Endotoxemia-induced protein C surge protects mice against venous thrombosis based on transient lowering of natural anticoagulants.

Immunothrombosis is the process by which inflammatory stimuli promote coagulation and thrombus formation. Bacterial sepsis is a well established risk factor for venous thrombosis, and numerous experimental studies have shown that sepsis indeed enhances thrombotic responses. In this study, we aimed to investigate the impact of endotoxemia - induced by either lipopolysaccharides or α-toxin - on venous thrombosis development in mice. Venous thrombosis was induced using a model based on siRNA-mediated transient inhibition of the natural anticoagulants - protein C (PC) and anti-thrombin (AT). Unexpectedly, endotoxemia attenuated rather than promoted venous thrombus formation. This counterintuitive finding appears to be explained by a transient increase in circulating protein C levels following endotoxemia. As our venous thrombosis mouse model strongly depends on the level of reduced protein C activity, this endotoxemia-induced elevation interfered with the intended prothrombotic conditions and compromised comparability between experimental groups. These results highlight the context-dependent effects of bacterial sepsis on venous thrombosis and underscore the importance of rigorous model validation in (immuno)thrombosis research.