An alternative pathway for hypofibrinolysis in type 2 diabetes: The role of complement C3

• Applicant: Privatdozentin Dr. Katharina Schütt
• Subject Area: Cardiology, Angiology
• Term: from 2010 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 180408678

Despite advances in treatment, individuals with diabetes remain at high risk of cardiovascular disease with 2-3 fold increase in mortality. In acute coronary syndrome plaque rupture is followed by the development of an occlusive arterial thrombus which is characterized by complex interactions between cellular and protein components of coagulation, leading to vascular occlusion mediated by formation of the fibrin clot. Structure of the fibrin network can determine predisposition to cardiovascular disease as dense and compact clots with impaired fibrinolysis are associated with premature and more severe vascular disease. Furthermore, inflammatory proteins are known to be involved in these processes. Our data suggest that complement C3, the central component of the complement system, gets incorporated into the fibrin clot. Complement C3 was able to prolong clot lysis, which is associated with an elevated cardiovascular risk. Furthermore, in patients with diabetes mellitus complement C3 plasma levels were elevated and prolongation of clot lysis was more pronounced. However, the underlying mechanisms are still to be determined. Therefore the present project seeks to adress the following questions: (I) how does complement C3 prolong clot lysis and which are the underlying mechanisms, (II) why are the effects more pronounced in patients with diabetes. Given that patients with diabetes are at an elevated cardiovascular risk the (III.) part seeks to find new tools to interrupt the interaction between the fibrin clot and complement C3 to improve clot lysis in these patients. Such strategies could pave the way for new therapeutic strategies to reduce the cardiovascular risk of patients with diabetes mellitus.

• DFG Programme: Research Grants
• International Connection: United Kingdom
• Participating Person: Professor Dr. Ramzi Ajjan