An accompanying genetic severe deficiency of tissue factor protects mice with a protein C deficiency from lethal endotoxemia

Abstract

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 ...

Host Defense Peptides of Thrombin Modulate Inflammation and Coagulation in Endotoxin-Mediated Shock and Pseudomonas aeruginosa Sepsis

“…This observation is compatible with the crucial role of TF for activation of coagulation in vivo , and therefore, the inhibitory effects by GKY25 on TF are of importance due to this factor's pivotal role as mediator between coagulation and inflammation. For example, mice with low levels of TF have been found to display decreased mortality in animal endotoxemia models [13], [49], an observation which is compatible with the observed therapeutic effects of GKY25 in this work. Disseminated intravascular coagulation (DIC) is a frequent complication of sepsis [30].…”

Abnormal Whole Blood Thrombi in Humans with Inherited Platelet Receptor Defects

“…Thus, MA F is minimal (Figure 6C; Table 2). Additionally, in the case of a fibrinogen deficiency, activated platelets, alone, do not provide a thrombus that is of measurable viscoelastic strength, with MA values being essentially zero [17]. These data suggest that both functional platelets and fibrinogen are critical to development of a stable viscoelastic thrombus.…”

Radiotherapy-Induced Malignancies: Review of Clinical Features, Pathobiology, and Evolving Approaches for Mitigating Risk

“…SMNs comprise a significant fraction of subsequent malignancies in cancer survivors (Table 1). SMNs account for most of the ∼90,000 s cancers diagnosed annually in the United States (Bhatia and Sklar, 2002), and are a significant and growing late complication in survivors (Guibout et al, 2005; Henderson et al, 2007; Armstrong et al, 2009a,b; Laverdiere et al, 2009; Meadows et al, 2009; Breslow et al, 2010; Friedman et al, 2010; Ginsberg et al, 2010; Castellino et al, 2011). Radiation-induced tumors comprise the majority of SMNs.…”

“…This broad nodal irradiation results in diverse normal tissues receiving radiation, with multiple late toxicities potentially developing. Consequently, survivors of HD are at risk for developing radiation-induced breast cancers (Dores et al, 2002; Aleman et al, 2003; Basu et al, 2008; Crump and Hodgson, 2009; Milano et al, 2010; Castellino et al, 2011), lung cancer (Gilbert et al, 2003), as well as thyroid cancer (Hancock et al, 1991). Notably, the risk of radiation-induced breast cancers in survivors of HD has been estimated to be similar to that of individuals with BRCA1 mutations (Travis et al, 2005a).…”