Activation of FXII by heat-inactivated Staphylococcus aureus (HI-SA) results in activation of the contact pathway of coagulation leading to kallikrein-triggered generation of bradykinin (resulting in vascular leakage) and downstream activation of coagulation resulting in enhanced fibrinolysis accompanied by the direct release of tPA induced by HI-SA. Elevated FXIIa also results in neutrophil accumulation in the lung and neutrophil activation, alongside multiorgan dysfunction leading to organ failure and mortality. Furthermore, elevated FXIIa directly activates the complement pathway of inflammation and results in a cytokine storm of elevated systemic markers of inflammation. Inhibition of all these activities of FXIIa using 5C12 attenuates all these pathways resulting in improved outcomes in this model of HI-SA–induced sepsis. GM-CSF, granulocytemacrophage colony stimulating factor.