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Volume 22
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10.3390/ijms22042115
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Article

Role of Shear Stress and tPA Concentration in the Fibrinolytic Potential of Thrombi

by
Claire S. Whyte
1,
Hadj Ahmed. Mostefai
1,
Kim M. Baeten
1,
Andrew J. Lucking
2,
David E. Newby
2,
Nuala A. Booth
1,† and
Nicola J. Mutch
1,*,†
1
Aberdeen Cardiovascular and Diabetes Centre, Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK
2
Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4SB, Scotland, UK
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2021, 22(4), 2115; https://doi.org/10.3390/ijms22042115
Submission received: 1 February 2021 / Revised: 11 February 2021 / Accepted: 13 February 2021 / Published: 20 February 2021
(This article belongs to the Special Issue Fibrinogen/Fibrin, Factor XIII and Fibrinolysis in Diseases)
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Abstract

The resolution of arterial thrombi is critically dependent on the endogenous fibrinolytic system. Using well-established and complementary whole blood models, we investigated the endogenous fibrinolytic potential of the tissue-type plasminogen activator (tPA) and the intra-thrombus distribution of fibrinolytic proteins, formed ex vivo under shear. tPA was present at physiologically relevant concentrations and fibrinolysis was monitored using an FITC-labelled fibrinogen tracer. Thrombi were formed from anticoagulated blood using a Chandler Loop and from non-anticoagulated blood perfused over specially-prepared porcine aorta strips under low (212 s−1) and high shear (1690 s−1) conditions in a Badimon Chamber. Plasminogen, tPA and plasminogen activator inhibitor-1 (PAI-1) concentrations were measured by ELISA. The tPA–PAI-1 complex was abundant in Chandler model thrombi serum. In contrast, free tPA was evident in the head of thrombi and correlated with fibrinolytic activity. Badimon thrombi formed under high shear conditions were more resistant to fibrinolysis than those formed at low shear. Plasminogen and tPA concentrations were elevated in thrombi formed at low shear, while PAI-1 concentrations were augmented at high shear rates. In conclusion, tPA primarily localises to the thrombus head in a free and active form. Thrombi formed at high shear incorporate less tPA and plasminogen and increased PAI-1, thereby enhancing resistance to degradation.
Keywords: plasminogen activator inhibitor-1; fibrinolysis; tissue plasminogen activator; thrombi; shear plasminogen activator inhibitor-1; fibrinolysis; tissue plasminogen activator; thrombi; shear

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MDPI and ACS Style

Whyte, C.S.; Mostefai, H.A.; Baeten, K.M.; Lucking, A.J.; Newby, D.E.; Booth, N.A.; Mutch, N.J. Role of Shear Stress and tPA Concentration in the Fibrinolytic Potential of Thrombi. Int. J. Mol. Sci. 2021, 22, 2115. https://doi.org/10.3390/ijms22042115

AMA Style

Whyte CS, Mostefai HA, Baeten KM, Lucking AJ, Newby DE, Booth NA, Mutch NJ. Role of Shear Stress and tPA Concentration in the Fibrinolytic Potential of Thrombi. International Journal of Molecular Sciences. 2021; 22(4):2115. https://doi.org/10.3390/ijms22042115

Chicago/Turabian Style

Whyte, Claire S., Hadj Ahmed. Mostefai, Kim M. Baeten, Andrew J. Lucking, David E. Newby, Nuala A. Booth, and Nicola J. Mutch. 2021. "Role of Shear Stress and tPA Concentration in the Fibrinolytic Potential of Thrombi" International Journal of Molecular Sciences 22, no. 4: 2115. https://doi.org/10.3390/ijms22042115

APA Style

Whyte, C. S., Mostefai, H. A., Baeten, K. M., Lucking, A. J., Newby, D. E., Booth, N. A., & Mutch, N. J. (2021). Role of Shear Stress and tPA Concentration in the Fibrinolytic Potential of Thrombi. International Journal of Molecular Sciences, 22(4), 2115. https://doi.org/10.3390/ijms22042115

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