Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C–deficient mice

A Protein C Deficiency Exacerbates Inflammatory and Hypotensive Responses in Mice During Polymicrobial Sepsis in a Cecal Ligation and Puncture Model

“…Hemostasis factor differences between WT and PC ϩ/Ϫ mice were not evident and did not account for a severe DIC in a PC deficiency. These results are not in accord with the observed aggravation of DIC observed in PC ϩ/Ϫ mice after LPS, 9 and this likely reflects differences in the models used. Thus, it seems that the PC contribution to amelioration of sepsis does not necessarily depend on a protective role against DIC, although DIC enhances the progress of the disease, but more so as a modulator of hypotension and bradycardia, and on its anti-inflammatory properties.…”

“…A model of LPS-induced endotoxin shock was recently used in mice heterozygous for a targeted PC deficiency (PC ϩ/Ϫ ). 9 Although the LPS dosages in this case were very high and somewhat mechanistically unrealistic, PC ϩ/Ϫ mice showed a higher mortality rate, a more elevated inflammatory response, and a more severe DIC when compared to wild-type (WT) mice.…”

“…6 All of these pathways function at early stages of the infection in attempts to rid the system of the infectious agent, but undergo a loss of control in severe sepsis, leading to unregulated hemostasis. In many cases, disseminated intravascular coagulation (DIC) is established, [7][8][9] with resultant contributions to presentations of hypotension, hypoperfusion, and multi-ple organ dysfunction syndrome. This advanced stage of the disease normally culminates in multiple organ failure and death.…”

Endogenous platelet factor 4 stimulates activated protein C generation in vivo and improves survival after thrombin or lipopolysaccharide challenge

“…[3][4][5] All of these effects may contribute to the efficacy of APC infusions in improving outcome in various animal models of inflammation [6][7][8][9] and in reducing mortality in patients with sepsis. [10][11][12] In a lipopolysaccharide (LPS)-induced survival model of sepsis, heterozygous protein C-deficient (PC ϩ/Ϫ ) mice have enhanced vulnerability to death, 6,8 reinforcing the crucial role played by endogenously generated APC in this setting. Recent clinical studies demonstrate that basal PC levels are an independent predictor of sepsis outcome 13 and that endogenous vascular generation of APC is a crucial determinant of survival in sepsis.…”

“…17 We found that platelet PF4 content correlated with APC generation after thrombin infusion and survival after thrombin or LPS challenge and that released PF4 can compensate for the lower PC levels in PC ϩ/Ϫ mice. 6,8 Further, infusion of platelets with high PF4 content is protective in the LPS challenge model, supporting endogenous PF4 as an important variable in outcome from sepsis and suggesting a novel therapy for sepsis. …”