Mice are protected from sepsis-induced death by an APC variant that lacks its anticlotting activity (circle).

The only drug that can save patients from severe sepsis carries a risk of internal bleeding. Kerschen et al. (page 2439) have now engineered a variant version that offers the same benefits as the original but minimizes the risk.

Sepsis is a system-wide inflammation that occurs when an infecting microbe enters the bloodstream. The inflammation is meant to fight the pathogen, but it also triggers widespread clotting. Clotting proteins, in turn, reinforce inflammation by activating oxidants and proteases, ultimately causing organ failure. Because the exact cause of death in sepsis patients is unknown, scientists don't know what problem to target when designing an effective therapy.

Antiinflammatory agents such as steroids and cytokine antagonists have failed as therapies. So too have anticlotting agents. The only treatment that has had any degree of success is activated protein C (APC).

APC is both a clot-busting enzyme and a signaling molecule that blocks apoptosis, inflammatory cytokine production, and immune cell recruitment. APC is therefore thought to work against sepsis by breaking the inflammation/clotting cycle. But patients dosed with APC can experience internal bleeding thanks to the drug's anticlotting activity.

Kerschen and colleagues now test whether APC might still be effective but less dangerous if its anticlotting activity is reduced. They engineered an APC variant that was 90% less effective at stopping clotting. This variant was just as good as normal APC at saving septic mice, suggesting that the protective effect of APC did not stem from its anticlotting function but from its signaling ability.

Exactly why APC's antiinflammatory signaling activity succeeds in treating sepsis where other antiinflammatory drugs have failed is unclear, but this might be due to its broader effects on both the inflammatory and apoptotic pathways.