Clearance of Tissue Plasminogen Activator (TPA) and TPA/Plasminogen Activator Inhibitor Type 1 (PAI-1) Complex: Relationship to Elevated TPA Antigen in Patients With High PAI-1 Activity Levels
Abstract
Background To evaluate the effect of plasminogen activator inhibitor type 1 (PAI-1) levels on the clearance of total tissue plasminogen activator (TPA) antigen, we studied the clearance of active TPA and TPA/PAI-1 complex in subjects with low (181±109 pmol/L; n=7) and high (1166±322 pmol/L; n=4) baseline active PAI-1. Methods and Results A 5-μg/kg bolus of TPA was infused over a 15-second period followed by measurement of TPA activity, TPA antigen, TPA/PAI-1, TPA/C1 inhibitor, PAI-1 activity, and PAI-1 antigen over a 4-hour period. α-Phase clearance of total TPA antigen was faster in subjects with low PAI-1 (t 1/2 of 3.5±0.7 minutes) versus high PAI-1 (t 1/2 of 5.3±0.9 minutes) ( P =.006). Clearance of all factors was best fit by a two-compartment pharmacokinetic model based on a computer-simulated human circulatory system. The average hepatic clearance fraction in the two-compartment model was greater for active TPA (89±10%, t 1/2 of 2.4±0.3 minutes) than for TPA/PAI-1 complex (48±17%, t 1/2 of 5.0±1.8 minutes) ( P =.0006). Conclusions Plasma clearance of active TPA was faster than clearance of TPA/PAI-1 complex. High levels of active PAI-1 converted more TPA into TPA/PAI-1 complex, effectively slowing the clearance of total TPA antigen and explaining in part why high levels of PAI-1 activity are associated with increases in total TPA antigen.
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T-PA antigen levels are associated with increased risk of thrombotic events, but this is largely because 80% of t-PA antigen circulates complexed to PAI-1.
“T-PA antigen levels are also associated with increased risk of thrombotic events, but this is largely because 80% of t-PA antigen circulates complexed to PAI-1.”
From The Vasculature in Prediabetes (2018) · cites this paper as [124]
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- Authors
- Chandler, W. L., Alessi, M. C., Aillaud, M. F., Henderson, P., Vague, P., & Juhan-Vague, I.
- Affiliations
- Inserm (FR)
- Venue
- Circulation
- Published
- 1997-08-05
- Volume
- 96
- Issue
- 3
- Pages
- 761-768
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W1998362943
- Cited by
- 245
- References
- 54
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 7 · 2023: 7 · 2022: 10 · 2021: 11 · 2020: 9 · 2019: 5 · 2018: 4 · 2017: 4 · 2016: 14 · 2015: 5 · 2014: 8 · 2013: 9 · 2012: 6
- FWCI
- 6.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Genetics › Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Keywords
- tissue plasminogen activator, plasminogen activator inhibitor-1, t-PA/PAI-1 complex, plasma clearance, pharmacokinetics, hepatic clearance, fibrinolysis, two-compartment model
- MeSH terms
- Adult, Antigens, Computer Simulation, Female, Humans, Male, Middle Aged, Models, Biological, Tissue Plasminogen Activator, Plasminogen Activator Inhibitor 1
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