Recombinant activated
protein C (APC) and APC variants with reduced
anticoagulant activity were used to reduce mortality in murine models of
sepsis. These models included endotoxemia and
bacteremia models. We discovered that single or multiple bolus doses of APC, especially of APC variants such as RR230 / 231AA-APC, KKK192-194AAA-APC and 5A-APC (containing the combination of mutations present in the first two APC variants) given as a single bolus reduces 7-day mortality of mice given lethal doses of endotoxin. Administrations of a single bolus of 5A-APC after the
initiation of
sepsis also reduces mortality caused by LPS. 5A-APC with ≦8% of normal
anticoagulant activity (which has
reduced risk of bleeding) reduces mortality when given as two bolus administrations at 3 hours and then at 10 hours after
initiation of bacterial infection, i.e. after onset of
sepsis. This shows, first, that one or more bolus injections of APC or of APC variants, especially 5A-APC, can reduce mortality when given beginning hours after the onset of sepsis and, second, that it is not necessary to administer APC as a
continuous infusion which is the current standard of practice because one or more bolus administrations can reduce mortality. Furthermore, dosages of approximately 0.06 to 0.4 mg / kg of APC and APC variants are identified to be sufficient to reduce mortality in sepsis.