Background Increasing evidence suggests that FXI is an attractive target for antithrombotic therapy because it reduces thrombosis without increasing bleeding risk. Patients with decreased levels of FXI are at reduced risk of cardiovascular diseases and thromboembolic events. We have already revealed that depletion of FXI inhibits the vascular coagulation-inflammatory circuit in angiotensin II-induced arterial hypertension. However, the effect of FXI depletion on cardiac inflammation and vascular function in ischemia/reperfusion (I/R) injury is unknown. Purpose Using FXI-depleted mice to investigate the role of FXI in inflammation response post cardiac I/R injury. Methods 8–12 weeks old C57BL/6J male mice were injected intraperitoneally with FXI antisense oligonucleotide (FXI ASO) or scrambled controls for a period of 2 weeks. Then we temporarily ligated the left anterior descending (LAD) for 45 minutes to induce myocardial ischemia, followed by the reperfusion for 72 hours (ischemia/reperfusion injury, IRI). Myocardial inflammation and vascular function were analyzed by flow cytometry, real-time PCR, vascular relaxation studies from isolated aortic segment in organ chamber and chemiluminescence photon counting of oxidative burst in whole blood. Results FXI ASO treatment reduced hepatic FXI mRNA levels and prolonged activated partial thromboplastin time. Compared to scrambled ASO injected mice, oxidative burst from whole blood and endothelial dysfunction were decreased in FXI ASO injected mice with IRI. Compared to control groups, depletion of FXI attenuated cardiac infiltration of CD45+CD11b+ cells, especially LyG-LyChigh monocytes and LyG+ neutrophils at day 3 in I/R injury. Furthermore, the expression levels of adhesion molecules and expression of pro-inflammatory cytokines, such as Vcam-1, CCL2, IL-6 and IL-1b, in ischemic myocardium were significantly decreased in the FXI depleted mice of I/R injury. Conclusion Our results suggest that Inhibition of FXI leads to reduction of vascular dysfunction and ROS production in I/R injury, as well as attenuation of the inflammatory response and the influx of inflammatory cells in ischemic myocardium. This indicates that FXI could be a potential target for further treatment in cardiac IRI. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): TICARDIO project has received funding from the European Union's Horizon 2020 research and Innovation programme under the Marie Skłodowska-Curie grant agreement No 813409.

The 4th Maastricht Consensus Conference on Thrombosis (MCCT), included the following themes: Theme 1: The “coagulome” as a critical driver of cardiovascular disease Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow and kidney. Four investigators shared their views on these organ-specific topics. Theme 2: Novel mechanisms of thrombosis Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infections associated-coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies This theme included state of the art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: how to utilize ex vivo models? Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularised organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation (ECMO) associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management Plenary presentations addressed controversial areas, ie thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies and clinically tested factor XI(a) inhibitors,both possibly with reduced bleeding risk. Finally, Covid-19 associated coagulopathy is revisited.

How to cite this article: Luo Q, Wenzel P. Properdin (factor P) as a new target cleaved by factor XIa: Intrinsic coagulation at the crossroads with inflammation.