An Inhibitory Anti-factor IX Antibody Effectively Reduces Thrombus Formation in a Rat Model of Venous Thrombosis

Feuerstein, Giora; Toomey, John R.; Valocik, Richard E.; Koster, Paul F.; Patel, Arun; Blackburn, Michael N.

doi:10.1055/s-0037-1614852

Cited by 46 publications

(25 citation statements)

References 18 publications

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“…A bolus dose of 3.0 mg/kg had been shown previously to be an effective antithrombotic dose in rat models of arterial and venous thrombosis without a bleeding liability. 25,28,29 The pharmacodynamic effects of a bolus 3.0-mg/kg dose of SB 249417 lasted between 4 and 6 hours in rats with thromboembolic stroke, with peak factor IX inhibition (85Ϯ6%) at 1 hour after dosing comparable to that observed in naive animals ( Figure 2B). In rat safety pharmacology studies, the antibody did not affect cardiovascular or hemodynamic indices such as heart rate or blood pressure, nor were there any drug-related changes in body temperature or respiratory function (not shown).…”

Section: Factor IX Activitymentioning

confidence: 88%

Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

Toomey

Valocik

Koster

et al. 2002

Stroke

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Background and Purpose-Although used clinically to prevent stroke, there are few examples of anticoagulant investigations in the treatment of acute thromboembolic stroke in animal models. The treatment of thromboembolic stroke in experimental models has been investigated almost exclusively around the use of tissue plasminogen activator (tPA). In this study, using a rat thromboembolic stroke model, we investigated the use of an inhibitory anti-factor IX(a) monoclonal antibody (SB 249417) for the treatment of thromboembolic stroke and compared its efficacy to that of tPA. Methods-Stroke was initiated by delivering 6 clots into the internal carotid artery. After 2, 4, or 6 hours, rats received either intravenous vehicle, 10.0 mg/kg tPA, or 1.0, 2.0, or 3.0 mg/kg SB 249417. At 24 hours after stroke, infarct volumes and neurological deficits were assessed. Results-Treatment with tPA 2, 4, or 6 hours after stroke reduced infarct volumes by 35% (PϭNS), 45%, and 39%, respectively. tPA treatment did not improve neurological deficits at any time point. Treatment with SB 249417 (3.0 mg/kg) 2, 4, or 6 hours after stroke reduced infarct volumes by 44%, 50%, and 13% (PϭNS), respectively. Neurological deficits were reduced by 49%, 42%, and 13% (PϭNS), respectively. Neither mortality nor hemorrhage was affected by either treatment. Conclusions-The data indicate that the inhibition of factor IX(a) within 4 hours of thromboembolic stroke produced a more favorable outcome than tPA. When treatment was initiated 6 hours after stroke, the benefits of factor IX(a) inhibition were lost, whereas tPA continued to suppress lesion development, albeit without a corresponding improvement in functional deficits. This study suggests that cerebral ischemia and the resultant perfusion deficit are exacerbated by the activation of blood coagulation and that anticoagulants like SB 249417 may find utility in the treatment of ischemic stroke. (Stroke. 2002;33:578-585.)

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Section: Factor IX Activitymentioning

confidence: 88%

Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

Toomey

Valocik

Koster

et al. 2002

Stroke

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“…13,14 Specific modifications used in this particular work are briefly summarized here. All animal procedures were performed according to the guidelines of the US Animal Welfare Act and approved by the Institutional Animal Care and Use Committee at SUNY Downstate Medical Center.…”

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confidence: 99%

Vascular thrombus imaging in vivo via near-infrared fluorescent nanodiamond particles bioengineered with the disintegrin bitistatin (Part II)

Gerstenhaber¹,

Barone²,

Marcinkiewicz³

et al. 2017

IJN

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The aim of this feasibility study was to test the ability of fluorescent nanodiamond particles (F-NDP) covalently conjugated with bitistatin (F-NDP-Bit) to detect vascular blood clots in vivo using extracorporeal near-infrared (NIR) imaging. Specifically, we compared NIR fluorescence properties of F-NDP with N-V (F-NDP NV ) and N-V-N color centers and sizes (100–10,000 nm). Optimal NIR fluorescence and tissue penetration across biological tissues (rat skin, porcine axillary veins, and skin) was obtained for F-NDP NV with a mean diameter of 700 nm. Intravital imaging (using in vivo imaging system [IVIS]) in vitro revealed that F-NDP NV -loaded glass capillaries could be detected across 6 mm of rat red-muscle barrier and 12 mm of porcine skin, which equals the average vertical distance of a human carotid artery bifurcation from the surface of the adjacent skin (14 mm). In vivo, feasibility was demonstrated in a rat model of occlusive blood clots generated using FeCl 3 in the carotid artery bifurcation. Following systemic infusions of F-NDP NV -Bit (3 or 15 mg/kg) via the external carotid artery or femoral vein (N=3), presence of the particles in the thrombi was confirmed both in situ via IVIS, and ex vivo via confocal imaging. The presence of F-NDP NV in the vascular clots was further confirmed by direct counting of fluorescent particles extracted from clots following tissue solubilization. Our data suggest that F-NDP NV -Bit associate with vascular blood clots, presumably by binding of F-NDP NV -Bit to activated platelets within the blood clot. We posit that F-NDP NV -Bit could serve as a noninvasive platform for identification of vascular thrombi using NIR energy monitored by an extracorporeal device.

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“…15 Similar findings were reported with another anti-F.IX/IXa antibody, BC2, in rat models of arterial and venous thrombosis. 16,17 Although 10C12 was extremely potent in a guinea pig arterial thrombosis model, it was considerably less so in a rat, ferric chloride (FeCl 3 )-induced model of arterial thrombosis. 15 Because of this discrepancy in potency, it remained unclear whether this antibody was an unusually potent antithrombotic with a very broad safety margin or not.…”

mentioning

confidence: 99%

A Human Antibody That Inhibits Factor IX/IXa Function Potently Inhibits Arterial Thrombosis Without Increasing Bleeding

Refino¹,

Jeet²,

Deguzman³

et al. 2002

ATVB

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Abstract-10C12, a human antibody F(abЈ) 2 , which specifically binds to the ␥-carboxyglutamic acid domain of factor IX/factor IXa (F.IX/IXa), interferes with all known coagulation processes in which F.IX/IXa is involved. In a rabbit model of carotid artery injury, intravenous administration of 10C12 or heparin decreased thrombosis dose dependently. The dose that resulted in a 90% reduction of thrombus mass (ED 90 ) was a 30-g/kg bolus of 10C12 or a 100-U/kg bolus plus 1.0 U · kg Ϫ1 · min Ϫ1 infusion of heparin. Heparin, at and below the ED 90 , significantly prolonged coagulation times and cuticle bleeding times. In contrast, 10C12 had no effect on coagulation or bleeding times at doses up to 4 times the ED 90 . To further evaluate the effect of 10C12 on bleeding, it was compared with heparin in a novel model of blood loss. At the ED 90 of heparin, blood loss induced by a standardized injury to the vasculature of the rabbit tibia increased to more than 2 times that of saline controls. In contrast, the dose of 10C12 required to produce a similar increase in blood loss was more than 30 times the ED 90 . The antithrombotic potency and relative safety of this fully human antibody suggests that it may have therapeutic value for treatment of thrombotic disorders.

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An Inhibitory Anti-factor IX Antibody Effectively Reduces Thrombus Formation in a Rat Model of Venous Thrombosis

Cited by 46 publications

References 18 publications

Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

Vascular thrombus imaging in vivo via near-infrared fluorescent nanodiamond particles bioengineered with the disintegrin bitistatin (Part II)

A Human Antibody That Inhibits Factor IX/IXa Function Potently Inhibits Arterial Thrombosis Without Increasing Bleeding

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