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Hypofibrinolytic effects of complement C3 and its modulation
which may be important for the development of agents that improve the efficiency of fibrinolysis, particularly in patients with high vascular risk. These findings open a new avenue for the identification of therapeutic targets to modulate the hypofibrinolytic environment in high- risk patients, which may have future clinical implica- tions.
In conclusion, our work shows that C3 represents a credible therapeutic target to reduce thrombosis risk. The b chain of fibrinogen represents an interaction site with C3, and modulation of this interaction can abolish C3- induced prolongation of clot lysis in a specific manner. This targeted approach has the potential for use in the development of novel therapeutic agents for the reduction of thrombotic vascular occlusion.
Future work should concentrate on investigating the in vivo role of affimer A6 in limiting vascular occlusion, using animal models of thrombosis. Additionally, our data sug- gest that a specific site of the b chain of fibrinogen, which may be amenable to small molecule intervention, repre- sents a possible new therapeutic target to improve fibri- nolysis and reduce thrombosis in high-risk conditions.
Contributions
RJK and KS performed the research, analyzed data and wrote the manuscript. CT, VJ and KS performed the research, ana- lyzed data and revised the manuscript. VJ and AT researched data and revised the manuscript. SP, MJM and RFS revised the manuscript. CWGF and DT designed experiments and revised the manuscript. RAA conceived the study, designed experiments, analyzed data and wrote the manuscript.
Funding
RJK was funded by a PhD Fellowship from the Sir Jules Thorn Charitable Trust. KS is supported by the German Research Foundation (DFG)[SFB/TRR219 C-07; HE 5666/1-2 to KS (née Hess)] and by a grant from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University (K7-2). VJ was supported by the German Research Foundation (DFG)(SFB/TRR219 S-03, C-04, M-05, IHST 948/4S-1 FU6.6). We also wish to thank Diabetes UK for funding part of this work, the National Institute of Health Research and British Heart Foundation for constant support, along with help from the Biomedical Health Research Centre for the BioScreening Technology Group and the Stratified Medicine Hub at the University of Leeds who funded the initial NABP screens. We would also like to thank AVACTA Life Sciences for their support.
Disclosures
No conflicts of interest to disclose.
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