithrombotic effect of a monoclonal antibody against tissue factor in a rabbit model of platelet-mediated arterial thrombosis.

Jang, Ik–Kyung; Gold, Herman K.; Leinbach, Robert C.; Fallon, John T.; Collen, D.; Wilcox, Josiah N.

doi:10.1161/01.atv.12.8.948

Cited by 44 publications

(22 citation statements)

References 20 publications

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“…Studies using inhibitors of TF activity, including antibodies to TF, 37,38 active site-inactivated factor VIIa, 39 and TF pathway inhibitor (TFPI) 40,41 have provided evidence that TF plays a critical role in mediating arterial thrombosis. However, the relative contributions of arterial wall and circulating TF to thrombosis remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

Vascular smooth muscle–derived tissue factor is critical for arterial thrombosis after ferric chloride–induced injury

Wang

Miller

Swarthout

et al. 2009

Blood

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Tissue factor (TF) initiates coagulation, regulates hemostasis, and plays a critical role in mediating arterial thrombosis. TF is up-regulated in vascular smooth muscle cells (VSMCs) in atherosclerosis and arterial injury. To examine the biologic role of VSMC-derived TF, we crossed TF flox/flox mice with SM22␣Cre ؉/؊ mice. TF mRNA and activity were decreased in the aortic media of TF-deficient mice by 96% and 94.8%, respectively. There were no differences in TF activity measured in plasma or concentrated microparticles. TF-deficient mice were generated with the expected frequency, showed no evidence of bleeding or increased mortality, and had similar activated partial thromboplastin and tail vein bleeding times. Thrombus-mediated flow reduction in response to ferric chloride injury of the carotid arteries was significantly attenuated in VSMC-specific TF-deficient. IntroductionTissue factor (TF) is a glycoprotein that initiates coagulation, regulates hemostasis, and plays a critical role in mediating arterial thrombosis. 1,2 TF is expressed at low levels in normal intima and media, is rapidly induced after arterial injury in medial vascular smooth muscle cells (VSMCs), and subsequently accumulates in the VSMCs of the resulting neointima. 3 TF is also abundant in atherosclerotic plaques, particularly in macrophages, intimal VSMCs, and the lipid-rich necrotic core. 4 It has generally been thought that arterial thrombosis occurs when TF induced by injury to the arterial surface or exposed by plaque rupture comes into contact with blood coagulant factors.Recent studies have demonstrated that TF is present in the circulation, 5-8 mostly in microparticles (MPs). Although the cellular sources of circulating TF have not been precisely defined, current data suggest that platelets, 9-12 monocyte/macrophages, 13,14 and endothelial cells [15][16][17] are important contributors. Although some studies have suggested that circulating TF contributes to thrombus generation, 18,19 others have suggested that the levels of TF in human blood are too low to be clinically important. 20,21 Various studies have found increased levels of circulating TF in patients with acute coronary syndromes, 5 diffuse intravascular coagulopathy, 8 endotoxemia, 13 and cancer. 7 However, a recent study nested in the European Prospective Investigation into Cancer and Nutrition found that high levels of circulating TF were not independently predictive of cardiovascular events in apparently healthy individuals. 22 Studies using animal models of thrombosis have attempted to address the role of circulating TF. Total TF deletion in mice results in intrauterine lethality. [23][24][25] However, TF null embryos can be rescued with a minigene containing the human TF promoter and cDNA. These mice (referred to as low TF mice) express 1% of the TF activity of wild-type mice 26 and have decreased thrombosis in response to carotid arterial injury. 27 Transplanting bone marrow from low TF mice into wild-type mice decreased the size of thrombus induced by laser injury t...

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Section: Discussionmentioning

confidence: 99%

Vascular smooth muscle–derived tissue factor is critical for arterial thrombosis after ferric chloride–induced injury

Wang

Miller

Swarthout

et al. 2009

Blood

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“…49,50,52 Other studies have examined the effects of anti-TF therapy in animal models of thrombosis. Administration of anti-TF antibody prevents re-occlusion in femoral vessels, 53 decreases the incidence of restenosis after carotid thrombosis, 54 and reduces the required dose of tPA for effective thrombolysis in carotid thrombosis models. 55 We can now extend this list of beneficial effects of anti-TF therapy to myocardial I/R injury.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Tissue Factor-Thrombin Pathway Limits Infarct Size after Myocardial Ischemia-Reperfusion Injury by Reducing Inflammation

Erlich

Boyle

Labriola

et al. 2000

The American Journal of Pathology

192

170

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Functional inhibition of tissue factor (TF) has beenshown to improve coronary blood flow after myocardial ischemia/reperfusion (I/R) injury. TF initiates the coagulation protease cascade, resulting in the generation of the serine protease thrombin and fibrin deposition. Thrombin can also contribute to an inflammatory response by activating various cell types, including vascular endothelial cells. We used a rabbit coronary ligation model to investigate the role of TF in acute myocardial I/R injury. At-risk areas of myocardium showed increased TF expression in the sarcolemma of cardiomyocytes, which was associated with a low level of extravascular fibrin deposition. Functional inhibition of TF activity with an anti-rabbit TF monoclonal antibody administered either 15 minutes before or 30 minutes after coronary ligation reduced infarct size by 61% (P ‫؍‬ 0.004) and 44% (P ‫؍‬ 0.014), respectively. Similarly, we found that inhibition of thrombin with hirudin reduced infarct size by 59% (P ‫؍‬ 0.014). In contrast, defibrinogenating the rabbits with ancrod had no effect on infarct size, suggesting that fibrin deposition does not significantly contribute to infarct size. Functional inhibition of thrombin reduced chemokine expression and inhibition of either TF or thrombin reduced leukocyte infiltration. We propose that cardiomyocyte TF initiates extravascular thrombin generation, which enhances inflammation and injury during myocardial I/R. (Am J Pathol 2000, 157:1849 -1862)

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“…The administration of FFR-rFVIIa in combination with UFH in a small study in 24 patients undergoing percutaneous coronary intervention resulted in a significant reduction of ex vivo thrombus formation (perfusion chamber study) (63). Inhibitors of VIIa, TF, or the VIIa/TF complex Various inhibitors of VIIa, TF or VIIa/TF complex are in the early stages of development, such as humanised antibodies against TF (D3H44), soluble TF mutants or small synthetic inhibitors designed to block VIIa (50,54,76,96). None of these agents has been tested in humans so far.…”

Section: Active Site-inhibited Factor Viiamentioning

confidence: 99%

Novel Anticoagulants for the Prevention and Treatment of Venous Thromboembolism

Weltermann

Kyrle²,

Eichinger

2003

Wien Med Wochenschr

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Unfractionated heparin, low molecular weight heparin and vitamin K antagonists are anticoagulants currently used for the prevention and treatment of deep vein thrombosis and pulmonary embolism. Considerable limitations of these agents, such as a narrow therapeutic window, a variable dose response or lack of oral bioavailability, created the need for new anticoagulants. Numerous new compounds with different mechanisms of action have been developed and some have been already approved for clinical use. Quite recently, fondaparinux, an indirect anti-factor Xa inhibitor, has been licensed in Europe and in the US for prevention of VTE in patients undergoing hip or knee replacement surgery. In addition, lepirudin, a recombinant hirudin derivative, and the heparinoid danaparoid, have been approved in Austria for treatment of heparin-induced thrombocytopenia. Recombinant nematode anticoagulant protein c2, the orally available thrombin inhibitor ximelagatran and ART-123, a recombinant soluble thrombomodulin, are in advanced stages of clinical development. This article reviews mechanisms and sites of action, and the current state of preclinical and clinical research of these and various other agents with respect to the prevention and treatment of venous thromboembolism).

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Antithrombotic effect of a monoclonal antibody against tissue factor in a rabbit model of platelet-mediated arterial thrombosis.

Cited by 44 publications

References 20 publications

Vascular smooth muscle–derived tissue factor is critical for arterial thrombosis after ferric chloride–induced injury

Vascular smooth muscle–derived tissue factor is critical for arterial thrombosis after ferric chloride–induced injury

Inhibition of the Tissue Factor-Thrombin Pathway Limits Infarct Size after Myocardial Ischemia-Reperfusion Injury by Reducing Inflammation

Novel Anticoagulants for the Prevention and Treatment of Venous Thromboembolism

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