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



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.

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Fig. 1



Complement C3


C-reactive protein


Edinburgh Type 2 Diabetes Study


Plasminogen activator inhibitor-1


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J. F. Price and M. W. Strachan are principal investigators for the ET2DS and would like to thank staff and participants at the Wellcome Trust Clinical Research Facility in Edinburgh.

Some of the data were presented as an abstract at the XXIV Congress of the International Society on Thrombosis and Haemostasis in 2013 and the European Society of Cardiology in 2012.


KH is supported by the Deutsche Forschungsgemeinschaft HE 5666/1-2 and by the Stiftung der Herzkranke Diabetiker. SHA is supported by Diabetes Centre at King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia. We also wish to thank the UK’s National Institute for Health Research, British Heart Foundation and Bayer HealthCare Pharmaceuticals for their generous support.

The Edinburgh Type 2 Diabetes Study (ET2DS) was funded by the Medical Research Council and Pfizer.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

KH contributed to the concept and design, data acquisition, analysis and interpretation, and drafting of the article. JFP and MWS contributed to the concept and design, data acquisition and revision of the article. SHA, PDB, NO, RK, TG and VS contributed to the data acquisition and analysis, and revision of the article. RAA contributed to the concept and design, data acquisition, analysis and interpretation data, and revision of the article. RAA is the guarantor of the work. All authors approved the final version.

Author information

Correspondence to Ramzi A. Ajjan.

Additional information

K. Hess and S. H. Alzahrani contributed equally to this work.

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Hess, K., Alzahrani, S.H., Price, J.F. et al. Hypofibrinolysis in type 2 diabetes: the role of the inflammatory pathway and complement C3. Diabetologia 57, 1737–1741 (2014).

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  • Complement C3
  • C-reactive protein
  • CRP
  • Diabetes
  • Fibrinolysis