Purba Mukherjee1, Patrick Lyden2, José A Fernández1, Thomas P Davis3, Kent E Pryor4, Berislav V Zlokovic5, John H Griffin1. 1. Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA (P.M., J.A.F., J.H.G.). 2. Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.). 3. Department of Medical Pharmacology, University of Arizona, Tucson (T.P.D.). 4. ZZ Biotech LLC, Houston, TX (K.E.P.). 5. Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA (B.V.Z.).
Abstract
BACKGROUND AND PURPOSE: A recombinant engineered variant of APC (activated protein C), 3K3A-APC, lacks anticoagulant properties (<10%) while preserving APCs anti-inflammatory, anti-apoptotic, and neuroprotective functions and is very promising in clinical trials for ischemic stroke. Therapeutic intervention with single bolus administration of the third-generation tPA (tissue-type plasminogen activator), tenecteplase, is anticipated to be widely adopted for treatment of acute ischemic stroke. 3K3A-APC is well-tolerated in stroke patients dosed with alteplase, and in vitro studies show 3K3A-APC does not interfere with alteplase-induced clot lysis. The purpose of this in vitro study was to assess the influence of 3K3A-APC on tenecteplase-induced clot lysis. METHODS: Tenecteplase-mediated lysis of thrombin generated plasma clots of human normal pooled plasma was monitored in the presence of varying doses of 3K3A-APC. The effects on fibrinolysis by tenecteplase and alteplase were compared. RESULTS: The presence of 3K3A-APC shortened the time for clot lysis induced by tenecteplase at very low levels but not at higher therapeutic concentrations of tenecteplase. Comparisons of alteplase-mediated clot lysis to tenecteplase clot lysis showed that both thrombolytic agents behaved similarly in the presence of 3K3A-APC. CONCLUSIONS: These results indicate that 3K3A-APC does not interfere with tenecteplase's clot lysis function.
BACKGROUND AND PURPOSE: A recombinant engineered variant of APC (activated protein C), 3K3A-APC, lacks anticoagulant properties (<10%) while preserving APCs anti-inflammatory, anti-apoptotic, and neuroprotective functions and is very promising in clinical trials for ischemic stroke. Therapeutic intervention with single bolus administration of the third-generation tPA (tissue-type plasminogen activator), tenecteplase, is anticipated to be widely adopted for treatment of acute ischemic stroke. 3K3A-APC is well-tolerated in strokepatients dosed with alteplase, and in vitro studies show 3K3A-APC does not interfere with alteplase-induced clot lysis. The purpose of this in vitro study was to assess the influence of 3K3A-APC on tenecteplase-induced clot lysis. METHODS: Tenecteplase-mediated lysis of thrombin generated plasma clots of human normal pooled plasma was monitored in the presence of varying doses of 3K3A-APC. The effects on fibrinolysis by tenecteplase and alteplase were compared. RESULTS: The presence of 3K3A-APC shortened the time for clot lysis induced by tenecteplase at very low levels but not at higher therapeutic concentrations of tenecteplase. Comparisons of alteplase-mediated clot lysis to tenecteplase clot lysis showed that both thrombolytic agents behaved similarly in the presence of 3K3A-APC. CONCLUSIONS: These results indicate that 3K3A-APC does not interfere with tenecteplase's clot lysis function.
Entities:
Keywords:
anticoagulants; fibrinolysis; protein C; tenecteplase; tissue-type plasminogen activator
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