New Variant of Human Tissue Plasminogen Activator (TPA) With Enhanced Efficacy and Lower Incidence of Bleeding Compared With Recombinant Human TPA

Benedict, Claude R.; Refino, Canio J.; Keyt, Bruce A.; Pakala, Rajbabu; Paoni, Nicholas F.; Thomas, George; Bennett, William F.

doi:10.1161/01.cir.92.10.3032

Cited by 165 publications

(104 citation statements)

References 39 publications

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“…Bleeding after treatment with fibrinolytic drugs may arise through several mechanisms including plasmin-mediated lysis of fibrin clot and antiplatelet actions (Benedict et al, 1995;Moser et al, 1999;Serebruany et al, 2003;Gurbel et al, 2005). The fibrinolytics also reduce plasma concentrations of antiplasmin leading to plasminaemia and depletion of fibrinogen and other clotting factors, notably factor V (Tracy et al, 1997;Stangl et al, 1998).…”

Section: Fibrinolytic Drugsmentioning

confidence: 99%

Guideline on the management of bleeding in patients on antithrombotic agents

et al. 2012

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Section: Fibrinolytic Drugsmentioning

confidence: 99%

Guideline on the management of bleeding in patients on antithrombotic agents

et al. 2012

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“…We chose 1.5 mg/kg as the high dose for TNK because it has been shown to produce Ͼ80% recanalization in a dose-response study using a rabbit model of carotid artery thrombosis. 18 We chose 0.6 mg/kg as the low dose for TNK because that dose has previously been shown to produce complete clot lysis over 2 hours, while decreasing the hemorrhage rate, in a model similar to our model. 3 We administered TNK at a constant rate over 3 minutes.…”

Section: Drug Administrationmentioning

confidence: 99%

Comparison of TNK With Wild-Type Tissue Plasminogen Activator in a Rabbit Embolic Stroke Model

Chapman¹,

Lyden²,

Lapchak³

et al. 2001

Stroke

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Background and Purpose-Tissue plasminogen activator (tPA) is an effective treatment for stroke, but its utility is limited by fear of cerebral hemorrhage. Tenecteplase (TNK), a genetically modified form of wild-type tPA, exhibits a longer biological half-life and greater fibrin specificity, features that could lead to fewer cerebral hemorrhages than wild-type tPA in stroke patients. Methods-We injected radiolabeled blood clots into the cerebral circulation of New Zealand White rabbits. One hour later, we administered tPA (nϭ57), 0.6 mg/kg TNK (nϭ43), 1.5 mg/kg TNK (nϭ27), or vehicle control (nϭ37). A blinded observer examined the brains for macroscopic hemorrhage using a semiquantitative score. We estimated thrombolysis by assessing the amount of radiolabel remaining in the cerebral vessels postmortem. Results-Both wild-type tPA and TNK caused thrombolysis in most subjects. Hemorrhage was detected in 26% (6/23) of the control group, 66% (27/41) of the wild-type tPA group, 55% (16/29) in the 0.6-mg/kg TNK group, and 53% (9/17) in the 1.5-mg/kg TNK group (PϽ0.05, 2 test). The tPA group was statistically significantly different from the control group, but the TNK and tPA groups did not differ from each other. Neither TNK nor tPA affected the size of the hemorrhages. Conclusions-TNK shows comparable rates of recanalization compared with wild-type tPA in a model of embolic stroke.While tPA increases hemorrhage rate, the hemorrhage associated with TNK treatment is not statistically different compared with controls or the tPA group. These findings suggest that TNK shows promise as an alternative thrombolytic treatment for stroke, but we could not demonstrate improved safety compared with wild-type tPA.

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“…Treatment requires administration of PAs in doses several orders of magnitude above physiological levels to attain therapeutic efficacy, posing a considerable risk of hemorrhage (Ridker et al, 1994). To date, modifications in the design and delivery of plasminogen activators to attain greater affinity for fibrin, longer circulation time, and greater resistance to inhibitors have been of rather modest clinical benefit (Keyt et al, 1994;Benedict et al, 1995;Liberatore et al, 2003;Rijken et al, 2004;Inoue et al, 2005).…”

mentioning

confidence: 99%

The Glycocalyx Protects Erythrocyte-Bound Tissue-Type Plasminogen Activator from Enzymatic Inhibition

Ganguly¹,

Murciano²,

Westrick³

et al. 2007

J Pharmacol Exp Ther

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Coupling tissue-type plasminogen activator (tPA) to carrier red blood cells (RBC) prolongs its intravascular life span and permits its use for thromboprophylaxis. Here, we studied the susceptibility of RBC/tPA to PA inhibitors including plasminogen activator inhibitor-1 (PAI-1) that constrain its activity and may reduce the duration of its effect. Despite lesser spatial and diffusional limitations, soluble tPA was far less effective than RBC/tPA in dissolving clots formed in vitro from blood of wildtype (WT) mice (40 versus 80% lysis at equal doses of tPA). Furthermore, after i.v. injection, soluble tPA lost activity faster in transgenic mice expressing a high level of PAI-1 than in WT mice, whereas the activity of RBC/tPA was unaffected. PAI-1 inactivated soluble tPA at equimolar ratios in vitro, but it had no effect on the amidolytic or fibrinolytic activity of RBC/tPA. RBC/ tPA was also more resistant than soluble tPA to in vitro inhibition by other serpins (␣ 2 -macroglobulin and ␣ 1 -antitrypsin) and pathologically high levels of glucose. However, coupling to RBC did not protect a truncated tPA mutant, Retavase, from plasma inhibitors. Chemical removal of the RBC glycocalyx negated tPA protection from inhibitors: tPA coupled to glycocalyx-stripped RBC bound twice as much 125 I-PAI-1 as did tPA coupled to naive RBC, and susceptibility of the bound tPA to inhibition by PAI-1 was restored. Thus, the RBC glycocalyx protects RBC-coupled tPA against inhibition. Resistance to high levels of inhibitors in vivo contributes to the potential utility of RBC/tPA for thromboprophylaxis.

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New Variant of Human Tissue Plasminogen Activator (TPA) With Enhanced Efficacy and Lower Incidence of Bleeding Compared With Recombinant Human TPA

Cited by 165 publications

References 39 publications

Guideline on the management of bleeding in patients on antithrombotic agents

Guideline on the management of bleeding in patients on antithrombotic agents

Comparison of TNK With Wild-Type Tissue Plasminogen Activator in a Rabbit Embolic Stroke Model

The Glycocalyx Protects Erythrocyte-Bound Tissue-Type Plasminogen Activator from Enzymatic Inhibition

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