Thromb Haemost 2014; 112(05): 901-908
DOI: 10.1160/th14-02-0184
Theme Issue Article
Schattauer GmbH

Clot properties and cardiovascular disease

Katherine I. Bridge
1   Theme Thrombosis, Division of Cardiovascular and Diabetes Research, Leeds institute for Genetics, Health and Therapeutics, Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK
,
Helen Philippou
1   Theme Thrombosis, Division of Cardiovascular and Diabetes Research, Leeds institute for Genetics, Health and Therapeutics, Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK
,
Robert A. S. Ariëns
1   Theme Thrombosis, Division of Cardiovascular and Diabetes Research, Leeds institute for Genetics, Health and Therapeutics, Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK
› Author Affiliations
Financial support: KIB is in receipt of a Clinical Research Training Fellowship from the British Heart Foundation. RASA and HP are supported by the British Heart Foundation (RG/13/3/30104, SP/12/ 11/29786 and SP/14/1/30717) and by the Medical Research Council (G0901546). RASA is supported by the Garfield Weston Trust for Medical Research into Diseases of the Heart.
Further Information

Publication History

Received: 27 February 2014

Accepted after minor revision: 29 March 2014

Publication Date:
20 November 2017 (online)

Summary

Fibrinogen is cleaved by thrombin to fibrin, which provides the blood clot with its essential structural backbone. As an acute phase protein, the plasma levels of fibrinogen are increased in response to inflammatory conditions. In addition to fibrinogen levels, fibrin clot structure is altered by a number of factors. These include thrombin levels, treatment with common cardiovascular medications, such as aspirin, anticoagulants, statins and fibrates, as well as metabolic disease states such as diabetes mellitus and hyperhomocysteinaemia. In vitro studies of fibrin clot structure can provide information regarding fibre density, clot porosity, the mechanical strength of fibres and fibrinolysis. A change in fibrin clot structure, to a denser clot with smaller pores which is more resistant to lysis, is strongly associated with cardiovascular disease. This pathological change is present in patients with arterial as well as venous diseases, and is also found in a moderate form in relatives of patients with cardiovascular disease. Pharmacological therapies, aimed at both the treatment and prophylaxis of cardiovascular disease, appear to result in positive changes to the fibrin clot structure. As such, therapies aimed at ‘normalising’ fibrin clot structure may be of benefit in the prevention and treatment of cardiovascular disease.

 
  • References

  • 1 Danesh J, Lewington S, Thompson SG. et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. J Am Med Assoc 2005; 294: 1799-1809.
  • 2 Henschen A, Lottspeich F, Kehl M. et al. Covalent structure of fibrinogen. Ann NY Acad Sci 1983; 408: 28-43.
  • 3 Weisel JW, Medved L. The structure and function of the alpha C domains of fibrinogen. Ann NY Acad Sci 2001; 936: 312-327.
  • 4 Yang Z, Mochalkin I, Doolittle RF. A model of fibrin formation based on crystal structures of fibrinogen and fibrin fragments complexed with synthetic peptides. Proc Natl Acad Sci USA 2000; 97: 14156-14161.
  • 5 Tsurupa G, Hantgan RR, Burton RA. et al. Structure, stability, and interaction of the fibrin(ogen) alphaC-domains. Biochemistry 2009; 48: 12191-12201.
  • 6 Redman CM, Xia H. Fibrinogen biosynthesis. Assembly, intracellular degradation, and association with lipid synthesis and secretion. Ann NY Acad Sci 2001; 936: 480-495.
  • 7 Dalmon J, Laurent M, Courtois G. The human beta fibrinogen promoter contains a hepatocyte nuclear factor 1-dependent interleukin-6-responsive element. Mol Cell Biol 1993; 13: 1183-1193.
  • 8 Lane A, Graham L, Cook M. et al. Cytokine production by cholesterol-loaded human peripheral monocyte-macrophages: the effect on fibrinogen mRNA levels in a hepatoma cell-line (HepG2). Biochim Biophys Acta 1991; 1097: 161-165.
  • 9 Scarabin PY, Arveiler D, Amouyel P. et al. Plasma fibrinogen explains much of the difference in risk of coronary heart disease between France and Northern Ireland. The PRIME study. Atherosclerosis 2003; 166: 103-109.
  • 10 Tatli E, Ozcelik F, Aktoz M. Plasma fibrinogen level may predict critical coronary artery stenosis in young adults with myocardial infarction. Cardiol J 2009; 16: 317-320.
  • 11 Bartlett JW, De Stavola BL, Meade TW. Assessing the contribution of fibrinogen in predicting risk of death in men with peripheral arterial disease. J Thromb Haemost 2009; 7: 270-276.
  • 12 Parry DJ, Al-Barjas HS, Chappell L. et al. Haemostatic and fibrinolytic factors in men with a small abdominal aortic aneurysm. Br J Surg 2009; 96: 870-877.
  • 13 Klovaite J, Nordestgaard BG, Tybjaerg-Hansen A. et al. Elevated fibrinogen levels are associated with risk of pulmonary embolism, but not with deep venous thrombosis. Am J Resp Crit Care Med 2013; 187: 286-293.
  • 14 Smith EB. Lipids and plasma fibrinogen: early and late composition of the atherosclerotic plaque. Cardiologia 1994; 39 (12) (Suppl. 01) 169-172.
  • 15 Smith EB. Fibrinogen, fibrin and fibrin degradation products in relation to atherosclerosis. Clin Haematol 1986; 15: 355-370.
  • 16 van der Bom JG, de Maat MP, Bots ML. et al. Elevated plasma fibrinogen: cause or consequence of cardiovascular disease?. Arterioscler Thromb Vasc Biol 1998; 18: 621-625.
  • 17 Hong SN, Gona P, Fontes JD. et al. Atherosclerotic biomarkers and aortic atherosclerosis by cardiovascular magnetic resonance imaging in the Framing-ham Heart Study. J Am Heart Assoc 2013; 2: e000307.
  • 18 Sabater-Lleal M, Huang J, Chasman D. et al. Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. Circulation 2013; 128: 1310-1324.
  • 19 Cilia La Corte AL, Philippou H, Ariëns RA. Role of fibrin structure in thrombosis and vascular disease. Adv Protein Chem Struct Biol 2011; 83: 75-127.
  • 20 Blomback B, Hessel B, Hogg D. et al. A two-step fibrinogen--fibrin transition in blood coagulation. Nature 1978; 275: 501-505.
  • 21 Ariens RA. Fibrin(ogen) and thrombotic disease. J Thromb Haemost 2013; 11 (Suppl. 01) 294-305.
  • 22 Weisel JW. Fibrin assembly. Lateral aggregation and the role of the two pairs of fibrinopeptides. Biophys J 1986; 50: 1079-1093.
  • 23 Ariens RA, Lai TS, Weisel JW. et al. Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms. Blood 2002; 100: 743-754.
  • 24 Hethershaw EL, Cilia La Corte AL, Duval C. et al. The effect of blood coagulation factor XIII on fibrin clot structure and fibrinolysis. J Thromb Haemost. 2013 Epub ahead of print.
  • 25 Duval C, Allan P, Connell SD. et al. Roles of fibrin alpha- and gamma-chain specific cross-linking by FXIIIa in fibrin structure and function. Thromb Haemost 2014; 111: 842-850.
  • 26 Gaffney PJ, Whitaker AN. Fibrin crosslinks and lysis rates. Thromb Res 1979; 14: 85-94.
  • 27 McDonagh Jr., RP, McDonagh J, Duckert F. The influence of fibrin crosslinking on the kinetics of urokinase-induced clot lysis. Br J Haematol 1971; 21: 323-332.
  • 28 Mutch NJ, Koikkalainen JS, Fraser SR. et al. Model thrombi formed under flow reveal the role of factor XIII-mediated cross-linking in resistance to fibrinolysis. J Thromb Haemost 2010; 8: 2017-2024.
  • 29 Francis CW, Marder VJ, Martin SE. Plasmic degradation of crosslinked fibrin. I. Structural analysis of the particulate clot and identification of new macromolecular-soluble complexes. Blood 1980; 56: 456-464.
  • 30 Lorand L. Factor XIII: structure, activation, and interactions with fibrinogen and fibrin. Ann NY Acad Sci 2001; 936: 291-311.
  • 31 Fraser SR, Booth NA, Mutch NJ. The antifibrinolytic function of factor XIII is exclusively expressed through alpha(2)-antiplasmin cross-linking. Blood 2011; 117: 6371-6374.
  • 32 Lee KN, Jackson KW, Christiansen VJ. et al. A novel plasma proteinase potentiates alpha2-antiplasmin inhibition of fibrin digestion. Blood 2004; 103: 3783-3788.
  • 33 Valnickova Z, Enghild JJ. Human procarboxypeptidase U, or thrombin-activable fibrinolysis inhibitor, is a substrate for transglutaminases. Evidence for transglutaminase-catalyzed cross-linking to fibrin. J Biol Chem 1998; 273: 27220-27224.
  • 34 Ritchie H, Lawrie LC, Mosesson MW. et al. Characterization of crosslinking sites in fibrinogen for plasminogen activator inhibitor 2 (PAI-2). Ann NY Acad Sci 2001; 936: 215-218.
  • 35 Standeven KF, Ariens RA, Grant PJ. The molecular physiology and pathology of fibrin structure/function. Blood Rev 2005; 19: 275-288.
  • 36 Weisel JW, Nagaswami C. Computer modeling of fibrin polymerization kinetics correlated with electron microscope and turbidity observations: clot structure and assembly are kinetically controlled. Biophys J 1992; 63: 111-128.
  • 37 Wolberg AS, Monroe DM, Roberts HR. et al. Elevated prothrombin results in clots with an altered fiber structure: a possible mechanism of the increased thrombotic risk. Blood 2003; 101: 3008-3013.
  • 38 Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev 2007; 21: 131-142.
  • 39 Konings J, Govers-Riemslag JW, Philippou H. et al. Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin. Blood 2011; 118: 3942-3951.
  • 40 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: 712-717.
  • 41 He S, Bark N, Wang H. et al. Effects of acetylsalicylic acid on increase of fibrin network porosity and the consequent upregulation of fibrinolysis. J Cardiovasc Pharmacol 2009; 53: 24-29.
  • 42 He S, Blomback M, Yoo G. et al. Modified clotting properties of fibrinogen in the presence of acetylsalicylic acid in a purified system. Ann NY Acad Sci 2001; 936: 531-535.
  • 43 Greilich PE, Carr ME, Zekert SL. et al. Quantitative assessment of platelet function and clot structure in patients with severe coronary artery disease. Am J Med Sci 1994; 307: 15-20.
  • 44 Neergaard-Petersen S, Ajjan R, Hvas AM. et al. Fibrin clot structure and platelet aggregation in patients with aspirin treatment failure. PloS One 2013; 8: e71150.
  • 45 Lauricella AM, Quintana I, Castanon M. et al. Influence of homocysteine on fibrin network lysis. Blood Coagul Fibrinolysis 2006; 17: 181-186.
  • 46 Sauls DL, Wolberg AS, Hoffman M. Elevated plasma homocysteine leads to alterations in fibrin clot structure and stability: implications for the mechanism of thrombosis in hyperhomocysteinemia. J Thromb Haemost 2003; 1: 300-306.
  • 47 Undas A, Brozek J, Jankowski M. et al. Plasma homocysteine affects fibrin clot permeability and resistance to lysis in human subjects. Arterioscler Thromb Vasc Biol 2006; 26: 1397-1404.
  • 48 Bhasin N, Ariens RA, West RM. et al. Altered fibrin clot structure and function in the healthy first-degree relatives of subjects with intermittent claudication. J Vasc Surg 2008; 48: 1497-1503 503 e1.
  • 49 Mills JD, Ariens RA, Mansfield MW. et al. Altered fibrin clot structure in the healthy relatives of patients with premature coronary artery disease. Circulation 2002; 106: 1938-1942.
  • 50 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; 112: 4272-4278.
  • 51 Dunn EJ, Ariens RA, de Lange M. et al. Genetics of fibrin clot structure: a twin study. Blood 2004; 103: 1735-1740.
  • 52 Ajjan R, Lim BC, Standeven KF. et al. Common variation in the C-terminal region of the fibrinogen beta-chain: effects on fibrin structure, fibrinolysis and clot rigidity. Blood 2008; 111: 643-650.
  • 53 Gu L, Liu W, Yan Y. et al. Influence of the beta-fibrinogen-455G/A polymorphism on development of ischemic stroke and coronary heart disease. Thromb Res. 2014 Epub ahead of print.
  • 54 Oszajca K, Wronski K, Janiszewska G. et al. Association analysis of genetic polymorphisms of factor V, factor VII and fibrinogen beta chain genes with human abdominal aortic aneurysm. Exp Ther Med 2012; 4: 514-518.
  • 55 Standeven KF, Grant PJ, Carter AM. et al. Functional analysis of the fibrinogen Aalpha Thr312Ala polymorphism: effects on fibrin structure and function. Circulation 2003; 107: 2326-2330.
  • 56 Carter AM, Catto AJ, Kohler HP. et al. alpha-fibrinogen Thr312Ala polymorphism and venous thromboembolism. Blood 2000; 96: 1177-1179.
  • 57 Rasmussen-Torvik LJ, Cushman M, Tsai MY. et al. The association of alpha-fibrinogen Thr312Ala polymorphism and venous thromboembolism in the LITE study. Thromb Res 2007; 121: 1-7.
  • 58 Le Gal G, Delahousse B, Lacut K. et al. Fibrinogen Aalpha-Thr312Ala and factor XIII-A Val34Leu polymorphisms in idiopathic venous thromboembolism. Thromb Res 2007; 121: 333-338.
  • 59 Li JF, Lin Y, Yang YH. et al. Fibrinogen Aalpha Thr312Ala polymorphism specifically contributes to chronic thromboembolic pulmonary hypertension by increasing fibrin resistance. PloS One 2013; 8: e69635.
  • 60 Ariens RA, Philippou H, Nagaswami C. et al. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood 2000; 96: 988-995.
  • 61 Lim BC, Ariens RA, Carter AM. et al. Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk. Lancet 2003; 361: 1424-1431.
  • 62 Antalfi B, Pongracz E, Csiki Z. et al. Factor XIII-A subunit Val34Leu polymorphism in fatal hemorrhagic stroke. Int J Lab Hematol 2013; 35: 88-91.
  • 63 Chen F, Qiao Q, Xu P. et al. Effect of Factor XIII-A Val34Leu Polymorphism on Myocardial Infarction Risk: A Meta-Analysis. Clin Appl Thromb Hemost. 2013 Epub ahead of print.
  • 64 de la Red G, Tassies D, Espinosa G. et al. Factor XIII-A subunit Val34Leu polymorphism is associated with the risk of thrombosis in patients with antiphospholipid antibodies and high fibrinogen levels. Thromb Haemost 2009; 101: 312-316.
  • 65 Li B, Zhang L, Yin Y. et al. Lack of evidence for association between factor XIII-A Val34Leu polymorphism and ischemic stroke: a meta-analysis of 8,800 subjects. Thromb Res 2012; 130: 654-660.
  • 66 Wolfenstein-Todel C, Mosesson MW. Human plasma fibrinogen heterogeneity: evidence for an extended carboxyl-terminal sequence in a normal gamma chain variant (gamma’). Proc Natl Acad Sci USA 1980; 77: 5069-5073.
  • 67 Komaromi I, Bagoly Z, Muszbek L. Factor XIII: novel structural and functional aspects. J Thromb Haemost 2011; 9: 9-20.
  • 68 Meh DA, Siebenlist KR, Mosesson MW. Identification and characterization of the thrombin binding sites on fibrin. J Biol Chem 1996; 271: 23121-23125.
  • 69 Gersh KC, Nagaswami C, Weisel JW. et al. The presence of gamma’ chain impairs fibrin polymerization. Thromb Res 2009; 124: 356-363.
  • 70 Cooper AV, Standeven KF, Ariens RA. Fibrinogen gamma-chain splice variant gamma’ alters fibrin formation and structure. Blood 2003; 102: 535-540.
  • 71 Allan P, Uitte de Willige S, Abou-Saleh RH. et al. Evidence that fibrinogen gamma’ directly interferes with protofibril growth: implications for fibrin structure and clot stiffness. J Thromb Haemost 2012; 10: 1072-1080.
  • 72 Lovely RS, Yang Q, Massaro JM. et al. Assessment of genetic determinants of the association of gamma’ fibrinogen in relation to cardiovascular disease. Arterioscler Thromb Vasc Biol 2011; 31: 2345-2352.
  • 73 Mannila MN, Lovely RS, Kazmierczak SC. et al. Elevated plasma fibrinogen gamma’ concentration is associated with myocardial infarction: effects of variation in fibrinogen genes and environmental factors. J Thromb Haemost 2007; 5: 766-773.
  • 74 Moroi M, Aoki N. Isolation and characterization of alpha2-plasmin inhibitor from human plasma. A novel proteinase inhibitor which inhibits activator-induced clot lysis. J Biol Chem 1976; 251: 5956-5965.
  • 75 Ritchie H, Robbie LA, Kinghorn S. et al. Monocyte plasminogen activator inhibitor 2 (PAI-2) inhibits u-PA-mediated fibrin clot lysis and is cross-linked to fibrin. Thromb Haemost 1999; 81: 96-103.
  • 76 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: 1354-1361.
  • 77 Longstaff C, Thelwell C, Williams SC. et al. The interplay between tissue plasminogen activator domains and fibrin structures in the regulation of fibrinolysis: kinetic and microscopic studies. Blood 2011; 117: 661-668.
  • 78 Mutch NJ, Engel R, Uitte de Willige S. et al. Polyphosphate modifies the fibrin network and down-regulates fibrinolysis by attenuating binding of tPA and plasminogen to fibrin. Blood 2010; 115: 3980-3988.
  • 79 Undas A, Ariens RA. Fibrin clot structure and function: a role in the patho-physiology of arterial and venous thromboembolic diseases. Arterioscler Thromb Vasc Biol 2011; 31: e88-99.
  • 80 Collet JP, Allali Y, Lesty C. et al. Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis. Arterioscler Thromb Vasc Biol 2006; 26: 2567-2573.
  • 81 Siegerink B, Meltzer ME, de Groot PG. et al. Clot lysis time and the risk of myocardial infarction and ischaemic stroke in young women; results from the RATIO case-control study. Br J Haematol 2012; 156: 252-258.
  • 82 Undas A, Plicner D, Stepien E. et al. Altered fibrin clot structure in patients with advanced coronary artery disease: a role of C-reactive protein, lipoprotein(a) and homocysteine. J Thromb Haemost 2007; 5: 1988-1990.
  • 83 Lu D, Owens J, Kreutz RP. Plasma and whole blood clot strength measured by thrombelastography in patients treated with clopidogrel during acute coronary syndromes. Thromb Res 2013; 132: e94-98.
  • 84 Dunn EJ, Ariens RA. Fibrinogen and fibrin clot structure in diabetes. Herz 2004; 29: 470-479.
  • 85 Bochenek M, Zalewski J, Sadowski J. et al. Type 2 diabetes as a modifier of fibrin clot properties in patients with coronary artery disease. J Thromb Thrombolysis 2013; 35: 264-270.
  • 86 Pretorius E, Steyn H, Engelbrecht M. et al. Differences in fibrin fiber diameters in healthy individuals and thromboembolic ischemic stroke patients. Blood Coagul Fibrinolysis 2011; 22: 696-700.
  • 87 Undas A, Podolec P, Zawilska K. et al. Altered fibrin clot structure/function in patients with cryptogenic ischemic stroke. Stroke 2009; 40: 1499-1501.
  • 88 Undas A, Slowik A, Wolkow P. et al. Fibrin clot properties in acute ischemic stroke: relation to neurological deficit. Thromb Res 2010; 125: 357-361.
  • 89 Scott DJ, Prasad P, Philippou H. et al. Clot architecture is altered in abdominal aortic aneurysms and correlates with aneurysm size. Arterioscler Thromb Vasc Biol 2011; 31: 3004-3010.
  • 90 Martinez MR, Cuker A, Mills AM. et al. Enhanced lysis and accelerated establishment of viscoelastic properties of fibrin clots are associated with pulmonary embolism. Am J Physiol Lung Cell Mol Physiol 2014; 306: L397-404.
  • 91 Undas A, Celinska-Lowenhoff M, Lowenhoff T. et al. Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease. J Thromb Haemost 2006; 4: 1029-1036.
  • 92 Parise P, Morini M, Agnelli G. et al. Effects of low molecular weight heparins on fibrin polymerization and clot sensitivity to t-PA-induced lysis. Blood Coagul Fibrinolysis 1993; 4: 721-727.
  • 93 Yeromonahos C, Marlu R, Polack B. et al. Antithrombin-independent effects of heparins on fibrin clot nanostructure. Arterioscler Thromb Vasc Biol 2012; 32: 1320-1324.
  • 94 Varin R, Mirshahi S, Mirshahi P. et al. Clot structure modification by fondaparinux and consequence on fibrinolysis: a new mechanism of antithrombotic activity. Thromb Haemost 2007; 97: 27-31.
  • 95 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: e100-109.
  • 96 Blomback M, He S, Bark N. et al. Effects on fibrin network porosity of anticoagulants with different modes of action and reversal by activated coagulation factor concentrate. Br J Haematol 2011; 152: 758-765.
  • 97 Ammollo CT, Semeraro F, Incampo F. et al. Dabigatran enhances clot susceptibility to fibrinolysis by mechanisms dependent on and independent of thrombin-activatable fibrinolysis inhibitor. J Thromb Haemost 2010; 8: 790-798.
  • 98 He S, Blomback M, Bark N. et al. 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: 1076-1084.