Patients with severe sepsis vary markedly in their ability to generate activated protein C

Abstract

Activated protein C (APC) supplementation significantly reduces mortality in patients with severe sepsis, presumably by down-regulating coagulation, inflammation, and apoptosis. In vivo, endogenous APC is generated from protein C (PC) "on demand" in response to elevated thrombin levels. Thrombomodulin and endothelial cell protein C receptor are endothelial receptors required to generate APC endogenously. Since these receptors may be down-regulated in sepsis, we measured plasma markers of APC generation in 32 patients with severe sepsis to determine whether APC generation is impaired and whether markers of APC generation correlate with 28-day mortality. Relative to normals, all patients had elevated F1 ؉ 2 and thrombin-antithrombin complex (TAT) levels (markers of thrombin generation and inhibition, respectively), and 28 of 32 patients had reduced PC levels. In 20 patients, APC levels paralleled elevated F1 ؉ 2 levels, whereas 12 patients had low APC levels despite elevated F1 ؉ 2 levels, suggesting that APC generation is impaired in the latter. No significant differences exist between survivors and nonsurvivors with respect to baseline PC levels, F1 ؉ 2 levels, and APACHE II (acute physiology and chronic health evaluation) scores. Baseline APC levels were higher in survivors (P ‫؍‬ .024), and baseline F1 ؉ 2/APC ratios were lower in survivors (P ‫؍‬ .047). Larger studies are warranted to establish whether APC generation profiles aid in managing sepsis. IntroductionSepsis is a devastating disorder characterized by systemic activation of the inflammatory and coagulation cascades in response to microbial infection. 1 Sepsis is defined as systemic inflammatory response syndrome (SIRS) in the presence of documented or suspected infection. 2 When sepsis is associated with acute organ dysfunction, the sepsis is considered severe. 2 In the United States, approximately 750 000 episodes of severe sepsis occur each year, of which 215 000 result in death, 3 a value similar to the number of deaths due to acute myocardial infarction. 4 The mortality rate is approximately 30% and increases to 40% in the elderly, 3 and the incidence of severe sepsis is projected to increase by 1.5% per annum due to the growing proportion of elderly persons in society. 3 Over the past 15 years, many treatments for sepsis have shown early promise yet failed to improve survival in septic patients. These therapies were directed at treating sepsis largely through attenuation of inflammatory mediators or by neutralization of endotoxin. 5 It is now well accepted that inflammation, coagulation, and apoptosis occur concomitantly in sepsis and are intimately linked. Recently, a large phase 3 multinational placebo-controlled randomized clinical trial demonstrated the efficacy and safety of recombinant activated protein C (APC) for severe sepsis. 6 Compared with placebo, a 4-day infusion of recombinant APC resulted in a reduction in the relative risk of death of 19.4% and an absolute reduction in the risk of death of 6.1% (P ϭ .005). This was the first ra...

Activated Protein C Up-Regulates IL-10 and Inhibits Tissue Factor in Blood Monocytes

“…Serial samples were obtained daily for the first week and once a week thereafter until study completion. Blood was collected into buffered trisodium citrate tubes as previously described (29). This study was approved by the Research Ethics Board of the Hamilton Health Sciences Corporation.…”

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

“…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. 14 We have shown previously that platelet factor 4 (PF4, CXCL4) can enhance APC generation in vitro 15 and in vivo 16 ; however, the biologic impact of endogenous, platelet-derived PF4 in regulating systemic APC generation has not been tested. In this study, we examined whether endogenously released PF4 from activated platelets stimulates APC generation in response to thrombin infusion and improves outcome in thrombosis/inflammatory models.…”

Adenosine regulates thrombomodulin and endothelial protein C receptor expression in folliculostellate cells of the pituitary gland

“…Activation of EPCR and THBD in the pituitary gland will have a role in inhibiting these inflammatory molecules and other inflammatory responses, thereby modulating the progress of sepsis. EPCR and THBD are necessary for the generation of APC from inactive protein C and addition of exogenous APC has been shown to significantly reduce mortality in patients with severe sepsis [49,50].…”