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

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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.

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          Real-time in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse.

          Glenn Merrill-Skoloff, Bruce Furie, Peter Gross … (2002)
          We have used confocal and widefield microscopy to image thrombus formation in real time in the microcirculation of a living mouse. This system provides high-speed, near-simultaneous acquisition of images of multiple fluorescent probes and of a brightfield channel. Vascular injury is induced with a laser focused through the microscope optics. We observed platelet deposition, tissue factor accumulation and fibrin generation after laser-induced endothelial injury in a single developing thrombus. The initiation of blood coagulation in vivo entailed the initial accumulation of tissue factor on the upstream and thrombus-vessel wall interface of the developing thrombus. Subsequently tissue factor was associated with the interior of the thrombus. Tissue factor was biologically active, and was associated with fibrin generation within the thrombus.
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            Multiscale mechanics of fibrin polymer: gel stretching with protein unfolding and loss of water.

            André Brown, Dennis E. Discher, Nupur K. Purohit … (2009)
            Blood clots and thrombi consist primarily of a mesh of branched fibers made of the protein fibrin. We propose a molecular basis for the marked extensibility and negative compressibility of fibrin gels based on the structural and mechanical properties of clots at the network, fiber, and molecular levels. The force required to stretch a clot initially rises linearly and is accompanied by a dramatic decrease in clot volume and a peak in compressibility. These macroscopic transitions are accompanied by fiber alignment and bundling after forced protein unfolding. Constitutive models are developed to integrate observations at spatial scales that span six orders of magnitude and indicate that gel extensibility and expulsion of water are both manifestations of protein unfolding, which is not apparent in other matrix proteins such as collagen.
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              Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed: dynamic and structural approaches by confocal microscopy.

              J P Collet, D. Park, C. Lesty … (2000)
              Abnormal fibrin architecture is thought to be a determinant factor of hypofibrinolysis. However, because of the lack of structural knowledge of the process of fibrin digestion, relationships between fibrin architecture and hypofibrinolysis remain controversial. To elucidate further structural and dynamic changes occurring during fibrinolysis, cross-linked plasma fibrin was labeled with colloidal gold particles, and fibrinolysis was followed by confocal microscopy. Morphological changes were characterized at fibrin network and fiber levels. The observation of a progressive disaggregation of the fibrin fibers emphasizes that fibrinolysis proceeds by transverse cutting rather than by progressive cleavage uniformly around the fiber. Plasma fibrin clots with a tight fibrin conformation made of thin fibers were dissolved at a slower rate than those with a loose fibrin conformation made of thicker (coarse) fibers, although the overall fibrin content remained constant. Unexpectedly, thin fibers were cleaved at a faster rate than thick ones. A dynamic study of FITC-recombinant tissue plasminogen activator distribution within the fibrin matrix during the course of fibrinolysis showed that the binding front was broader in coarse fibrin clots and moved more rapidly than that of fine plasma fibrin clots. These dynamic and structural approaches to fibrin digestion at the network and the fiber levels reveal aspects of the physical process of clot lysis. Furthermore, these results provide a clear explanation for the hypofibrinolysis related to a defective fibrin architecture as described in venous thromboembolism and in premature coronary artery disease.
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                Author and article information

                Contributors
                Beate Heissig: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 20 February 2021
                Publication date Collection: February 2021
                Volume: 22
                Issue: 4
                Electronic Location Identifier: 2115
                Affiliations
                [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; c.s.whyte@ 123456abdn.ac.uk (C.S.W.); mostefaih@ 123456yahoo.fr (H.A.M.); kimbaeten1@ 123456gmail.com (K.M.B.); n.a.booth@ 123456abdn.ac.uk (N.A.B.)
                [2 ]Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4SB, Scotland, UK; Andrew.Lucking@ 123456ouh.nhs.uk (A.J.L.); D.E.Newby@ 123456ed.ac.uk (D.E.N.)
                Author notes
                [* ]Correspondence: n.j.mutch@ 123456abdn.ac.uk ; Tel.: +44-1224-437492
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-8127-6102
                https://orcid.org/0000-0001-7745-3882
                Article
                Publisher ID: ijms-22-02115
                DOI: 10.3390/ijms22042115
                PMC ID: 7924342
                PubMed ID: 33672724
                SO-VID: 7b91ab0f-e197-4f6a-bc7b-dc9937f07b5c
                Copyright © © 2021 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 01 February 2021
                Date accepted : 13 February 2021
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: plasminogen activator inhibitor-1,fibrinolysis,tissue plasminogen activator,thrombi,shear
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: plasminogen activator inhibitor-1, fibrinolysis, tissue plasminogen activator, thrombi, shear

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