New Variant of Human Tissue Plasminogen Activator (TPA) With Enhanced Efficacy and Lower Incidence of Bleeding Compared With Recombinant Human TPA
| Autor: | G R Thomas, Rajbabu Pakala, N F Paoni, Claude R. Benedict, B A Keyt, C J Refino, W F Bennett |
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| Rok vydání: | 1995 |
| Předmět: |
Male
medicine.medical_specialty Platelet Aggregation medicine.medical_treatment Molecular Sequence Data Urology Hemorrhage Tissue plasminogen activator Fibrin Bolus (medicine) Fibrinolytic Agents Kringles Physiology (medical) medicine Animals Humans Carotid Artery Thrombosis integumentary system biology T-plasminogen activator business.industry Thrombolysis Arterial occlusion Surgery medicine.anatomical_structure Tissue Plasminogen Activator biology.protein Rabbits Cardiology and Cardiovascular Medicine business Plasminogen activator medicine.drug Artery |
| Zdroj: | Circulation. 92:3032-3040 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | Background The thrombolytic properties of a new variant of tissue plasminogen activator (TPA) (T103N, N117Q, KHRR 296-299 AAAA, or TNK-TPA) with longer plasma half-life, greater fibrin specificity, and increased resistance to inhibition by plasminogen activator inhibitor (PAI-1) were investigated in a rabbit thrombosed carotid artery model. Methods and Results After 60 minutes of arterial occlusion, TPA (1.5, 3.0, 6.0, or 9.0 mg/kg as a front-loaded IV infusion for 90 minutes; n=22) or TNK-TPA (0.38, 0.75, or 1.5 mg/kg as IV bolus; n=16) was administered. Blood flow through the artery was monitored for an additional 120 minutes. Bleeding was assessed by weighing the amount of blood absorbed in a gauze pad placed in a subcutaneous muscular incision. Recanalization rates and duration of recanalization were dose dependent. The doses that produced >80% recanalization rates with the longest duration of recanalization were 9.0 mg/kg for TPA and 1.5 mg/kg for TNK-TPA. At these doses, time to reperfusion (mean±SEM) was significantly faster (11±2 versus 23±7 minutes) and duration of recanalization longer (77±9 versus 51±18 minutes) for TNK-TPA compared with TPA ( P P =.004). Concentrations of fibrinogen, plasminogen, and α 2 -antiplasmin at 120 minutes were significantly higher for TNK-TPA–treated animals compared with TPA-treated animals ( P P Conclusions From these data, we conclude that TNK-TPA, given as a bolus, produces faster and more complete recanalization of occluded arteries in a rabbit experimental model compared with TPA, without increasing systemic plasmin generation or peripheral bleeding. In addition, we observed that TNK-TPA, unlike TPA, did not potentiate collagen-induced aggregation of platelets obtained from human plasma. This lack of effect on platelet aggregation by TNK-TPA potentially could be associated with a decreased risk of reocclusion after successful thrombolysis. |
| Databáze: | OpenAIRE |
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