Mice with a severe genetic deficiency of protein C (PC), PC ؊/؊ PC(tg4), display enhanced susceptibility to lethal effects of gram-negative endotoxemia induced by lipopolysaccharide (LPS), whereas mice severely deficient in tissue factor (TF), TF ؊/؊ hTF(tg), are protected from LPSmediated lethality. In this study, we show that a simultaneous severe deficiency of TF protected low-PC mice from LPSinduced death, resulting in a survival profile similar to that experienced by wild-type (WT) mice. Plasma and whole blood coagulation assays, the latter measured by thromboelastography, demonstrated development of coagulopathies in LPS-treated mice, which were more severe in the case of the doubly deficient TF ؊/؊ hTF(tg)/PC ؊/؊ PC(tg4) mice, mainly reflecting earlier signs of disseminated intravascular coagulation in this latter cohort. Markers of inflammation were also elevated in response to LPS in both groups of mice at times just preceding death. We conclude that whereas coagulopathies are more exacerbated in LPStreated TF ؊/؊ hTF(tg)/PC ؊/؊ PC(tg4) mice, the lowering of TF levels in mice with an accompanying severe PC deficiency confers protection against death compared with mice with a single severe PC deficiency. This suggests that proteases generated as a result of factor VIIa/TFmediated thrombin generation play a mechanistic role in the enhanced lethality seen under very low PC conditions in an endotoxemia model in mice. (Blood. 2011; 117(1):283-289)
IntroductionThe hemostasis system is intricately involved in the innate immune response, in part, via linkages between coagulation and inflammation. The interactions between these systems are profoundly displayed in sepsis/endotoxemia, wherein pathogenic challenge up-regulates tissue factor (TF) on monocytes 1 and endothelial cells, 2 that not only leads to a hypercoagulation potential, but also provides several proteases (eg, thrombin) that are capable of signaling the inflammatory response through interaction with cellular receptors. 3 The resulting inflammatory mediators downregulate anticoagulant activated protein C (aPC) generation and inhibit fibrinolysis, thus enhancing the hypercoagulable state. In severe cases of sepsis, lethal disseminated intravascular coagulation (DIC) occurs. Some success in treatment of severe sepsis has been achieved with aPC administration, 4 which is grounded in the anticoagulant, profibrinolytic, anti-inflammatory, endothelial barrier protective, and antiapoptotic activities of aPC. 5,6 A deficiency of PC is symptomatic in humans, resulting in conditions such as purpura fulminans, 7 and in experimental animals in a variety of challenge models. 6 It has also been previously shown that embryos with total deficiencies of PC (PC Ϫ/Ϫ ) do not live beyond the early neonatal stage, 8 but embryos can survive to adulthood with PC levels greater than approximately 1% of wild-type (WT). 9 In addition, maternal plasma PC levels are critical to embryonic survival. In that regard, we found that minimal maternal PC concentrations, approximating ...