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Thromb Haemost 2014; 112(06): 1142-1150
DOI: 10.1160/th14-05-0468
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

The influence of type 2 diabetes on fibrin clot properties in patients with coronary artery disease

Søs Neergaard-Petersen
1   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
2   Division of Cardiovascular and Diabetes Research, University of Leeds, Leeds, UK
,
Anne-Mette Hvas
3   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
,
Steen D. Kristensen
1   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
,
Erik L. Grove
1   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
,
Sanne B. Larsen
1   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
,
Fladia Phoenix
2   Division of Cardiovascular and Diabetes Research, University of Leeds, Leeds, UK
,
Zeyad Kurdee
2   Division of Cardiovascular and Diabetes Research, University of Leeds, Leeds, UK
,
Peter J. Grant
2   Division of Cardiovascular and Diabetes Research, University of Leeds, Leeds, UK
,
Ramzi A. Ajjan
2   Division of Cardiovascular and Diabetes Research, University of Leeds, Leeds, UK
› Author Affiliations
Further Information

Publication History

Received: 26 May 2014

Accepted after major revision: 22 July 2014

Publication Date:
29 November 2017 (online)

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Summary

Type 2 diabetes mellitus (T2DM) increases the risk of coronary thrombosis and both conditions are associated with altered fibrin clot properties. However, the influence of T2DM on fibrin clot properties in patients with coronary artery disease (CAD) remains unclear. We aimed to investigate the influence of T2DM on fibrin clot properties in patients with CAD. Fibrin clot structure and fibrinolysis were investigated in 581 CAD patients (148 with T2DM) using turbidimetric assays, confocal and scanning electron microscopy. Clots made from plasma and plasma-purified fibrinogen were studied, and plasma levels of inflammatory markers were analysed. T2DM patients had increased clot maximum absorbance compared with non-diabetic patients (0.36 ± 0.1 vs 0.33 ± 0.1 au; p=0.01), displayed longer lysis time (804 [618;1002] vs 750 [624;906] seconds; p=0.03) and showed more compact fibrin structure assessed by confocal and electron microscopy. Fibrinogen levels were elevated in T2DM (p< 0.001), but clots made from purified fibrinogen showed no differences in fibrin properties in the two populations. Adjusting for fibrinogen levels, T2DM was associated with C-reactive protein and complement C3 plasma levels, with the former correlating with clot maximum absorbance (r=0.24, p< 0.0001) and the latter with lysis time (r=0.30, p< 0.0001). Independent of fibrinogen levels, females had more compact clots with prolonged lysis time compared with males (all p-values< 0.001). In conclusion, T2DM is associated with prothrombotic changes in fibrin clot properties in patients with CAD. This is related to quantitative rather than qualitative changes in fibrinogen with a possible role for inflammatory proteins.

Keywords

Fibrin clot - fibrinolysis - coronary artery disease - type 2 diabetes mellitus - inflammation
 

  • References

  • 1 Lozano R, Naghavi M, Foreman K. et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2095-2128.
    CrossrefPubMedSearch in Google Scholar
  • 2 Grant PJ. Inflammatory, atherothrombotic aspects of type 2 diabetes. Curr Med Res Opin 2005; 21 (Suppl. 01) S5-12.
    PubMedSearch in Google Scholar
  • 3 Fox CS, Coady S, Sorlie PD. et al. Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study. Circulation 2007; 115: 1544-1550.
    CrossrefPubMedSearch in Google Scholar
  • 4 Cubbon RM, Wheatcroft SB, Grant PJ. et al. Temporal trends in mortality of patients with diabetes mellitus suffering acute myocardial infarction: a comparison of over 3000 patients between 1995 and 2003. Eur Heart J 2007; 28: 540-545.
    PubMedSearch in Google Scholar
  • 5 Norhammar A, Lindback J, Ryden L. et al. Improved but still high short- and long-term mortality rates after myocardial infarction in patients with diabetes mellitus: a time-trend report from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admission. Heart 2007; 93: 1577-1583.
    PubMedSearch in Google Scholar
  • 6 Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. Br Med J 2006; 332: 73-78.
    CrossrefPubMedSearch in Google Scholar
  • 7 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.
    CrossrefPubMedSearch in Google Scholar
  • 8 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.
    CrossrefPubMedSearch in Google Scholar
  • 9 Baigent C, Blackwell L, Collins R. et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849-1860.
    CrossrefPubMedSearch in Google Scholar
  • 10 Mortensen SB, Larsen SB, Grove EL. et al. Reduced platelet response to aspirin in patients with coronary artery disease and type 2 diabetes mellitus. Thromb Res 2010; 126: 318-322.
    CrossrefPubMedSearch in Google Scholar
  • 11 Larsen SB, Neergaard-Petersen S, Grove EL. et al. Increased platelet aggregation and serum thromboxane levels in aspirin-treated patients with prior myocardial infarction. Thromb Haemost 2012; 108: 140-147.
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Neergaard-Petersen S, Ajjan R, Hvas AM. et al. Fibrin clot structure and platelet aggregation in patients with aspirin treatment failure. PLoS One 2013; 08: e71150.
    CrossrefPubMedSearch in Google Scholar
  • 13 Tehrani S, Antovic A, Mobarrez F. et al. High-dose aspirin is required to influence plasma fibrin network structure in patients with type 1 diabetes. Diabetes Care 2012; 35: 404-408.
    CrossrefPubMedSearch in Google Scholar
  • 14 Ajjan R, Storey RF, Grant PJ. Aspirin resistance and diabetes mellitus. Diabetologia 2008; 51: 385-390.
    CrossrefPubMedSearch in Google Scholar
  • 15 Ajjan R, Grant PJ. Coagulation and atherothrombotic disease. Atherosclerosis 2006; 186: 240-259.
    CrossrefPubMedSearch in Google Scholar
  • 16 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.
    CrossrefPubMedSearch in Google Scholar
  • 17 Undas A, Kolarz M, Kopec G. et al. Altered fibrin clot properties in patients on long-term haemodialysis: relation to cardiovascular mortality. Nephrol Dial Transplant 2008; 23: 2010-2015.
    CrossrefPubMedSearch in Google Scholar
  • 18 Dunn EJ, Ariens RA, Grant PJ. The influence of type 2 diabetes on fibrin structure and function. Diabetologia 2005; 48: 1198-1206.
    CrossrefPubMedSearch in Google Scholar
  • 19 Fatah K, Silveira A, Tornvall P. et al. Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at a young age. Thromb Haemost 1996; 76: 535-540.
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 Dunn EJ, Philippou H, Ariens RA. et al. Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus. Diabetologia 2006; 49: 1071-1080.
    CrossrefPubMedSearch in Google Scholar
  • 21 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.
    CrossrefPubMedSearch in Google Scholar
  • 22 Alzahrani SH, Hess K, Price JF. et al. Gender-specific alterations in fibrin structure function in type 2 diabetes: associations with cardiometabolic and vascular markers. J Clin Endocrinol Metab 2012; 97: E2282-E2287.
    CrossrefPubMedSearch in Google Scholar
  • 23 Ajjan RA, Gamlen T, Standeven KF. et al. Diabetes is associated with posttranslational modifications in plasminogen resulting in reduced plasmin generation and enzyme-specific activity. Blood 2013; 122: 134-142.
    CrossrefPubMedSearch in Google Scholar
  • 24 Alzahrani SH, Ajjan RA. Coagulation and fibrinolysis in diabetes. Diab Vasc Dis Res 2010; 07: 260-273.
    CrossrefPubMedSearch in Google Scholar
  • 25 Sjoland JA, Sidelmann JJ, Brabrand M. et al. Fibrin clot structure in patients with end-stage renal disease. Thromb Haemost 2007; 98: 339-345.
    Thieme ConnectPubMedSearch in Google Scholar
  • 26 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; 05: 1988-1990.
    CrossrefPubMedSearch in Google Scholar
  • 27 Howes JM, Richardson VR, Smith KA. et al. Complement C3 is a novel plasma clot component with anti-fibrinolytic properties. Diab Vasc Dis Res 2012; 09: 216-225.
    CrossrefPubMedSearch in Google Scholar
  • 28 Hess K, Alzahrani SH, Mathai M. et al. A novel mechanism for hypofibrinolysis in diabetes: the role of complement C3. Diabetologia 2012; 55: 1103-1113.
    CrossrefPubMedSearch in Google Scholar
  • 29 Carter AM, Cymbalista CM, Spector TD. et al. Heritability of clot formation, morphology, and lysis: the EuroCLOT study. Arterioscler Thromb Vasc Biol 2007; 27: 2783-2789.
    CrossrefPubMedSearch in Google Scholar
  • 30 Al-Barjas HS, Ariens R, Grant P. et al. Raised plasma fibrinogen concentration in patients with abdominal aortic aneurysm. Angiology 2006; 57: 607-614.
    CrossrefPubMedSearch in Google Scholar
  • 31 Human Complement C3 ELISA Quantification Kit, Manual, Catolog number: 40-288-20073F. GenWay Biotech, Inc , San Diego, CA,; USA: 2012
    Search in Google Scholar
  • 32 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.
    CrossrefPubMedSearch in Google Scholar
  • 33 Takebe M, Soe G, Kohno I. et al. Calcium ion-dependent monoclonal antibody against human fibrinogen: preparation, characterization, and application to fibrinogen purification. Thromb Haemost 1995; 73: 662-667.
    Thieme ConnectPubMedSearch in Google Scholar
  • 34 James S, Angiolillo DJ, Cornel JH. et al. Ticagrelor vs clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2010; 31: 3006-3016.
    CrossrefPubMedSearch in Google Scholar
  • 35 Patrono C, Rocca B. Drug insight: aspirin resistance--fact or fashion?. Nat Clin Pract Cardiovasc Med 2007; 04: 42-50.
    CrossrefPubMedSearch in Google Scholar
  • 36 Pieters M, Covic N, Loots dT. et al. The effect of glycaemic control on fibrin network structure of type 2 diabetic subjects. Thromb Haemost 2006; 96: 623-629.
    Thieme ConnectPubMedSearch in Google Scholar
  • 37 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: 691-700.
    Thieme ConnectPubMedSearch in Google Scholar
  • 38 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.
    CrossrefPubMedSearch in Google Scholar
  • 39 Neergaard-Petersen S, Hvas AM, Ajjan R. et al. Platelet count, platelet turnover and fibrin clot structure in patients with coronary artery disease. Thromb Res 2014; 133: 1161-1163.
    CrossrefPubMedSearch in Google Scholar
  • 40 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 2014; 12: 197-205.
    CrossrefPubMedSearch in Google Scholar
  • 41 Lutjens A, Jonkhoff-Slok TW, Sandkuijl C. et al. Polymerisation and crosslinking of fibrin monomers in diabetes mellitus. Diabetologia 1988; 31: 825-830.
    CrossrefPubMedSearch in Google Scholar
  • 42 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.
    Thieme ConnectPubMedSearch in Google Scholar
  • 43 Vaccarino V, Badimon L, Corti R. et al. Presentation, management, and outcomes of ischaemic heart disease in women. Nat Rev Cardiol 2013; 10: 508-518.
    CrossrefPubMedSearch in Google Scholar
  • 44 Dey S, Flather MD, Devlin G. et al. Sex-related differences in the presentation, treatment and outcomes among patients with acute coronary syndromes: the Global Registry of Acute Coronary Events. Heart 2009; 95: 20-26.
    CrossrefPubMedSearch in Google Scholar
  • 45 Berger JS, Elliott L, Gallup D. et al. Sex differences in mortality following acute coronary syndromes. J Am Med Assoc 2009; 302: 874-882.
    CrossrefPubMedSearch in Google Scholar