Epidemic Meningococcemia and Purpura Fulminans with Induced Protein C Deficiency

Powars, Darleen R.; Larsen, Robert A.; Johnson, Jeffrey P.; Hulbert, T. V.; Sun, Tianshu; Patch, Mary Jane; Francis, Robert B.; Chan, Linda S.

doi:10.1093/clinids/17.2.254

Cited by 148 publications

(82 citation statements)

References 52 publications

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“…6 Part of the rationale for using APC to treat sepsis was that endogenous protein C levels drop rapidly in severe sepsis, 36,37 attributed in part to increased conversion of protein C to its active form APC, and subsequent inactivation of APC by serine protease inhibitors such as ␣1-antitrypsin. The decrease in protein C levels can be rapid and often occurs hours before the onset of symptoms.…”

Section: Discussionmentioning

confidence: 99%

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

Liaw

Esmon

Kahnamoui

et al. 2004

Blood

148

117

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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...

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Section: Discussionmentioning

confidence: 99%

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

Liaw

Esmon

Kahnamoui

et al. 2004

Blood

148

117

View full text Add to dashboard Cite

show abstract

“…57 Serologic tests and biomarker assays may one day be critical in the assessment and treatment of the patient with sepsis. 58 Likely candidates include C-reactive protein (CRP), [59][60][61][62][63] endotoxin (a component of Gram-negative cell walls), 58,64 brain natriuretic peptide (an indicator of myocardial dysfunction), [65][66][67] procalcitonin, 68-75 interleukin-6 and endogenous protein C. [76][77][78][79][80][81] At present their use is limited because these assay results as yet lack diagnostic accuracy, prognostic capability and timeliness; but one day, these markers may provide bedside tests to help diagnose and treat the entire spectrum of sepsis disease.…”

Section: The Clinical Link Identification Of the High-risk Patientmentioning

confidence: 99%

Early and innovative interventions for severe sepsis and septic shock: taking advantage of a window of opportunity

Rivers

McIntyre

Morro

et al. 2005

Canadian Medical Association Journal

141

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“…In our study was showed from negative correlation between protein C activity and ICAM-1 (r = -0.76 with Spearman's rho) which may suggested endothelial dysfunction with high serum ICAM-1 level correlated with low plasma protein C activity level. The low level of plasma protein C activity found i n sepsis patients and increasing risk of death (17,18,19,20). This study could not give a good evidence for protein C activity testing as a predictor marker for clinical outcome from the first admission into the ICU or for monitoring in serial testing.…”

Section: Discussionmentioning

confidence: 75%

Lipopolysaccharide Binding Protein, Soluble-Intercellular Adhesion Molecule-1, Procalcitonin, and Protein C Activity and Clinical Outcome in Systemic Inflammatory Response Syndrome (SIRS) or Sepsis Patients

2009

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BACKGROUND: Biochemical markers may be used in diagnosis, prognostic and monitoring treatment and therapy for sepsis patients. In this study we used Lipopolysacharide Binding Protein (LBP), serum-Intercellular Adhesion Molecule-1 (ICAM-1), Procalcitonin (PCT) and protein C activity. LBP is related to lipopolysachharide or gram-negative bacterial endotoxin which bound to LBP and induced inflammatory response. ICAM-1 is associated with endothelial dysfunction in response to systemic inflammatory and septic condition. PCT increased in bacterial infection and in severe systemic inflammatory. Role of Protein C is protecting the intravascular system to systemic inflammation, sepsis and the concomitant intravascular coagulopathy. The aim of this study was to examine the associations between levels of serum LBP, sICAM-1, PCT, and protein C activity with the clinical outcome of SIRS or sepsis patients.METHODS: We included 19 post surgery patients with SIRS criteria from intensive care unit (ICU) and evaluated the level of LBP serum with Chemiliuminescent Enzyme Immunoassay (Diagnostic Product Co.), ICAM-1 with ELISA (R&D System), PCT with immunochromatography (BRAHMS), protein C activity with chromogenic method (Dade Behring). We performed the samples serially at the first admission of patients and after 72 hours. Data were analysed by non-parametric with Wilcoxon test and Mann-Whitney test. Correlation study between biomarkers calculated by Kendall’s tau and Spearman’s rho.RESULTS: Of 19 patients, 9 (47,4%) died and 10 (52,6%) surviving. The level of LBP serum decreased after 72 hours in surviving-sepsis patients, and increased in nonsurviving sepsis patients with significant different levels at 72 hours examination (P<0.05). The level of soluble-ICAM-1 which was high in the first admission showed in non-surviving sepsis patients, but the difference levels was not significant between surviving and non-surviving patients (P>0.05). In all patients were found high level of PCT serum since the first admission examination, decreasing levels were occurred significantly in surviving patients after 72 hours (P<0.05) where high PCT levels were found in non-surviving patients after 72 hours. The median level of plasma protein C activity was low at the first admission especially in non-surviving sepsis patients, the decreasing level was not significantly different after 72 hours (P>0.05) both in surviving and non-surviving patients.CONCLUSIONS: Increasing level of LBP and PCT in sepsis patients showed that those biomarkers useful for predict the clinical outcome in sepsis patients. Decreasing protein C activity level was not a good predictor in worsening clinical outcomes. Soluble ICAM-1 level was not a good marker for predict risk of sepsis severity. LBP and PCT tests were more useful in serially testing from the first admission of sepsis patients, those tests are more faster than bacterial culture.KEYWORDS: Sepsis, SIRS, Lipopolysachharide Binding Protein, soluble- Intercellular Adhesion Molecule-1, Procalcitonin, Protein C

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Epidemic Meningococcemia and Purpura Fulminans with Induced Protein C Deficiency

Cited by 148 publications

References 52 publications

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

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

Early and innovative interventions for severe sepsis and septic shock: taking advantage of a window of opportunity

Lipopolysaccharide Binding Protein, Soluble-Intercellular Adhesion Molecule-1, Procalcitonin, and Protein C Activity and Clinical Outcome in Systemic Inflammatory Response Syndrome (SIRS) or Sepsis Patients

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