Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence of severe sepsis increases dramatically with advanced age, with a mortality rate that approaches 50%. The main purpose of this investigation was to determine both short- and long-term survival outcomes among 386 patients aged >or=75 years who were enrolled in the Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) trial. Subjects who were treated with drotrecogin alfa (activated; DAA) had absolute risk reductions in 28-day and in-hospital mortality of 15.5% and 15.6%, respectively (P=.002 for both), compared with placebo recipients. The relative risk (RR) for 28-day mortality was 0.68 (95% confidence interval [CI], 0.54-0.87), and the in-hospital RR was 0.70 (95% CI, 0.56-0.88). Resource use and patient disposition for DAA-treated patients compared favorably with those for placebo recipients. In addition, long-term follow-up data were available for 375 subjects (97.2%), and survival rates for DAA recipients were significantly higher over a 2-year period (P=.02). The incidences of serious adverse bleeding during the 28-day study period in the DAA and placebo groups were 3.9% and 2.2%, respectively (P=.34). There was no interaction between age and bleeding rates (P=.97). In conclusion, older patients with severe sepsis have higher short- and long-term survival rates when treated with DAA than when treated with placebo but an increased risk of serious bleeding that is not aged related.
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PMID:Drotrecogin alfa (activated) treatment of older patients with severe sepsis. 1285 11

The protein C anticoagulant pathway serves as a major system for controlling thrombosis, limiting inflammatory responses, and potentially decreasing endothelial cell apoptosis in response to inflammatory cytokines and ischemia. The essential components of the pathway involve thrombin, thrombomodulin, the endothelial cell protein C receptor (EPCR), protein C, and protein S. Thrombomodulin binds thrombin, directly inhibiting its clotting and cell activation potential while at the same time augmenting protein C (and thrombin activatable fibrinolysis inhibitor [TAFI]) activation. Furthermore, thrombin bound to thrombomodulin is inactivated by plasma protease inhibitors > 20 times faster than free thrombin, resulting in increased clearance of thrombin from the circulation. The inhibited thrombin rapidly dissociates from thrombomodulin, regenerating the anticoagulant surface. Thrombomodulin also has direct anti-inflammatory activity, minimizing cytokine formation in the endothelium and decreasing leukocyte-endothelial cell adhesion. EPCR augments protein C activation approximately 20-fold in vivo by binding protein C and presenting it to the thrombin-thrombomodulin activation complex. Activated protein C (APC) retains its ability to bind EPCR, and this complex appears to be involved in some of the cellular signaling mechanisms that down-regulate inflammatory cytokine formation (tumor necrosis factor, interleukin-6). Once APC dissociates from EPCR, it binds to protein S on appropriate cell surfaces where it inactivates factors Va and VIIIa, thereby inhibiting further thrombin generation. Clinical studies reveal that deficiencies of protein C lead to microvascular thrombosis (purpura fulminans). During severe sepsis, a combination of protein C consumption, protein S inactivation, and reduction in activity of the activation complex by oxidation, cytokine-mediated down-regulation, and proteolytic release of the activation components sets in motion conditions that would favor an acquired defect in the protein C pathway, which in turn favors microvascular thrombosis, increased leukocyte adhesion, and increased cytokine formation. APC has been shown clinically to protect patients with severe sepsis. Protein C and thrombomodulin are in early stage clinical trials for this disease, and each has distinct potential advantages and disadvantages relative to APC.
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PMID:The protein C pathway. 1297 Jan 21

Severe sepsis is common, frequently fatal, and expensive. Many factors related to the pathogenesis of severe sepsis have made it difficult to effectively design clinical trials for the management of this disease. Hence, multiple trials of compounds for the treatment of severe sepsis have yielded largely negative results, except in small subsets of patients. This review provides a synopsis of the complex nature of sepsis and the problems associated with sepsis trials. Emphasis is placed on the difficulties in evaluating investigational agents in patients with severe sepsis because of the heterogeneity of the disorder, lack of correlation between animal and human models, the complexity of the insult and the host reaction, and the interaction between inflammation and coagulation in severe sepsis. Additionally, positive results from trials of steroids, intensive insulin therapy, and activated protein C (drotrecogin alfa [activated]) will be discussed. Because drotrecogin alfa (activated) is the only Food and Drug Administration-approved therapy for severe sepsis, the Phase 3 Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial results will be discussed in detail to help define a model for further clinical trials on severe sepsis.
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PMID:Clinical trial design and outcomes in patients with severe sepsis. 1475 95

In separate studies on Neisseria meningitidis sepsis, Powars and Fiynvandraat suggested that low protein C levels may be responsible for disseminated intravascular coagulopathy and purpura fulminans. Following on this observation, we used protein C concentrate in an 18-year-old male patient with septic shock and purpura fulminans. The patient's coagulation parameters were seriously altered: AT 45%; protein C 21%; PT 50%; platelets 55000; D-dimer 2400. Early treatment included immediate administration of 3000 IU of antithrombin and intensive therapy: antibiotic therapy, volemic replacement, supported by inotropic drugs and oxygen therapy. Given the patient's low protein C levels and the progression of purpura, replacement therapy with protein C concentrate was instituted. The initial dose of 80 IU/kg/bw (5600 IU) in bolus, was adjusted according to blood laboratory values and then set at 2000 IU every 8 hours for 4 days. An increase in protein C was observed (78%) after the 1st administration, while the D-dimer levels fell by 50%. By day 7, the patient's cardiocirculatory conditions had stabilized and the coagulation parameters had normalized; the patient was discharged from the intensive care unit. Protein C replacement therapy normalized the coagulation parameters and blocked the evolution of the skin injuries.
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PMID:Replacement treatment with protein C in an 18-year-old man with meningococcal sepsis and purpura fulminans. 1456 39

In recent years, we have considerably widened our knowledge of the pathophysiology of sepsis and some procedures, aiming both to relieve symptoms and control the inflammation/coagulation reaction, have proven to be effective in increasing survival. This improves when mechanical ventilation is applied with low tidal volumes, fluid replacement and the use of cardioactive drugs are titrated on the oxygen saturation of hemoglobin in the central venous system and blood glucose does not exceed certain limits. It is also evident that inflammation and coagulation are closely related to each other. The inhibition of only one pathway, such as the inhibition of inflammation with high dosage steroids or the inhibition of coagulation with antithrombin, does not produce a survival improvement. The only molecule which has proven to be notably effective in reducing mortality is Activated Protein C interacting on coagulation/fibrinolysis, as well as on inflammation processes. Multinodal modulation of several interdependent processes may be the probable reason for the proven effectiveness of this treatment.
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PMID:Sepsis: state of the art. 1456 52

Neonatal thrombosis is a serious event that can cause mortality or result in severe morbidity and disability. The most important risk factor for the development of thrombosis during the neonatal period is the presence of an indwelling central line and consequently the vessels involved tend to be those most frequently used for catheterization. Other documented risk factors for the development of neonatal thrombosis include asphyxia, septicemia, dehydration, maternal diabetes and cardiac disease. Main laboratory findings for the diagnosis of hypercoagulable states, include shortened aPTT, decreased levels of inhibitors (AT III, Protein C and Protein S), increased resistance to activated protein C, defective fibrinolysis (basal and after stimuli), increased levels of clotting factors (fibrinogen, factor VII, factor VIII, etc.), increased and/or hyperactive platelets, increased whole blood and/or plasma viscosity, Antiphospholipid antibodies and presence of prothrombotic molecular defects like FV Leiden, P20210 and MTHFR. Approximately 4% and 2% respectively of Caucasians are heterozygous for these gene defects. Their causative role in neonatal thrombosis is unknown but they may have a contributory role in the pathogenesis of thrombosis in neonates.
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PMID:Neonatal thrombosis. 1470 31

Drotrecogin alfa (activated) [Xigris] (DAA), the recombinant form of human activated protein C, is approved as an adjunctive therapy for patients with severe sepsis (sepsis associated with > or = 1 organ system failure [OSF]). In the international, randomised, double-blind, placebo-controlled PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) study, the absolute reduction in 28-day all-cause mortality with intravenous DAA 24 micro g/kg/h for 96 hours plus conventional care versus conventional care alone was 6.1%. Although lacking statistical power, a prospectively planned subgroup analysis of this study suggested that the absolute reduction in mortality increased in patients with a baseline APACHE (Acute Physiology and Chronic Health Evaluation) II score of > or = 25 or > or = 2 OSFs, with no clear treatment effect in patients with an APACHE II score of < or = 24 or 1 OSF. Three fully published cost-effectiveness/cost-utility models of DAA plus conventional care relative to conventional care alone adopted a national healthcare payer's and/or societal perspective in North America. The base-case (baseline) discounted incremental cost per life-year gained (LYG) with DAA for all patients with severe sepsis was $US15,801-33,300 (year of costing 2000-2002). The results were more favourable for patients with an APACHE II score of > or = 25 ($US10,833-19,723 per LYG), but considerably worse for patients with an APACHE II score of < or = 24 based on a post hoc reanalysis by the US FDA. Among several fully or partly published cost-effectiveness/cost-utility models that adopted a national healthcare payer's perspective in continental Western European countries, the base-case (baseline) undiscounted incremental cost per LYG was broadly similar and more favourable for patients with > or = 2 OSFs (9660-11,300 euros; year of costing/publication 1998/1999, 2000, 2002 or 2003) than for all patients with severe sepsis (13,436-15,071 euros) in those studies that reported both analyses. The DAA acquisition cost accounts for up to 95% of the additional cost of using the drug. In conclusion, DAA is a major advance in the treatment of severe sepsis, based on the significant mortality reduction observed in the PROWESS study. From a hospital/hospital pharmacy perspective, the drug is associated with a high acquisition cost and a small increase in other short-term costs. From a societal or national healthcare payer's perspective, however, its administration to patients who meet the PROWESS study inclusion criteria, especially individuals with more severe disease (e.g APACHE II score of > or =25 and/or > or = 2 OSFs), has a lifetime cost-effectiveness profile that compares well to that of many widely accepted therapies.
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PMID:Drotrecogin alfa (activated): a pharmacoeconomic review of its use in severe sepsis. 1513 83

Protein C is a vitamin-K-dependent zymogen, whose congenital deficiency state leads to increased risk for venous thrombosis. Activated Protein C (aPC) exerts its anticoagulant function by inhibiting the cofactors in the clotting cascade, Factors Va and VIIIa. In addition, aPC displays anti-inflammatory, anti-apoptotic and profibrinolytic activities. A recombinant form of human aPC (rhAPC) is the first drug reported to improve survival in patients with severe sepsis. The major toxicity associated with treatment is bleeding. Appropriate use of rhAPC depends on an understanding of its mechanisms of action and risk:benefit profile. The goals of this review are: to describe the Protein C pathway; to discuss the definitions, epidemiology and pathophysiology of severe sepsis; to provide a conceptual framework for understanding the role of rhAPC in this syndrome; and to address frequently asked questions about the day-to-day use of this agent.
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PMID:Natural anticoagulant inhibitors: activated Protein C. 1517 65

The coagulation disturbance, typical of septic conditions, is associated to a reduction of clotting factors in plasma with an "acquired" deficiency (from consumption) of protein C. As observed with "purpura fulminans" in neonates affected by congenital protein C deficiency, administration of protein C concentrate has proved to reduce thrombotic manifestations and to improve morbidity and mortality of children with septic shock. The Protein C concentrate is presently utilized as a therapy for patients with a congenital deficiency of protein C and several papers in the literature support the efficacy of protein C concentrate in the treatment of children with meningococcus septicemia, with the aim of correcting the acquired protein C deficiency often seen in septic conditions and shown to be strongly correlated to a higher morbidity and mortality. Protein C, given as a plasma concentrate, can exert its therapeutic actions only after activation once in the blood stream: clinical trials with the use of protein C concentrate failed to show any increased risk of bleeding or related disorders. At our PICU 8 children, with sepsis, septic shock and purpura have been treated with protein C concentrate (Ceprotin); because the plasma protein C level was lower than the normal range (mean value 0.32 IU/ml, range 0.11-0.6 IU/ml). Six children have shown a rapid response to all therapeutic efforts and survived without sequelae and two are died. No adverse reaction was observed during and after Ceprotin administration to all patients.
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PMID:[Use of protein C concentrate in critical conditions: clinical experience in pediatric patients with sepsis]. 1518 16

No identifiable cause can be found in more than half of the cases of portal vein thrombosis (PVT). Our aim was to assess the prevalence of factor V Leiden mutation and other thrombophilic factors as risk factors in the development of PVT in the pediatric age group. From March 2001 to January 2002, 40 children with PVT were enrolled in the study, in addition to 20 age-matched and sex-matched controls. Protein C, protein S, antithrombin III, and activated protein C resistance (APCR) were assayed. Molecular study of factor II and factor V mutations was carried out. Of the patients, 25 had detectable hereditary thrombophilia (62.5%), 12 had factor V Leiden mutation (30%), 11 had protein C deficiency (27.5%), 6 had factor II mutation (15%), 1 had antithrombin III deficiency (2.5%), and none had protein S deficiency. Five children had concurrence of more than one defect. Factor V Leiden mutation is the most common hereditary thrombophilia associated with PVT and the relative risk of factor V Leiden mutation, as a cause of PVT, was six times more than in controls (odds ratio=6). Concurrence of more than one hereditary thrombophilic factor was seen in 12.5% of our patients. Circumstantial risk factors (neonatal sepsis, umbilical sepsis, umbilical catheterization) were not more significantly prevalent among patients with hereditary thrombophilia than among those with no detectable abnormalities in anticoagulation.
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PMID:Prevalence of factor V Leiden mutation and other hereditary thrombophilic factors in Egyptian children with portal vein thrombosis: results of a single-center case-control study. 1530 26


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