RSS-Feed abonnieren
DOI: 10.1160/TH14-01-0085
Fibrinogen and factor XIII at the intersection of coagulation, fibrinolysis and inflammation
Publikationsverlauf
Received:
27. Januar 2014
Accepted after major revision:
09. Juli 2014
Publikationsdatum:
20. November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201404/lookinside/thumbnails/10-1160-th14-01-0085-1.jpg)
Summary
Fibrinogen and factor XIII are two essential proteins that are involved directly in fibrin gel formation as the final step of a sequence of reactions triggered by a procoagulant stimulus. Haemostasis is the most obvious function of the resulting fibrin clot. Different variables affect the conversion of fibrinogen to fibrin as well as the mode of fibrin polymerisation and fibrin crosslinking, hereby, critically influencing the architecture of the resulting fibrin network and consequently determining its mechanical strength and resistance against fibrinolysis. Due to fibrinogen’s structure with a multitude of domains and binding motifs the fibrin gel allows for complex interactions with other coagulation factors, with profibrinolytic as well as antifibrinolyic proteins, with complement factors and with various cellular receptors. These interactions enable the fibrin network to control its own further state (i. e. expansion or degradation), to influence innate immunity, and to function as a scaffold for cell migration processes. During the whole process of fibrin gel formation biologically active peptides and protein fragments are released that additionally influence cellular processes via chemotaxis or by modulating cell-cell interactions. Thus, it is not surprising that fibrinogen and factor XIII in addition to their haemostatic function influence innate immunity as well as cell-mediated reactions like wound healing, response to tissue injury or inflammatory processes. The present review summarises current knowledge of fibrinogen’s and factor XIII’s function in coagulation and fibrinolysis giving special emphasis on their relation to inflammation control.
-
References
- 1 Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost 2005; 3: 1894-1904.
- 2 Hoppe B, Dorner T. Coagulation and the fibrin network in rheumatic disease: a role beyond haemostasis. Nat Rev Rheumatol 2012; 8: 738-746.
- 3 Ichinose A. Factor XIII is a key molecule at the intersection of coagulation and fibrinolysis as well as inflammation and infection control. Int J Hematol 2012; 95: 362-370.
- 4 Muszbek L. et al. Factor XIII: a coagulation factor with multiple plasmatic and cellular functions. Physiol Rev 2011; 91: 931-972.
- 5 Weisel JW. Fibrinogen and fibrin. Adv Protein Chem 2005; 70: 247-299.
- 6 Cooper AV. et al. Fibrinogen gamma-chain splice variant gamma’ alters fibrin formation and structure. Blood 2003; 102: 535-540.
- 7 Jennewein C. et al. Novel aspects of fibrin(ogen) fragments during inflammation. Mol Med 2011; 17: 568-573.
- 8 Mosesson MW. et al. The structure and biological features of fibrinogen and fibrin. Ann NY Acad Sci 2001; 936: 11-30.
- 9 Bach TL. et al. Endothelial cell VE-cadherin functions as a receptor for the beta15-42 sequence of fibrin. J Biol Chem 1998; 273: 30719-30728.
- 10 Petzelbauer P. et al. The fibrin-derived peptide Bbeta15-42 protects the myocardium against ischemia-reperfusion injury. Nat Med 2005; 11: 298-304.
- 11 Skogen WF. et al. Fibrinogen-derived peptide B beta 1-42 is a multidomained neutrophil chemoattractant. Blood 1988; 71: 1475-1479.
- 12 Yakovlev S. et al. Interaction of fibrin with VE-cadherin and anti-inflammatory effect of fibrin-derived fragments. J Thromb Haemost 2011; 9: 1847-1855.
- 13 Groger M. et al. Peptide Bbeta(15-42) preserves endothelial barrier function in shock. PLoS One 2009; 4: e5391.
- 14 Ugarova TP, Yakubenko VP. Recognition of fibrinogen by leukocyte integrins. Ann NY Acad Sci 2001; 936: 368-385.
- 15 Yakovlev S. et al. Interaction of fibrin(ogen) with leukocyte receptor alpha M beta 2 (Mac-1): further characterization and identification of a novel binding region within the central domain of the fibrinogen gamma-module. Biochemistry 2005; 44: 617-626.
- 16 Loike JD. et al. CD11c/CD18 on neutrophils recognizes a domain at the N terminus of the A alpha chain of fibrinogen. Proc Natl Acad Sci USA 1991; 88: 1044-1048.
- 17 Ugarova TP. et al. Conformational changes in fibrinogen elicited by its interaction with platelet membrane glycoprotein GPIIb-IIIa. J Biol Chem 1993; 268: 21080-21087.
- 18 Fish RJ, Neerman-Arbez M. Fibrinogen gene regulation. Thromb Haemost 2012; 108: 419-426.
- 19 Jacquemin B. et al. Common genetic polymorphisms and haplotypes of fibrinogen alpha, beta, and gamma chains affect fibrinogen levels and the response to proinflammatory stimulation in myocardial infarction survivors: the AIR-GENE study. J Am Coll Cardiol 2008; 52: 941-952.
- 20 Danik JS. et al. Novel loci, including those related to Crohn disease, psoriasis, and inflammation, identified in a genome-wide association study of fibrinogen in 17 686 women: the Women’s Genome Health Study. Circ Cardiovasc Genet 2009; 2: 134-141.
- 21 Dehghan A. et al. Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. Circ Cardiovasc Genet 2009; 2: 125-133.
- 22 Reiner AP, Carty CL, Carlson CS. et al. Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study. J Thromb Haemost 2006; 4: 1279-1287.
- 23 Siegerink B. et al. Genetic variation in fibrinogen; its relationship to fibrinogen levels and the risk of myocardial infarction and ischemic stroke. J Thromb Haemost 2009; 7: 385-390.
- 24 Brull DJ. et al. The effect of fibrinogen genotype on fibrinogen levels after strenuous physical exercise. Thromb Haemost 2002; 87: 37-41.
- 25 Peters A. et al. Fibrinogen genes modify the fibrinogen response to ambient particulate matter. Am J Respir Crit Care Med 2009; 179: 484-491.
- 26 Ariens RA. et al. Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms. Blood 2002; 100: 743-754.
- 27 Ariens RA. et al. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood 2000; 96: 988-995.
- 28 Balogh I. et al. Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia. Blood 2000; 96: 2479-2486.
- 29 Wartiovaara U. et al. Effect of Val34Leu polymorphism on the activation of the coagulation factor XIII-A. Thromb Haemost 2000; 84: 595-600.
- 30 Schroder V, Kohler HP. Effect of factor XIII Val34Leu on alpha2-antiplasmin incorporation into fibrin. Thromb Haemost 2000; 84: 1128-1130.
- 31 Luscher EF. Fibrin-stabilising factor from thrombocytes. Schweiz Med Wochenschr 1957; 87: 1220-1221.
- 32 Muszbek L. et al. Factor XIII of blood coagulation in human monocytes. Thromb Res 1985; 37: 401-410.
- 33 Rex S. et al. Immune versus thrombotic stimulation of platelets differentially regulates signalling pathways, intracellular protein-protein interactions, and alpha-granule release. Thromb Haemost 2009; 102: 97-110.
- 34 Amara U. et al. Molecular intercommunication between the complement and coagulation systems. J Immunol 2010; 185: 5628-5636.
- 35 Okamoto M. et al. Factor XIII-dependent generation of 5th complement component(C5)-derived monocyte chemotactic factor coinciding with plasma clotting. Biochim Biophys Acta 1992; 1138: 53-61.
- 36 Endo Y. et al. Interactions of ficolin and mannose-binding lectin with fibrinogen/fibrin augment the lectin complement pathway. J Innate Immun 2010; 2: 33-42.
- 37 Ricklin D. et al. Complement: a key system for immune surveillance and homeostasis. Nat Immunol 2010; 11: 785-797.
- 38 Nikolajsen CL. et al. Human complement C3 is a substrate for transglutaminases. A functional link between non-protease-based members of the coagulation and complement cascades. Biochemistry 2012; 51: 4735-4742.
- 39 Richardson VR. et al. Complement C3 is a substrate for activated factor XIII that is cross-linked to fibrin during clot formation. Br J Haematol 2013; 160: 116-119.
- 40 Entwistle RA, Furcht LT. C1q component of complement binds to fibrinogen and fibrin. Biochemistry 1988; 27: 507-512.
- 41 Dobo J. et al. MASP-1, a promiscuous complement protease: structure of its catalytic region reveals the basis of its broad specificity. J Immunol 2009; 183: 1207-1214.
- 42 Hajela K. et al. The biological functions of MBL-associated serine proteases (MASPs). Immunobiology 2002; 205: 467-475.
- 43 Krarup A. et al. The action of MBL-associated serine protease 1 (MASP1) on factor XIII and fibrinogen. Biochim Biophys Acta 2008; 1784: 1294-1300.
- 44 Hess K. et al. Effects of MASP-1 of the complement system on activation of coagulation factors and plasma clot formation. PLoS One 2012; 7: e35690.
- 45 Lim BC. et al. Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk. Lancet 2003; 361: 1424-1431.
- 46 Medved L, Nieuwenhuizen W. Molecular mechanisms of initiation of fibrinolysis by fibrin. Thromb Haemost 2003; 89: 409-419.
- 47 Doolittle RF. Fibrinogen and fibrin. Annu Rev Biochem 1984; 53: 195-229.
- 48 Kolev K, Machovich R. Molecular and cellular modulation of fibrinolysis. Thromb Haemost 2003; 89: 610-621.
- 49 Collet JP. 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: 1354-1361.
- 50 Lanir N. et al. Macrophage migration in fibrin gel matrices. II. Effects of clotting factor XIII, fibronectin, and glycosaminoglycan content on cell migration. J Immunol 1988; 140: 2340-2349.
- 51 Belkin AM. et al. Transglutaminase-mediated oligomerization of the fibrin(ogen) alphaC domains promotes integrin-dependent cell adhesion and signaling. Blood 2005; 105: 3561-3568.
- 52 Forsyth CB. et al. Integrin alpha(M)beta(2)-mediated cell migration to fibrinogen and its recognition peptides. J Exp Med 2001; 193: 1123-1133.
- 53 Liu X, Piela-Smith TH. Fibrin(ogen)-induced expression of ICAM-1 and chemokines in human synovial fibroblasts. J Immunol 2000; 165: 5255-5261.
- 54 Altieri DC. Regulation of leukocyte-endothelium interaction by fibrinogen. Thromb Haemost 1999; 82: 781-786.
- 55 Richardson DL. et al. Chemotaxis for human monocytes by fibrinogen-derived peptides. Br J Haematol 1976; 32: 507-513.
- 56 Senior RM. et al. Effects of fibrinogen derivatives upon the inflammatory response. Studies with human fibrinopeptide B. J Clin Invest 1986; 77: 1014-1019.
- 57 Persson K. et al. The conversion of fibrinogen to fibrin at the surface of curliated Escherichia coli bacteria leads to the generation of proinflammatory fibrinopep-tides. J Biol Chem 2003; 278: 31884-31890.
- 58 Robson SC. et al. Fibrin degradation product D-dimer induces the synthesis and release of biologically active IL-1 beta, IL-6 and plasminogen activator inhibitors from monocytes in vitro. Br J Haematol 1994; 86: 322-326.
- 59 Smiley ST. et al. Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4. J Immunol 2001; 167: 2887-2894.
- 60 Szaba FM, Smiley ST. Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo. Blood 2002; 99: 1053-1059.
- 61 Fan ST, Edgington TS. Integrin regulation of leukocyte inflammatory functions. CD11b/CD18 enhancement of the tumor necrosis factor-alpha responses of monocytes. J Immunol 1993; 150: 2972-2980.
- 62 Jensen T. et al. Fibrinogen and fibrin induce synthesis of proinflammatory cytokines from isolated peripheral blood mononuclear cells. Thromb Haemost 2007; 97: 822-829.
- 63 Perez RL, Roman J. Fibrin enhances the expression of IL-1 beta by human peripheral blood mononuclear cells. Implications in pulmonary inflammation. J Immunol 1995; 154: 1879-1887.
- 64 Qi J. et al. Fibrin regulation of interleukin-8 gene expression in human vascular endothelial cells. Blood 1997; 90: 3595-3602.
- 65 Lishko VK. et al. Regulated unmasking of the cryptic binding site for integrin alpha M beta 2 in the gamma C-domain of fibrinogen. Biochemistry 2002; 41: 12942-12951.
- 66 Loike JD. et al. The role of protected extracellular compartments in interactions between leukocytes, and platelets, and fibrin/fibrinogen matrices. Ann NY Acad Sci 1992; 667: 163-172.
- 67 Flick MJ. et al. Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2/Mac-1 is critical for host inflammatory response in vivo. J Clin Invest 2004; 113: 1596-1606.
- 68 Sanchez-Pernaute O. et al. A fibrin based model for rheumatoid synovitis. Ann Rheum Dis 2003; 62: 1135-1138.
- 69 Flick MJ. et al. Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin alphaMbeta2 binding motif. J Clin Invest 2007; 117: 3224-3235.
- 70 Loof TG. et al. Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense. Blood 2011; 118: 2589-2598.
- 71 Friedrich R. et al. Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation. Nature 2003; 425: 535-539.
- 72 McDevitt D. et al. Characterization of the interaction between the Staphylococcus aureus clumping factor (ClfA) and fibrinogen. Eur J Biochem 1997; 247: 416-424.
- 73 Collen D. Staphylokinase: a potent, uniquely fibrin-selective thrombolytic agent. Nat Med 1998; 4: 279-284.
- 74 Sun H. et al. Plasminogen is a critical host pathogenicity factor for group A streptococcal infection. Science 2004; 305: 1283-1286.
- 75 Degen JL. et al. Fibrin and fibrinolysis in infection and host defense. J Thromb Haemost 2007; 5 (Suppl. 01) 24-31.
- 76 Manocha S. et al. Fibrinogen-beta gene haplotype is associated with mortality in sepsis. J Infect 2007; 54: 572-577.
- 77 Kovar FM. et al. The fibrinogen -148 C/T polymorphism influences inflammatory response in experimental endotoxemia in vivo. Thromb Res 2007; 120: 727-731.
- 78 Hoppe B. et al. Fibrinogen and factor XIII A-subunit genotypes interactively influence C-reactive protein levels during inflammation. Ann Rheum Dis 2012; 71: 1163-1169.
- 79 Arlestig L. et al. Polymorphism of genes related to cardiovascular disease in patients with rheumatoid arthritis. Clin Exp Rheumatol 2007; 25: 866-871.
- 80 Ljungman P. et al. Modification of the interleukin-6 response to air pollution by interleukin-6 and fibrinogen polymorphisms. Environ Health Perspect 2009; 117: 1373-1379.
- 81 Esmon CT. The impact of the inflammatory response on coagulation. Thromb Res 2004; 114: 321-327.
- 82 Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010; 38 (02) Suppl S26-34.
- 83 Hoffman M, Monroe 3 DM. A cell-based model of haemostasis. Thromb Haemost 2001; 85: 958-965.
- 84 Egorina EM. et al. The role of tissue factor in systemic inflammatory response syndrome. Blood Coagul Fibrinolysis 2011; 22: 451-456.
- 85 Mackman N. The many faces of tissue factor. J Thromb Haemost 2009; 7 (Suppl. 01) 136-139.
- 86 Dahlback B, Villoutreix BO. Regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure-function relationships and molecular recognition. Arterioscler Thromb Vasc Biol 2005; 25: 1311-1320.
- 87 Nesheim M. et al. Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis. Thromb Haemost 1997; 78: 386-391.
- 88 Foley JH. et al. Insights into thrombin activatable fibrinolysis inhibitor function and regulation. J Thromb Haemost 2013; 11 (Suppl. 01) 306-315.
- 89 Myles T. et al. Thrombin activatable fibrinolysis inhibitor, a potential regulator of vascular inflammation. J Biol Chem 2003; 278: 51059-51067.
- 90 Naito M. et al. Thrombin-activatable fibrinolysis inhibitor protects against acute lung injury by inhibiting the complement system. Am J Respir Cell Mol Biol 2013; 49: 646-653.
- 91 Bruno NE. et al. Immune complex-mediated glomerulonephritis is ameliorated by thrombin-activatable fibrinolysis inhibitor deficiency. Thromb Haemost 2008; 100: 90-100.
- 92 Plow EF. Leukocyte elastase release during blood coagulation. A potential mechanism for activation of the alternative fibrinolytic pathway. J Clin Invest 1982; 69: 564-572.
- 93 Machovich R, Owen WG. The elastase-mediated pathway of fibrinolysis. Blood Coagul Fibrinolysis 1990; 1: 79-90.
- 94 Kolev K. et al. Quantitative comparison of fibrin degradation with plasmin, miniplasmin, neurophil leukocyte elastase and cathepsin G. Thromb Haemost 1996; 75: 140-146.
- 95 Machovich R, Owen WG. An elastase-dependent pathway of plasminogen activation. Biochemistry 1989; 28: 4517-4522.
- 96 Potempa J. et al. The serpin superfamily of proteinase inhibitors: structure, function, and regulation. J Biol Chem 1994; 269: 15957-15960.
- 97 Bagoly Z. et al. Down-regulation of activated factor XIII by polymorphonuclear granulocyte proteases within fibrin clot. Thromb Haemost 2007; 98: 359-367.
- 98 Bagoly Z. et al. Cleavage of factor XIII by human neutrophil elastase results in a novel active truncated form of factor XIII A subunit. Thromb Haemost 2008; 99: 668-674.
- 99 Seitz R, Leugner F, Katschinski M. et al. Ulcerative colitis and Crohn’s disease: factor XIII, inflammation and haemostasis. Digestion 1994; 55: 361-367.
- 100 Lorenz R. et al. Factor XIII substitution in ulcerative colitis. Lancet 1995; 345: 449-450.
- 101 Lorenz R. et al. Factor XIII in chronic inflammatory bowel diseases. Semin Thromb Haemost 1996; 22: 451-455.
- 102 Bregenzer N. et al. Lack of clinical efficacy of additional factor XIII treatment in patients with steroid refractory colitis. The Factor XIII Study Group. Z Gastroenterol 1999; 37: 999-1004.
- 103 Birnbaum J. et al. Effects of coagulation factor XIII on intestinal functional capillary density, leukocyte adherence and mesenteric plasma extravasation in experimental endotoxemia. Crit Care 2006; 10: R29.
- 104 Zaets SB. et al. Recombinant factor XIII diminishes multiple organ dysfunction in rats caused by gut ischemia-reperfusion injury. Shock 2009; 31: 621-626.
- 105 Zaets SB. et al. Recombinant factor XIII mitigates hemorrhagic shock-induced organ dysfunction. J Surg Res 2011; 166: e135-e142.
- 106 Katona E. et al. Factor XIII in bronchoalveolar lavage fluid from children with chronic bronchoalveolar inflammation. J Thromb Haemost 2005; 3: 1407-1413.
- 107 Perez RL. et al. Bronchoalveolar lavage fluid D dimer levels are higher and more prevalent in black patients with pulmonary sarcoidosis. Respiration 2007; 74: 297-303.
- 108 Rasmussen GG. et al. Lack of effect of tranexamic acid on rheumatoid arthritis. Scand J Rheumatol 1984; 13: 369-373.
- 109 van der Laan WH. et al. No therapeutic effect of plasmin antagonist tranexamic acid in rheumatoid arthritis. A double-blind placebo-controlled pilot study. Clin Exp Rheumatol 2003; 21: 359-362.
- 110 Varisco PA. et al. Effect of thrombin inhibition on synovial inflammation in antigen induced arthritis. Ann Rheum Dis 2000; 59: 781-787.
- 111 Marty I. et al. Amelioration of collagen-induced arthritis by thrombin inhibition. J Clin Invest 2001; 107: 631-640.
- 112 Jimenez JJ. et al. Safety and effectiveness of two treatment regimes with tranexamic acid to minimize inflammatory response in elective cardiopulmonary bypass patients: a randomized double-blind, dose-dependent, phase IV clinical trial. J Cardiothorac Surg 2011; 6: 138.
- 113 Later AF. et al. Antifibrinolytics attenuate inflammatory gene expression after cardiac surgery. J Thorac Cardiovasc Surg 2013; 145: 1611-1616 6 e1-4.