Semin Thromb Hemost 2021; 47(07): 775-786
DOI: 10.1055/s-0041-1729963
Review Article

Fibrin Network Porosity and Endo-/Exogenous Thrombin Cross-talk

Shu He
1   Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
2   Division of Coagulation Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
,
Håkan Wallén
1   Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
,
Charlotte Thålin
1   Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
,
Jan Svensson
1   Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
,
Margareta Blombäck
1   Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
2   Division of Coagulation Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
› Author Affiliations
Funding This study is supported by the Clas Groschinsky Memorial fund (org. nr. 802004-0195).

Abstract

The earliest assessment of fibrin network porosity used a liquid permeation system and confocal 3D microscopy, which was later replaced by scanning electron microscopy. Although the methods have extensively been applied in studies of health or disease, there remains debate on the choice of a proper clotting trigger. In this review, we assess published data and convey our opinions with regard to several issues. First, when the coagulation process is initiated by recombinant tissue factor (rTF) and phospholipids, the fibrin network porosity is regulated by the endogenous thrombin based on enzymatic activations of multiple coagulants. If purified thrombin (1.0 IU/mL) is employed as the clotting trigger, fibrin network porosity may be affected by exogenous thrombin, which directly polymerizes fibrinogen in plasma, and additionally by endogenous thrombin stemming from a “positive feedback loop” action of the added thrombin. Second, with use of either endogenous or exogenous thrombin, the concentration and clotting property of available fibrinogen both influence the fibrin network porosity. Third, in the assay systems in vitro, exogenous thrombin but not rTF-induced endogenous thrombin seems to be functional enough to activate factor XIII, which then contributes to a decrease in the fibrin network porosity. Fourth, fibrin network porosity determines the transport of fibrinolytic components into/through the clots and therefore serves as an indicator of the fibrinolysis potential in plasma.

Note

This review is dedicated to the memory of Professor Birger Blombäck (1926–2008) who was the first to set up the methods of determining fibrin network porosity.




Publication History

Article published online:
12 July 2021

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 
  • References

  • 1 Blombäck B, Bark N. Fibrinopeptides and fibrin gel structure. Biophys Chem 2004; 112 (2-3): 147-151
  • 2 Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost 2005; 3 (08) 1894-1904
  • 3 Blombäck B, Hessel B, Hogg D, Therkildsen L. A two-step fibrinogen: fibrin transition in blood coagulation. Nature 1978; 275 (5680): 501-505
  • 4 Fowler WE, Hantgan RR, Hermans J, Erickson HP. Structure of the fibrin protofibril. Proc Natl Acad Sci U S A 1981; 78 (08) 4872-4876
  • 5 Mosesson MW, Siebenlist KR, Amrani DL, DiOrio JP. Identification of covalently linked trimeric and tetrameric D domains in crosslinked fibrin. Proc Natl Acad Sci U S A 1989; 86 (04) 1113-1117
  • 6 Mosesson MW, Siebenlist KR, Hainfeld JF, Wall JS. The covalent structure of factor XIIIa crosslinked fibrinogen fibrils. J Struct Biol 1995; 115 (01) 88-101
  • 7 Byrnes JR, Wolberg AS. Newly-recognized roles of factor XIII in thrombosis. Semin Thromb Hemost 2016; 42 (04) 445-454
  • 8 Mosesson MW, DiOrio JP, Siebenlist KR, Wall JS, Hainfeld JF. Evidence for a second type of fibril branch point in fibrin polymer networks, the trimolecular junction. Blood 1993; 82 (05) 1517-1521
  • 9 Yakovlev S, Makogonenko E, Kurochkina N, Nieuwenhuizen W, Ingham K, Medved L. Conversion of fibrinogen to fibrin: mechanism of exposure of tPA- and plasminogen-binding sites. Biochemistry 2000; 39 (51) 15730-15741
  • 10 Collet JP, Lesty C, Montalescot G, Weisel JW. Dynamic changes of fibrin architecture during fibrin formation and intrinsic fibrinolysis of fibrin-rich clots. J Biol Chem 2003; 278 (24) 21331-21335
  • 11 Bok RA, Mangel WF. Quantitative characterization of the binding of plasminogen to intact fibrin clots, lysine-sepharose, and fibrin cleaved by plasmin. Biochemistry 1985; 24 (13) 3279-3286
  • 12 Tsurupa G, Medved L. Identification and characterization of novel tPA- and plasminogen-binding sites within fibrin(ogen) alpha C-domains. Biochemistry 2001; 40 (03) 801-808
  • 13 Nordenhem A, Leander K, Hallqvist J, de Faire U, Sten-Linder M, Wiman B. The complex between tPA and PAI-1: risk factor for myocardial infarction as studied in the SHEEP project. Thromb Res 2005; 116 (03) 223-232
  • 14 Sakata Y, Aoki N. Significance of cross-linking of alpha 2-plasmin inhibitor to fibrin in inhibition of fibrinolysis and in hemostasis. J Clin Invest 1982; 69 (03) 536-542
  • 15 Hevessy Z, Haramura G, Boda Z, Udvardy M, Muszbek L. Promotion of the crosslinking of fibrin and alpha 2-antiplasmin by platelets. Thromb Haemost 1996; 75 (01) 161-167
  • 16 Blombäck B, Okada M. Fibrin gel structure and clotting time. Thromb Res 1982; 25 (1-2): 51-70
  • 17 Blombäck B, Okada M. On pores in fibrin gels. Thromb Res 1982; 26 (02) 141-142
  • 18 Blombäck B, Carlsson K, Hessel B, Liljeborg A, Procyk R, Aslund N. Native fibrin gel networks observed by 3D microscopy, permeation and turbidity. Biochim Biophys Acta 1989; 997 (1-2): 96-110
  • 19 Blombäck B, Banerjee D, Carlsson K. et al. Native fibrin gel networks and factors influencing their formation in health and disease. Adv Exp Med Biol 1990; 281: 1-23
  • 20 Blombäck B, Carlsson K, Fatah K, Hessel B, Procyk R. Fibrin in human plasma: gel architectures governed by rate and nature of fibrinogen activation. Thromb Res 1994; 75 (05) 521-538
  • 21 Pieters M, Wolberg AS. Fibrinogen and fibrin: an illustrated review. Res Pract Thromb Haemost 2019; 3 (02) 161-172
  • 22 He S, Cao H, Antovic A, Blombäck M. Modifications of flow measurement to determine fibrin gel permeability and the preliminary use in research and clinical materials. Blood Coagul Fibrinolysis 2005; 16 (01) 61-67
  • 23 Ząbczyk M, Blombäck M, Majewski J. et al. Assays of fibrin network properties altered by VKAs in atrial fibrillation: importance of using an appropriate coagulation trigger. Thromb Haemost 2015; 113 (04) 851-861
  • 24 Varin R, Mirshahi S, Mirshahi P. et al. Whole blood clots are more resistant to lysis than plasma clots: greater efficacy of rivaroxaban. Thromb Res 2013; 131 (03) e100-e109
  • 25 Pieters M, Undas A, Marchi R, De Maat MPM, Weisel J, Ariëns RAS. Factor XIII And Fibrinogen Subcommittee Of The Scientific Standardisation Committee Of The International Society For Thrombosis And Haemostasis. An international study on the standardization of fibrin clot permeability measurement: methodological considerations and implications for healthy control values. J Thromb Haemost 2012; 10 (10) 2179-2181
  • 26 Ząbczyk M, Undas A. Plasma fibrin clot structure and thromboembolism: clinical implications. Pol Arch Intern Med 2017; 127 (12) 873-881
  • 27 Undas A, Zabczyk M. Antithrombotic medications and their impact on fibrin clot structure and function. J Physiol Pharmacol 2018; 69 (04) 1-8
  • 28 Undas A, Zawilska K, Ciesla-Dul M. et al. Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives. Blood 2009; 114 (19) 4272-4278
  • 29 He S, Blombäck M, Jacobsson Ekman G, Hedner U. The role of recombinant factor VIIa (FVIIa) in fibrin structure in the absence of FVIII/FIX. J Thromb Haemost 2003; 1 (06) 1215-1219
  • 30 He S, Ekman GJ, Hedner U. The effect of platelets on fibrin gel structure formed in the presence of recombinant factor VIIa in hemophilia plasma and in plasma from a patient with Glanzmann thrombasthenia. J Thromb Haemost 2005; 3 (02) 272-279
  • 31 Antovic A, Mikovic D, Elezovic I, Zabczyk M, Hutenby K, Antovic JP. Improvement of fibrin clot structure after factor VIII injection in haemophilia A patients treated on demand. Thromb Haemost 2014; 111 (04) 656-661
  • 32 Tehrani S, Jörneskog G, Ågren A, Lins PE, Wallén H, Antovic A. Fibrin clot properties and haemostatic function in men and women with type 1 diabetes. Thromb Haemost 2015; 113 (02) 312-318
  • 33 Jörneskog G, Egberg N, Fagrell B. et al. Altered properties of the fibrin gel structure in patients with IDDM. Diabetologia 1996; 39 (12) 1519-1523
  • 34 Fatah K, Silveira A, Tornvall P, Karpe F, Blombäck M, Hamsten A. Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at a young age. Thromb Haemost 1996; 76 (04) 535-540
  • 35 van Rooy MJ, Duim W, Ehlers R, Buys AV, Pretorius E. Platelet hyperactivity and fibrin clot structure in transient ischemic attack individuals in the presence of metabolic syndrome: a microscopy and thromboelastography study. Cardiovasc Diabetol 2015; 14: 86-98
  • 36 Dey S. A new rapid air-drying technique for scanning electron microscopy using tetramethylsilane: application to mammalian tissue. Cytobios 1993; 73 (292) 17-23
  • 37 Hemker HC, Giesen P, Al Dieri R. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33 (01) 4-15
  • 38 Castoldi E, Rosing J. Thrombin generation tests. Thromb Res 2011; 127 (Suppl. 03) S21-S25
  • 39 Butenas S, Mann KG. Blood coagulation. Biochemistry (Mosc) 2002; 67 (01) 3-12
  • 40 Smith SA, Travers RJ, Morrissey JH. How it all starts: initiation of the clotting cascade. Crit Rev Biochem Mol Biol 2015; 50 (04) 326-336
  • 41 He S, Cao H, Thålin C, Svensson J, Blombäck M, Wallén H. The clotting trigger is an important determinant for the coagulation pathway in vivo or in vitro: inference from data review. Semin Thromb Hemost 2021; 47 (01) 63-73
  • 42 He S, Blombäck M, Bark N, Johnsson H, Wallén NH. The direct thrombin inhibitors (argatroban, bivalirudin and lepirudin) and the indirect Xa-inhibitor (danaparoid) increase fibrin network porosity and thus facilitate fibrinolysis. Thromb Haemost 2010; 103 (05) 1076-1084
  • 43 Blombäck M, He S, Bark N, Wallén HN, Elg M. Effects on fibrin network porosity of anticoagulants with different modes of action and reversal by activated coagulation factor concentrate. Br J Haematol 2011; 152 (06) 758-765
  • 44 He S, Johnsson H, Zabczyk M, Hultenby K, Cao H, Blombäck M. A fibrinogen concentrate Haemocomplettan (Riastap) or a Factor XIII concentrate Fibrogammin combined with a mini dose of tranexamic acid can reverse the fibrin instability to fibrinolysis induced by thrombin- or FXa-inhibitor. Br J Haematol 2013; 160 (06) 806-816
  • 45 Janion-Sadowska A, Natorska J, Siudut J, Ząbczyk M, Stanisz A, Undas A. Plasma fibrin clot properties in the G20210A prothrombin mutation carriers following venous thromboembolism: the effect of rivaroxaban. Thromb Haemost 2017; 117 (09) 1739-1749
  • 46 Ząbczyk M, Natorska J, Malinowski KP, Undas A. Effect of enoxaparin on plasma fibrin clot properties and fibrin structure in patients with acute pulmonary embolism. Vascul Pharmacol 2020; 133–134: 106783
  • 47 Frączek P, Krzysztofik M, Stanisz A, Undas A. Clinical outcomes and plasma clot permeability and lysability in patients with venous thromboembolism on rivaroxaban: a cohort study. Pol Arch Intern Med 2019; 129 (06) 377-385
  • 48 Kopytek M, Zabczyk M, Natorska J, Malinowski KP, Undas A. Effects of direct oral anticoagulants on thromboelastographic parameters and fibrin clot properties in patients with venous thromboembolism. J Physiol Pharmacol 2020; 71 (01) 48-53
  • 49 Cervera R, Piette JC, Font J. et al; Euro-Phospholipid Project Group. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46 (04) 1019-1027
  • 50 Ząbczyk M, Celińska-Löwenhoff M, Plens K, Iwaniec T, Musiał J, Undas A. Antiphosphatidylserine/prothrombin complex antibodies as a determinant of prothrombotic plasma fibrin clot properties in patients with antiphospholipid syndrome. J Thromb Haemost 2019; 17 (10) 1746-1755
  • 51 Celinska-Löwenhoff M, Zabczyk M, Iwaniec T, Plens K, Musial J, Undas A. Reduced plasma fibrin clot permeability is associated with recurrent thromboembolic events in patients with antiphospholipid syndrome. Rheumatology (Oxford) 2018; 57 (08) 1340-1349
  • 52 Vikerfors A, Svenungsson E, Ågren A. et al. Studies of fibrin formation and fibrinolytic function in patients with the antiphospholipid syndrome. Thromb Res 2014; 133 (05) 936-944
  • 53 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 (02) 130-135
  • 54 Rooth E, Wallen NH, Blombäck M, He S. Decreased fibrin network permeability and impaired fibrinolysis in the acute and convalescent phase of ischemic stroke. Thromb Res 2011; 127 (01) 51-56
  • 55 He S, Johnsson H, Zabczyk M, Hultenby K, Wallén H, Blombäck M. Fibrinogen depletion after plasma-dilution: impairment of proteolytic resistance and reversal via clotting factor concentrates. Thromb Haemost 2014; 111 (03) 417-428
  • 56 Antovic A, Perneby C, Ekman GJ. et al. Marked increase of fibrin gel permeability with very low dose ASA treatment. Thromb Res 2005; 116 (06) 509-517
  • 57 He S, Bark N, Wang H, Svensson J, Blombäck M. Effects of acetylsalicylic acid on increase of fibrin network porosity and the consequent upregulation of fibrinolysis. J Cardiovasc Pharmacol 2009; 53 (01) 24-29
  • 58 Svensson J, Bergman AC, Adamson U, Blombäck M, Wallén H, Jörneskog G. Acetylation and glycation of fibrinogen in vitro occur at specific lysine residues in a concentration dependent manner: a mass spectrometric and isotope labeling study. Biochem Biophys Res Commun 2012; 421 (02) 335-342
  • 59 Hugenholtz GCG, Macrae F, Adelmeijer J. et al. Procoagulant changes in fibrin clot structure in patients with cirrhosis are associated with oxidative modifications of fibrinogen. J Thromb Haemost 2016; 14 (05) 1054-1066
  • 60 Pieters M, Covic N, van der Westhuizen FH. et al. Glycaemic control improves fibrin network characteristics in type 2 diabetes: a purified fibrinogen model. Thromb Haemost 2008; 99 (04) 691-700
  • 61 Greenhalgh KA, Strachan MW, Alzahrani S. et al. BβArg448Lys polymorphism is associated with altered fibrin clot structure and fibrinolysis in type 2 diabetes. Thromb Haemost 2017; 117 (02) 295-302
  • 62 Collet JP, Soria J, Mirshahi M. et al. Dusart syndrome: a new concept of the relationship between fibrin clot architecture and fibrin clot degradability: hypofibrinolysis related to an abnormal clot structure. Blood 1993; 82 (08) 2462-2469
  • 63 Casini A, Duval C, Pan X, Tintillier V, Biron-Andreani C, Ariëns RAS. Fibrin clot structure in patients with congenital dysfibrinogenaemia. Thromb Res 2016; 137: 189-195
  • 64 Ariëns RA, Philippou H, Nagaswami C, Weisel JW, Lane DA, Grant PJ. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood 2000; 96 (03) 988-995
  • 65 Longstaff C, Thelwell C, Williams SC, Silva MM, Szabó L, Kolev K. The interplay between tissue plasminogen activator domains and fibrin structures in the regulation of fibrinolysis: kinetic and microscopic studies. Blood 2011; 117 (02) 661-668
  • 66 Tutwiler V, Peshkova AD, Le Minh G. et al. Blood clot contraction differentially modulates internal and external fibrinolysis. J Thromb Haemost 2019; 17 (02) 361-370
  • 67 Collet JP, Park D, Lesty C. et al. 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 (05) 1354-1361
  • 68 Ajjan RA, Standeven KF, Khanbhai M. et al. Effects of aspirin on clot structure and fibrinolysis using a novel in vitro cellular system. Arterioscler Thromb Vasc Biol 2009; 29 (05) 712-717