Active site-blocked factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a canine thrombosis model.

Benedict, Claude R.; Ryan, J; Wolitzky, Barry A.; Ramos, Rui Fernando; Gerlach, Marlene L.; Tijburg, P; Stern, David M.

doi:10.1172/jci115495

Cited by 91 publications

(66 citation statements)

References 24 publications

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“…These studies thus extend previous studies reporting antithrombotic efficacy of FIXai in canine models of arterial thrombosis and cardiopulmonary bypass surgery. 17,27 Preliminary studies conducted in our laboratory also demonstrate that treatment with BC2 results in extended patency of the blood vessel; thus a single bolus injection of BC2 not only increased the incidence of vessel patency 60 minutes after BC2 administration but also 24 hours later at a time when aPTT was within normal range. This phenomenon may reflect the capacity of the vessel wall to initiate repair when coagulation is interrupted at FIX/IXa limiting the generation of factor Xa and thrombin.…”

Section: Discussionmentioning

confidence: 83%

“…15 Lollar and Fass 16 showed that active-site blocked factor IXa (FIXai) inhibits clot formation in vitro. Benedict et al demonstrated that administration of FIXai prevents thrombosis in experimental animal models, 17 indicating that modulation of FIX function can be achieved to gain therapeutic efficacy in thrombosis. Bajaj and coworkers 18 have described antibody mediated inhibition of FIX coagulant activity but did not explore in vivo application of the antibody as an antithrombotic agent.…”

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confidence: 99%

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Antithrombotic Efficacy of a Novel Murine Antihuman Factor IX Antibody in Rats

Feuerstein¹,

Patel²,

Toomey³

et al. 1999

ATVB

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Abstract-A murine antihuman factor IX monoclonal antibody (BC2) has been generated and evaluated for its capacity to prolong the activated partial thromboplastin time (aPTT) in vitro and ex vivo and to prevent arterial thrombosis in a rat model in vivo. BC2 extended aPTT to a maximum of 60 to 80 seconds at 100 to 1000 nmol/L in vitro (rat and human plasma, respectively) and ex vivo (rat) after dosing of rats up to 6 mg/kg in vivo. BC2, administered as bolus (1 to 6 mg/kg) followed by infusion (0.3 to 2 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 ), dose-dependently prevented thrombosis of an injured rat carotid artery (FeCl 3 -patch model), increased time to artery occlusion, and reduced incidence of vessel occlusion. BC2 efficacy in preventing arterial thrombosis exceeded that of heparin (bolus 15 to 120 U/kg followed by infusion 0.5 to 4.0 U ⅐ kg Ϫ1 ⅐ min Ϫ1 ), whereas the latter rendered the blood incoagulable (aPTTϾ1000 seconds). BC2 demonstrated complete antithrombotic efficacy also as a single bolus given either as prevessel or postvessel injury as evidenced by reduction of thrombus mass (from 4.18Ϯ0.49 to 1.80Ϯ0.3 mg, PϽ0.001), increasing vessel patency time (from 14.9Ϯ0.9 minutes to 58.3Ϯ1.7 minutes, PϽ0.001) and decreasing incidence of vessel occlusion from 100% to 0% in vehicle-versus BC2-treated rats, respectively. BC2 (3 mg/kg, IV) administered in a single bolus resulted in 50% reduction in thrombus mass (PϽ0.01), extended vessel patency time (PϽ0.001), extended aPTT only 4-fold, and had no effect on blood loss via a tail surgical wound; heparin, at doses that reduced thrombus mass to a similar extent, extended aPTT beyond 1000 seconds (over 500-fold) and increased blood loss from 1.8Ϯ0.7 to 3.3Ϯ0.6 mL (PϽ0.001). These data suggest that BC2 may provide enhanced therapeutic efficacy in humans at lesser interference with blood hemostasis than heparin.

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Section: Discussionmentioning

confidence: 83%

mentioning

confidence: 99%

Antithrombotic Efficacy of a Novel Murine Antihuman Factor IX Antibody in Rats

Feuerstein¹,

Patel²,

Toomey³

et al. 1999

ATVB

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“…sLA-LMWH can be added to a growing list of enzyme complex inhibitors, which include active site blocked f.Xa and f.IXa (51,52), f.IXa antibodies (53), and active site directed f.Xa inhibitors (54 -57). sLA-LMWH may have advantages over other agents because it simultaneously attenuates f.Xa and thrombin generation, with selectively greater inhibition of f.Xa generation by intrinsic tenase.…”

Section: Sla-lmwh Inhibits Intrinsic Tenase and Prothrombinasementioning

confidence: 99%

Hypersulfated Low Molecular Weight Heparin with Reduced Affinity for Antithrombin Acts as an Anticoagulant by Inhibiting Intrinsic Tenase and Prothrombinase

Anderson

Fredenburgh

Stafford

et al. 2001

Journal of Biological Chemistry

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In buffer systems, heparin and low molecular weight heparin (LMWH) directly inhibit the intrinsic factor Xactivating complex (intrinsic tenase) but have no effect on the prothrombin-activating complex (prothrombinase). Although chemical modification of LMWH, to lower its affinity for antithrombin (LA-LMWH) has no effect on its ability to inhibit intrinsic tenase, N-desulfation of LMWH reduces its activity 12-fold. To further explore the role of sulfation, hypersulfated LA-LMWH was synthesized (sLA-LMWH). sLA-LMWH is not only a 32-fold more potent inhibitor of intrinsic tenase than LA-LMWH; it also acquires prothrombinase inhibitory activity. A direct correlation between the extent of sulfation of LA-LMWH and its inhibitory activity against intrinsic tenase and prothrombinase is observed. In plasma-based assays of tenase and prothrombinase, sLA-LMWH produces similar prolongation of clotting times in plasma depleted of antithrombin and/or heparin cofactor II as it does in control plasma. In contrast, heparin has no effect in antithrombin-depleted plasma. When the effect of sLA-LMWH on various components of tenase and prothrombinase was examined, its inhibitory activity was found to be cofactor-dependent (factors Va and VIIIa) and phospholipid-independent. These studies reveal that sLA-LMWH acts as a potent antithrombin-independent inhibitor of coagulation by attenuating intrinsic tenase and prothrombinase.

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“…1 Therefore, one may infer that an approach to treat thrombotic disorders by interfering with F.IXa function would have an unacceptable bleeding liability. Yet, Benedict et al 2 were able to demonstrate that short-term inhibition of F.IXa function by active site-blocked F.IX (F.IXai) can be safe as well as effective in preventing thrombus formation in a canine model of electric currentinduced thrombosis. Subsequent in vivo studies with the prototypic inhibitor F.IXai further corroborated this paradigm, 3,4 indicating that the specific targeting of F.IXa activity could represent a promising therapeutic strategy.…”

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confidence: 99%

“…8,9,13 Based on the structural requirements for intrinsic Xase assembly, new approaches to specifically interfere with F.IXa activity are conceivable. To this end, we used a F.IX-Gla domain-directed phage display strategy to generate the antibody 10C12, a fully humanized F(abЈ) 2 that specifically binds to the Gla domain of F.IX/IXa. 14 In addition to inhibiting platelet-dependent intrinsic Xase activity, 14 10C12 was found to block F.IX activation by F.XIa and by the tissue factor:F.VIIa (TF:F.VIIa) complex.…”

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

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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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Active site-blocked factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a canine thrombosis model.

Cited by 91 publications

References 24 publications

Antithrombotic Efficacy of a Novel Murine Antihuman Factor IX Antibody in Rats

Antithrombotic Efficacy of a Novel Murine Antihuman Factor IX Antibody in Rats

Hypersulfated Low Molecular Weight Heparin with Reduced Affinity for Antithrombin Acts as an Anticoagulant by Inhibiting Intrinsic Tenase and Prothrombinase

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

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