Abstract 14996: Complement C3 and Thrombosis Risk in Diabetes: A Potential New Therapeutic Target
Clinical studies demonstrated an association between complement C3 plasma levels and increased cardiovascular risk. Although premature and more extensive cardiovascular disease is common in subjects with diabetes, little is known about the role of complement C3 in atherothrombosis in this population. Therefore the present study investigates i) the relationship between complement C3 and parameters of clot structure and ii) in vitro complement/fibrin interactions affecting clot structure and function. The cardiovascular and prothrombotic profile was analyzed in 444 type 2 diabetes subjects (age 67.9±0.2 yrs, 246 males). Using a turbidimetric assay, clot final turbidity (FT), an indicator of clot density, and time to 50% lysis (LT), a measure of fibrinolytic potential, were calculated. C3, measured by ELISA, only correlated with LT but not FT (r=0.282, p<0.01; r=0.059, p>0.1, respectively). Despite differences in clot structure characteristics comparing men and women, C3 correlated with LT in both groups (r=0.309, p<0.001 and r=0.250, p<0.05, respectively), indicating a specific effect of this protein on the fibrinolytic system. In contrast CRP levels did not correlate with LT in men or women. None of the medication used influenced C3 plasma levels, whereas CRP levels were modulated by glitazones and statins. Using a purified system, we further investigated the effects of C3 on fibrin clot lysis. Clots made using fibrinogen purified from diabetes subjects exhibited 244±64 sec prolongation in LT in the presence of C3, compared with 92±23 sec using fibrinogen from healthy controls (p<0.05). Confocal microscopy showed higher incorporation of fluorescent labelled C3 into clots made from diabetic fibrinogen compared with controls. Real time fibrinolysis confirmed that C3 incorporation into the clot prolonged lysis, which was more pronounced in diabetes clots compared with controls (LT=1192±8 and 545±37 sec, respectively; p<0.01). These results demonstrate a close interaction between inflammatory and thrombotic pathways in diabetes. Future research is needed to further elucidate the role of C3 in the thrombotic process in diabetes, which may offer novel treatment strategies to reduce cardiovascular events in this high risk population.
- © 2010 by American Heart Association, Inc.