Recombinant Tissue Plasminogen Activator and Mutant rt-PA: Binding Kinetics and Cytotoxicity on Brain Endothelial Cells—Relevance to Brain Hemorrhage
The effectiveness of recombinant tissue plasminogen activator (rt-PA) in thrombolytic therapy is theoretically dependent on the rate at which therapeutically administered rt-PA reaches the clot site and the proportion of rt-PA that is enzymatically active. Interaction between rt-PA and its specific plasma inhibitor PAI-1, and between rt-PA and the endothelial cell lining of blood vessels, are two factors that may limit efficacy. While rt-PA can restore blood flow to thrombosed cerebral arteries and revive function of ischemically impaired brain tissue, rt-PA may also provoke brain damage by causing brain hemorrhage. We report on our studies of rt-PA and mutant rt-PA (TNK), assessing the binding kinetics and cytotoxicity on brain endothelial cells (BEC) to determine their action and relevance in brain hemorrhage.
KeywordsPlasminogen Activator Thrombolytic Therapy Tissue Plasminogen Activator Human Endothelial Cell Brain Endothelial Cell
Unable to display preview. Download preview PDF.
- 10.Barnathan ES, Kuo A, Van der Keyl H, McCrae KR, Larsen GR, Cines DB (1988) Tissue-type plasminogen activator binding to human endothelial cells. Evidence for two distinct binding sites. J Biol Chem 263: 7792–7799Google Scholar
- 17.Korninger C, Stassen JM, Collen D (1981) Turnover of human extrinsic (tissue-type) plasminogen activator in rabbits. Thromb Haemostasis 46: 658–661Google Scholar
- 19.Emeis JJ, Van den Hoogen C, Jense D (1985) Hepatic clearance of tissue-type plasminogen activator in rats. Thromb Haemostasis 54: 661–664Google Scholar
- 23.Declerck DJ, Alessi M, Verstreken M, Kriuthof EKO, Juhan-Vague I, Collen D (1987) Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. Blood 71: 220–225Google Scholar
- 26.Verstraete M, Su CA, Transwell P, Feuerer W, Collen D (1986) Pharmacokinetics and effects on fibrinolytic and coagulation parameters of two doses of recombinant tissue-type plasminogen activator in healthy volunteers. Thromb Haemostasis 56: 1–5Google Scholar