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

Abstract

Aims/hypothesis: 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. Methods: 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. Results: 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. Conclusions/interpretation: 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. © 2014 Springer-Verlag.