ArticleBlood advances2026
Tenecteplase and other TNK formulations lose PAI-1 resistance in their 2-chain form: comparison with alteplase.
Article in Blood advances, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Acute Ischaemic Stroke: Therapeutic Targets and Key Modulators of the Fibrinolytic System and Clot Formation.Translational stroke research · 2026Review
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14 authors.
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Abstract
abstractAlteplase is synthesized as a single-chain protease that requires plasmin-mediated conversion to its fully active 2-chain form for maximal thrombolysis. Tenecteplase (TNK), an alteplase variant, is widely regarded as being more fibrin selective and more resistant to plasminogen activator inhibitor 1 (PAI-1) than alteplase. However, the PAI-1 sensitivity of TNK after 2-chain conversion and that of newly available TNK formulations has not been evaluated. Alteplase and 4 TNK formulations, Metalyse (Boehringer Ingelheim, Ingelheim am Rheim, Germany), Tenectase (Gennova, Pune, India), GenetPA (BioApower, Jiangsu, Yancheng, China), and Mingfule (CSPC Pharmaceutical Company Ltd, Guangdong, Guangzhou, China) were compared in their native state and after 2-chain conversion. Proteolytic activity and PAI-1 resistance and binding were evaluated using an amidolytic assay, fibrinolysis assays, and western blotting. Alteplase, but not Metalyse, was converted into its 2-chain form in plasma in a fibrinogen-dependent manner, resulting in off-target fibrinogenolysis. When directly reconstituted from the manufacturer's vial (native form), TNK was approximately fourfold more resistant to PAI-1 than alteplase; however, 2-chain conversion significantly reduced PAI-1 resistance by ∼40%, concomitant with increased PAI-1 binding. Native Metalyse contained approximately threefold more preexisting 2-chain species than the other TNK formulations, explaining its higher amidolytic activity. However, after 2-chain conversion, all TNK formulations showed similar fibrinolytic activity, although with substantially reduced PAI-1 resistance. Metalyse and all new TNK formulations display similar fibrinolytic activity in their fully active 2-chain states, but this is associated with substantial loss of PAI-1 resistance, challenging the view that the fully active 2-chain form of TNK maintains PAI-1 resistance during thrombolysis.
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