, Volume 57, Issue 8, pp 1737–1741 | Cite as

Hypofibrinolysis in type 2 diabetes: the role of the inflammatory pathway and complement C3

  • Katharina Hess
  • Saad H. Alzahrani
  • Jackie F. Price
  • Mark W. Strachan
  • Natalie Oxley
  • Rhodri King
  • Tobias Gamlen
  • Verena Schroeder
  • Paul D. Baxter
  • Ramzi A. Ajjan
Short Communication



Plasminogen activator inhibitor-1 (PAI-1) has been regarded as the main antifibrinolytic protein in diabetes, but recent work indicates that complement C3 (C3), an inflammatory protein, directly compromises fibrinolysis in type 1 diabetes. The aim of the current project was to investigate associations between C3 and fibrinolysis in a large cohort of individuals with type 2 diabetes.


Plasma levels of C3, C-reactive protein (CRP), PAI-1 and fibrinogen were analysed by ELISA in 837 patients enrolled in the Edinburgh Type 2 Diabetes Study. Fibrin clot lysis was analysed using a validated turbidimetric assay.


Clot lysis time correlated with C3 and PAI-1 plasma levels (r = 0.24, p < 0.001 and r = 0.22, p < 0.001, respectively). In a multivariable regression model involving age, sex, BMI, C3, PAI-1, CRP and fibrinogen, and using log-transformed data as appropriate, C3 was associated with clot lysis time (regression coefficient 0.227 [95% CI 0.161, 0.292], p < 0.001), as was PAI-1 (regression coefficient 0.033 [95% CI 0.020, 0.064], p < 0.05) but not fibrinogen (regression coefficient 0.003 [95% CI −0.046, 0.051], p = 0.92) or CRP (regression coefficient 0.024 [95% CI −0.008, 0.056], p = 0.14). No correlation was demonstrated between plasma levels of C3 and PAI-1 (r = −0.03, p = 0.44), consistent with previous observations that the two proteins affect different pathways in the fibrinolytic system.


Similarly to PAI-1, C3 plasma levels are independently associated with fibrin clot lysis in individuals with type 2 diabetes. Therefore, future studies should analyse C3 plasma levels as a surrogate marker of fibrinolysis potential in this population.


Complement C3 C-reactive protein CRP Diabetes Fibrinolysis 



Complement C3


C-reactive protein


Edinburgh Type 2 Diabetes Study


Plasminogen activator inhibitor-1

Supplementary material

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  1. 1.
    Alzahrani SH, Ajjan RA (2010) Coagulation and fibrinolysis in diabetes. Diabetes Vasc Dis Res 7:260–273CrossRefGoogle Scholar
  2. 2.
    Hess K, Alzahrani S, Mathai M et al (2012) A novel mechanism for hypofibrinolysis in diabetes: the role of complement C3. Diabetologia 55:1103–1113PubMedCrossRefGoogle Scholar
  3. 3.
    Alzahrani SH, Hess K, Price JF et al (2012) Gender-specific alterations in fibrin structure function in type 2 diabetes: associations with cardiometabolic and vascular markers. J Clin Endocrinol Metab 97:E2282–E2287PubMedCrossRefGoogle Scholar
  4. 4.
    Schroeder V, Carter AM, Dunne J, Mansfield MW, Grant PJ (2010) Proinflammatory and hypofibrinolytic phenotype in healthy first-degree relatives of patients with type 2 diabetes. J Thromb Haemost 8:2080–2082PubMedCrossRefGoogle Scholar
  5. 5.
    Price JF, Reynolds RM, Mitchell RJ et al (2008) The Edinburgh type 2 diabetes study: study protocol. BMC Endocr Disord 8:18PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Yasojima K, Schwab C, McGeer EG, McGeer PL (2001) Complement components, but not complement inhibitors, are upregulated in atherosclerotic plaques. Arterioscler Thromb Vasc Biol 21:1214–1219PubMedCrossRefGoogle Scholar
  7. 7.
    Széplaki G, Prohászka Z, Duba J et al (2004) Association of high serum concentration of the third component of complement (C3) with pre-existing severe coronary artery disease and new vascular events in women. Atherosclerosis 177:383–389PubMedCrossRefGoogle Scholar
  8. 8.
    Wei JN, Li HY, Sung FC et al (2012) Obesity and clustering of cardiovascular disease risk factors are associated with elevated plasma complement C3 in children and adolescents. Pediatr Diabetes 13:476–483PubMedCrossRefGoogle Scholar
  9. 9.
    Amara U, Flierl MA, Rittirsch D et al (2010) Molecular intercommunication between the complement and coagulation systems. J Immunol 185:5628–5636PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Katharina Hess
    • 1
  • Saad H. Alzahrani
    • 2
    • 3
  • Jackie F. Price
    • 4
  • Mark W. Strachan
    • 5
  • Natalie Oxley
    • 2
  • Rhodri King
    • 2
  • Tobias Gamlen
    • 2
  • Verena Schroeder
    • 6
  • Paul D. Baxter
    • 7
  • Ramzi A. Ajjan
    • 2
  1. 1.Department of CardiologyUniversity Hospital RWTH AachenAachenGermany
  2. 2.Division of Cardiovascular and Diabetes Research, Leeds Institute for Genetics, Health and Therapeutics, LIGHT Laboratories, Clarendon WayUniversity of LeedsLeedsUK
  3. 3.Specialized Diabetes and Endocrine CentreKing Fahad Medical CityRiyadhKingdom of Saudi Arabia
  4. 4.Centre for Population Health SciencesUniversity of EdinburghEdinburghUK
  5. 5.Metabolic UnitWestern General HospitalEdinburghUK
  6. 6.University Clinic of Hematology and Central Hematology Laboratory, Hemostasis Research LaboratoryUniversity Hospital and University of BernBernSwitzerland
  7. 7.Division of Epidemiology and BiostatisticsLeeds Institute of Genetics, Health and Therapeutics, University of LeedsLeedsUK

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