Administration of a small molecule tissue factor/Factor VIIa inhibitor in a non-human primate thrombosis model of venous thrombosis: effects on thrombus formation and bleeding time

Szalony, James A.; Suleymanov, Osman D.; Salyers, Anita K.; Panzer‐Knodle, Susan G.; Blom, Jason D.; Lachance, Rhonda M.; Case, Brenda L.; Parlow, John J.; South, Michael S.; Wood, Rhonda S.; Nicholson, Nancy S.

doi:10.1016/j.thromres.2003.10.017

Cited by 39 publications

(23 citation statements)

References 35 publications

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“…This VT model has been well characterized with anticoagulant drugs with different mechanisms of action, including warfarin [26,28,31,43]. This study shows that BMS-262084 prevented the formation of thrombus dosedependently in a similar fashion as previously reported anticoaguants in the VT model [26,28,31,43]. This finding suggests there is a strong component of FXIa in mediating VT in the rabbit VT model.…”

Section: Discussionsupporting

confidence: 83%

A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

Wong

Crain

Watson

et al. 2011

J Thromb Thrombolysis

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BMS-262084 is a 4-carboxy-2-azetidinone-containing irreversible inhibitor of FXIa, which is selective over other coagulation proteases. We evaluated the in vitro and in vivo properties of BMS-262084 in rabbits. Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrolytic-mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models. BMS-262084 was infused IV from 1 h before thrombus induction or cuticle transection to the end of the experiment. In vitro, BMS-262084 prolonged activated partial thromboplastin time (aPTT) with EC(2x) (concentration required to double aPTT) of 10.6 μM in rabbit plasma, and did not prolong prothrombin time (PT), thrombin time (TT) and HepTest. In vivo, BMS-262084 produced dose-dependent antithrombotic effects in rabbits with antithrombotic ED(50) (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT of 0.4, 0.7 and 1.5 mg/kg/h IV, respectively. BMS-262084 increased ex vivo aPTT dose-dependently without changes in PT and TT. The antithrombotic effect of BMS-262084 was significantly correlated with its ex vivo aPTT, supporting the use of ex vivo aPTT as a pharmacodynamic biomarker. BMS-262084 did not alter ex vivo rabbit platelet aggregation to ADP and collagen. BT (fold-increase) determined at 3 and 10 mg/kg/h of BMS-262084 were 1.17 ± 0.04 and 1.52 ± 0.07*, respectively (*P < 0.05 vs. control). This study demonstrated that BMS-262084 prevented experimental thrombosis at doses with low BT effects in rabbits, and suggests that a small molecule FXIa inhibitor may represent a promising antithrombotic therapy.

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Section: Discussionsupporting

confidence: 83%

A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

Wong

Crain

Watson

et al. 2011

J Thromb Thrombolysis

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“…For instance, anti-TF antibodies, active-site inactivated FVIIa, tissue factor pathway inhibitor (TFPI), and small molecule inhibitors of the TF:FVIIa complex reduce thrombus size in arterial and venous models of thrombosis using rabbits and nonhuman primates. [83][84][85][86][87][88][89][90][91] In addition, inhibition of the TF:FVIIa complex with recombinant nematode protein c2 reduced thrombin generation in patients undergoing elective coronary angioplasty. 92 Vascular smooth muscle cells in the arterial vessel wall express low levels of TF and a variety of cell types express TF in atherosclerotic lesions.…”

Section: Relative Contribution Of Vessel Wall Tf and Mp Tf To Arteriamentioning

confidence: 99%

Role of the Extrinsic Pathway of Blood Coagulation in Hemostasis and Thrombosis

Mackman

Tilley

Key

2007

ATVB

588

441

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Abstract-Hemostasis requires both platelets and the coagulation system. At sites of vessel injury, bleeding is minimized by the formation of a hemostatic plug consisting of platelets and fibrin. The traditional view of the regulation of blood coagulation is that the initiation phase is triggered by the extrinsic pathway, whereas amplification requires the intrinsic pathway. The extrinsic pathway consists of the transmembrane receptor tissue factor (TF) and plasma factor VII/VIIa (FVII/FVIIa), and the intrinsic pathway consists of plasma FXI, FIX, and FVIII. Under physiological conditions, TF is constitutively expressed by adventitial cells surrounding blood vessels and initiates clotting. In addition so-called blood-borne TF in the form of cell-derived microparticles (MPs) and TF expression within platelets suggests that TF may play a role in the amplification phase of the coagulation cascade. Under pathologic conditions, TF is expressed by monocytes, neutrophils, endothelial cells, and platelets, which results in an elevation of the levels of circulating TF-positive MPs. TF expression within the vasculature likely contributes to thrombosis in a variety of diseases. Understanding how the extrinsic pathway of blood coagulation contributes to hemostasis and thrombosis may lead to the development of safe and effective hemostatic agents and antithrombotic drugs. Key Words: coagulation Ⅲ arterial thrombosis Ⅲ deep vein thrombosis T he hemostatic system maintains blood in a fluid state under normal conditions and responds to vessel injury by the rapid formation of a clot. Disruption of the endothelium exposes platelets to collagen in the vessel wall and plasma factor VII/VIIa (FVII/FVIIa) to extravascular tissue factor (TF; Figure 1). Other proteins, such as von Willebrand factor (vWF), facilitate the binding of platelets to the injured vessel wall. The TF:FVIIa complex is traditionally referred to as the extrinsic pathway and is proposed to be the primary activator of the coagulation protease cascade in vivo. Subsequently, propagation of the thrombus involves recruitment of additional platelets and amplification of the coagulation cascade by the intrinsic pathway of blood coagulation, which includes the hemophilia factors FVIII and FIX (Figure 1). Importantly, platelets play a critical role in the amplification of the coagulation cascade by providing a thrombogenic surface. Finally, fibrin stabilizes the platelet-rich thrombus (Figure 1). This review focuses on the role of the extrinsic pathway (TF and FVIIa) in hemostasis and thrombosis. See cover TF and FVII in HemostasisHemostasis is the protective physiological response to vascular injury that results in exposure of blood components to the subendothelial layers of the vessel wall. TF is constitutively expressed by certain cells within the vessel wall and cells surrounding blood vessels, such as vascular smooth muscle cells, pericytes, and adventitial fibroblasts. 1-5 TF is also expressed in a tissue-specific pattern with high levels in the brain, lung, kidney, he...

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“…A cyclic dodecapeptide (PN7051) derived from the second EGF-like domain of FVII interferes with TF/FVII/FX complex to attenuate fibrin deposition, platelet-fibrin adhesion and platelet-thrombus formation [285]. PHA-798 diminishes thrombus formation in primates [286]. It remains to be determined concerning the antithombotic application of rNAPc2.…”

Section: Antagonisms Against Tf Signaling-evolving Thrombotic or mentioning

confidence: 99%

Tissue Factor, Blood Coagulation, and Beyond: An Overview

Chu

2011

International Journal of Inflammation

180

184

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Emerging evidence shows a broad spectrum of biological functions of tissue factor (TF). TF classical role in initiating the extrinsic blood coagulation and its direct thrombotic action in close relation to cardiovascular risks have long been established. TF overexpression/hypercoagulability often observed in many clinical conditions certainly expands its role in proinflammation, diabetes, obesity, cardiovascular diseases, angiogenesis, tumor metastasis, wound repairs, embryonic development, cell adhesion/migration, innate immunity, infection, pregnancy loss, and many others. This paper broadly covers seminal observations to discuss TF pathogenic roles in relation to diverse disease development or manifestation. Biochemically, extracellular TF signaling interfaced through protease-activated receptors (PARs) elicits cellular activation and inflammatory responses. TF diverse biological roles are associated with either coagulation-dependent or noncoagulation-mediated actions. Apparently, TF hypercoagulability refuels a coagulation-inflammation-thrombosis circuit in “autocrine” or “paracrine” fashions, which triggers a wide spectrum of pathophysiology. Accordingly, TF suppression, anticoagulation, PAR blockade, or general anti-inflammation offers an array of therapeutical benefits for easing diverse pathological conditions.

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Administration of a small molecule tissue factor/Factor VIIa inhibitor in a non-human primate thrombosis model of venous thrombosis: effects on thrombus formation and bleeding time

Cited by 39 publications

References 35 publications

A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

Role of the Extrinsic Pathway of Blood Coagulation in Hemostasis and Thrombosis

Tissue Factor, Blood Coagulation, and Beyond: An Overview

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