Complement activation leads to C3 & C5 dependent prothrombotic alterations of fibrin clots

• Komplementaktivierung führt zu C3- & C5-abhängigen prothrombotischen Veränderungen von Fibringerinnseln

Maxeiner, Sebastian; Marx, Nikolaus (Thesis advisor); Elling, Lothar (Thesis advisor); Jankowski, Joachim (Thesis advisor)

Aachen (2019, 2020)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2019

Abstract

Alterations of the fibrin network structure with thin fibrin fibers, increased fiber density, small pores, and hypofibrinolysis are associated with an increased risk of cardiovascular diseases. Interaction of the complement system and the coagulation cascade has been well established since the new millennium. Recent studies imply a negative influence of the native complement component C3 on the formation of the fibrin network structure toward a prothrombotic phenotype. This effect is even more prominent in patients with diabetes. However, so far it is unknown whether complement C3 activation has any impact on fibrin clot properties. Complement activation was initiated with CVF which forms soluble C3 and C5 convertases resulting in a complete consumption of all complement components downstream of C3. Activation of the complement system prior to the initiation of hemostasis led to the formation of dense fibrin networks with reduced fiber diameter and an increased lysis time compared to fibrin clots built from plasma without complement activation. These prothrombotic fibrin clot alterations increased with rising C3 plasma concentration under complement activation. Specific inhibition of the cleavage of complement component C3 by the circularized peptide CP40 partially prevented the complement activation mediated alterations of the fibrin network structure. Inhibition of the cleavage of complement component C5 by the FDA approved monoclonal antibody eculizumab also led to a partial restoration of the fibrin network structure and fibrin clot lysis time. Combined inhibition of C3 and C5 activation prevented the complement activation mediated alterations of the fibrin clot network structure and prolonged fibrinolysis. In summary this thesis demonstrates a complement activation mediated prothrombotic effect on the fibrin network structure of plasma clots with an increased lysis time, that could be prevented by the combined inhibition of C3 and C5 activation with specific inhibitors. These results are of particular interest as cardiovascular high-risk patients like patients with diabetes or chronic kidney disease (CKD) display an increased complement activation. Therefore, inhibiting the interaction of complement activation products with fibrin fibers in clots might be a future tool to reduce cardiovascular risk in those patients. However, further research is needed to determine the particular complement activation product(s) interacting with the fibrin clot and identifying their binding sites on fibrinogen.

Institutions

• Department of Biology [160000]
• Chair of Biotechnology [162610]
• [531010-2]