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Fibrin Gel Architecture Influences Endogenous Fibrinolysis and May Promote Coronary Artery Disease

2006; Lippincott Williams & Wilkins; Volume: 26; Issue: 11 Linguagem: Inglês

10.1161/01.atv.0000245798.26855.88

1524-4636

Angela Silveira, Anders Hamsten,

Adipokines, Inflammation, and Metabolic Diseases

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 26, No. 11Fibrin Gel Architecture Influences Endogenous Fibrinolysis and May Promote Coronary Artery Disease Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBFibrin Gel Architecture Influences Endogenous Fibrinolysis and May Promote Coronary Artery Disease Angela Silveira and Anders Hamsten Angela SilveiraAngela Silveira From the Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden. Search for more papers by this author and Anders HamstenAnders Hamsten From the Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden. Search for more papers by this author Originally published1 Nov 2006https://doi.org/10.1161/01.ATV.0000245798.26855.88Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2419–2420An altered fibrin network architecture has been associated with premature coronary artery disease (CAD).1,2 Hypofibrinolysis, ie, impaired dissolution of fibrin in blood clots, is another common finding in such patients. Hypofibrinolysis is associated with elevated activity of inhibitors of the fibrinolytic process, particularly of plasminogen activator inhibitor-1 (PAI-1)3 and thrombin activatable fibrinolysis inhibitor (TAFI),4 but it is also influenced by the characteristics of the fibrin network itself.5,6 However, previous studies on fibrin architecture, its regulation, and implications for CAD have been hampered by imperfect and/or incomplete methodology. Thus, the relationships between fibrin structure, fibrinolytic function, and premature CAD warrant further thorough examination. This issue of Arteriosclerosis, Thrombosis, and Vascular Biology features a comprehensive investigation of physical and viscoelastic characteristics of fibrin clots formed ex vivo from plasma samples, their relationships to fibrinolysis rate, and potential role in CAD.7See page 2567Both the morphology and mechanical properties of fibrin influence susceptibility to fibrinolysis. Fibrin structure is generally assessed by using liquid permeation, light scattering, scanning electron microscopy, and confocal microscopy, from which variables such as the fiber thickness, length and density, and the number of branch points and porosity of the network are derived.8 Blunted fibrinolysis is associated with a tight fibrin structure composed of thin and short fibers with increased number of branch points, and small pores.5,6 Individual thick fibers are actually lysed at a slower rate,9 but tight network configurations display a significantly higher fiber density compared with loose structures, which renders them more difficult to be lysed because there are more fibers to be processed6 and increased restriction to the permeation of fibrinolytic factors through the network.The mechanical properties of fibrin can be quantified by determining the response to forces to which fibers are subjected.10 Either static or dynamic measurements can be made, oscillatory motion being an example of the latter. Recording of the oscillations of a torsion pendulum attached to a sample (clot) on careful application of shear forces allows calculations of the storage modulus, which reflects the stiffness or resistance of the clot to deformation.11 In general, clots with increased stiffness are digested more slowly by plasmin than less stiff clots. This was clearly shown in experiments in which the stiffness of the clot and its resistance to fibrinolysis increased in parallel on addition of factor XIII, whereas inhibitors of the factor XIII-catalyzed reactions greatly reduced both clot stiffness and lytic resistance.12 Also, fibrin formed with a recombinant fibrinogen truncated at Aα chain residue 251 was less stiff and digested faster in plasmin-catalyzed experiments than control fibrin formed with recombinant fibrinogen with common Aα chains containing 610 amino acid residues, although the fibrin formed from the truncated fibrinogen was composed of thinner and denser fibers, with more branch points, than the control fibrin.13 Regarding mechanisms, little is known about the relationships between fibrin’s mechanical properties and rate of fibrinolysis.Genetic and environmental factors determining fibrin structure have been extensively studied in recent years (detailed reviews in references 14,15). In brief, fibrin with a tight network conformation is observed under circumstances with increased plasma fibrinogen concentration (genetically determined or raised in association with age, female gender, infection, inflammation, hypertension, diabetes and hyperlipidemia), as well as in the presence of increased thrombin (or prothrombin) concentration. Also, increased availability of modifiers (such as homocysteine or lipoprotein (a)) seems to contribute to a tighter fibrin structure as do certain proteins that cross-link to the fibrin network. In addition, qualitative modifications of the fibrinogen molecules originating from nonsynonymous genetic variation, alternative splicing, posttranslational modifications, and proteolytic degradation have also been observed to influence fibrin morphology. Determinants of the viscoelastic properties of fibrin, on the other hand, have been less studied. However, crosslinking (or ligation) of fibrin seems to be an established important factor.10 First, 5-fold increase in fibrin stiffness was observed when fibrin crosslinking was induced with factor XIII and normalization was achieved when factor XIII was inhibited.12 Second, decreased stiffness was observed in fibrin formed with recombinant fibrinogen truncated at Aα chain residue 251 that is associated with reduced crosslinking by factor XIII, compared with control fibrin.13 And third, fibrin gels formed with the recombinant fibrinogen γ′ variant were 3-fold stiffer than fibrin formed with the common γA variant, most likely because of greater crosslinking.16 The γ′ variant, which arises from alternative processing of the fibrinogen γ chain mRNA, serves as a carrier of factor XIII.The current knowledge of fibrin gel structure (morphology and mechanical properties), its influence on the rate of fibrinolysis, and the overall role of hypofibrinolysis in CAD has been generated through the work of many research groups in the past 40 to 50 years. The article by Dr Collet et al appearing in this issue of ATVB7 ties current concepts nicely together in one single study and provides exciting novel information. The authors studied the morphological and viscoelastic properties of fibrin formed ex vivo from plasma samples of patients with premature CAD by using confocal microscopy and a torsion pendulum, and examined the fibrinolysis rate by continuous monitoring of the viscoelastic properties after addition of tissue plasminogen activator. The fibrin formed from the patient plasmas was observed to be stiffer and composed of thinner and shorter fibers which were arranged in a denser and less porous network that lysed slower compared with fibrin networks formed from control plasmas. The stiffness and length of the fibers, and to a lesser extent the plasma PAI-1 concentration and gender, were found to be independent determinants of the fibrinolysis rate in multivariate statistical analysis. Most remarkable was the observation that fibrin stiffness was the sole independent correlate for premature CAD among a set of variables that included parameters of fibrin morphology and mechanics along with an array of established hemostatic, inflammatory, and metabolic risk indicators. This interesting novel finding suggests that some physical properties of fibrin may have a unique role in CAD and potentially constitute a link between impaired fibrinolytic function and increased risk of CAD. Indeed, a further corollary of this observation is that fibrin structure is likely to be a major regulator of (endogenous) fibrinolysis. In this respect, fibrin stiffness may be considered a sensitive measure of the contribution of many (hemostatic) factors which, by giving strength and resistance to the clot, favor the occurrence of thrombosis. The loose ends left in the work by Dr Collet et al include the identity of the factors that determine fibrin stiffness, which are not even touched on. One would for example have liked to learn more about the potential roles of factor XIII activity and fibrinogen γ′ concentration, including any effects of genetic variants that may, in turn, influence these potentially relevant actors. Needless to say, the relationships of fibrin stiffness to CAD also need to be demonstrated in a prospective study, circumventing the multiple confounders inherent in a small-scale retrospective case-control study.A better knowledge of the determinants of fibrin clot structure and thrombus susceptibility to lysis may have important implications for thrombolytic therapy. If fibrin stiffness proves to be a strong determinant of the fibrinolysis rate and an important risk factor for atherothrombotic diseases in future studies, it should be studied in greater detail to construct a platform from which rational approaches aiming at reducing stiffness and the ensuing lytic resistance of thrombi can be launched.DisclosuresNone.FootnotesCorrespondence to Dr Angela Silveira, PhD, King Gustaf V Research Institute, Karolinska University Hospital Solna, S-171 76 Stockholm, Sweden. E-mail [email protected] References 1 Fatah K, Hamsten A, Blombäck B, Blombäck M. Fibrin gel network characteristics and coronary heart disease: relations to plasma fibrinogen concentration, acute phase protein, serum lipoproteins and coronary atherosclerosis. Thromb Haemost. 1992; 68: 130–135.CrossrefMedlineGoogle Scholar2 Fatah K, Blombäck M, Tornvall P, Moor E, Silveira A, Hamsten A. Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at young age. Thromb Haemost. 1996; 76: 535–540.CrossrefMedlineGoogle Scholar3 Nguyen G, Horellou MH, Kruithof EK, Conard J, Samama MM. Residual plasminogen activator inhibitor activity after venous stasis as a criterion for hypofibrinolysis: a study in 83 patients with confirmed deep vein thrombosis. Blood. 1988; 72: 601–605.CrossrefMedlineGoogle Scholar4 Mosnier LO, von dem Borne PA, Meijers JC, Bouma BN. Plasma TAFI levels influence the clot lysis time in healthy individuals in the presence of an intact intrinsic pathway of coagulation. Thromb Haemost. 1998; 80: 829–835.CrossrefMedlineGoogle Scholar5 Carr ME Jr, Alving BM. Effect of fibrin structure on plasmin-mediated dissolution of plasma clots. Blood Coagul Fibrinolysis. 1995; 6: 567–573.CrossrefMedlineGoogle Scholar6 Collet JP, Park D, Lesty C, Soria J, Soria C, Montalescot G, Weisel JW. Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed: dynamic and structural approaches by confocal microscopy. Arterioscler Thromb Vasc Biol. 2000; 20: 1354–1361.CrossrefMedlineGoogle Scholar7 Collet JP, Allali Y, Lesty C, Tanguy ML, Silvain J, Ankri A, Blanchet B, Dumaine R, Gianetti J, Payot L, Weisel JW, Montalescot G. Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis. Arterioscler Thromb Vasc Biol. 2006; 26: 2567–2573.LinkGoogle Scholar8 Blombäck B, Carlsson K, Hessel B, Liljeborg A, Procyk R, Åslund N. Native fibrin gel networks observed by 3D microscopy, permeation and turbidity. Biochim Biophys Acta. 1989; 997: 96–110.CrossrefMedlineGoogle Scholar9 Collet JP, Shuman H, Ledger RE, Lee S, Weisel JW. The elasticity of an individual fibrin fiber in a clot. Proc Natl Acad Sci USA. 2005; 102: 9133–9137.CrossrefMedlineGoogle Scholar10 Weisel JW. The mechanical properties of fibrin for basic scientists and clinicians. Biophys Chem. 2004; 112: 267–276.CrossrefMedlineGoogle Scholar11 Janmey PA. A torsion pendulum for measurement of the viscoelasticity of biopolymers and its application to actin networks. J Biochem Biophys Methods. 1991; 22: 41–53.CrossrefMedlineGoogle Scholar12 Lorand L. Factor XIII and the clotting of fibrinogen: from basic research to medicine. J Thromb Haemost. 2005; 3: 1337–1348.CrossrefMedlineGoogle Scholar13 Collet JP, Moen JL, Veklich YI, Gorkun OV, Lord ST, Montalescot G, Weisel JW. The αC domains of fibrinogen affect the structure of the fibrin clot, its physical properties, and its susceptibility to fibrinolysis. Blood. 2005; 106: 3824–3830.CrossrefMedlineGoogle Scholar14 Scott EM, Ariens RA, Grant PJ. Genetic and environmental determinants of fibrin structure and function: relevance to clinical disease. Arterioscler Thromb Vasc Biol. 2004; 24: 1558–1566.LinkGoogle Scholar15 Standeven KF, Ariens RAS, Grant PJ. The molecular physiology and pathology of fibrin structure/function. Blood Rev. 2005; 19: 275–288.CrossrefMedlineGoogle Scholar16 Collet JP, Nagaswami C, Farrell DH, Montalescot G, Weisel JW. Influence of γ’ fibrinogen splice variant on fibrin physical properties and fibrinolysis rate. Arterioscler Thromb Vasc Biol. 2004; 24: 382–386.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Whelan C, Burnley-Hall N, Morris K, Rees D and James P (2022) The procoagulant effects of extracellular vesicles derived from hypoxic endothelial cells can be selectively inhibited by inorganic nitrite, Nitric Oxide, 10.1016/j.niox.2022.02.002, 122-123, (6-18), Online publication date: 1-May-2022. 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Kotlarchyk M, Shreim S, Alvarez-Elizondo M, Estrada L, Singh R, Valdevit L, Kniazeva E, Gratton E, Putnam A, Botvinick E and Egles C (2011) Concentration Independent Modulation of Local Micromechanics in a Fibrin Gel, PLoS ONE, 10.1371/journal.pone.0020201, 6:5, (e20201) November 2006Vol 26, Issue 11 Advertisement Article InformationMetrics https://doi.org/10.1161/01.ATV.0000245798.26855.88PMID: 17053173 Originally publishedNovember 1, 2006 PDF download Advertisement