Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the effects of substitution with a virus-inactivated protein C (PC) concentrate in disseminated intravascular coagulation (DIC) in infants and children with meningococcal sepsis associated with purpura fulminans. It was a prospective open-label study. Eight pediatric and adolescent patients age 0.2 to 18.25 years with DIC associated with severe acquired PC deficiency (range 0.02 to 0.48 IU/mL; median, 0.22 IU/mL) in meningococcal septic shock and purpura fulminans were studied. Replacement therapy was initiated with a virus-inactivated PC concentrate with an initial intravenous bolus of 80 to 120 IU/kg followed by 50 IU/kg up to six times per day as an adjunctive therapeutic regimen to otherwise optimal intensive care treatment. After initial PC administration, plasma PC levels rose to normal ranges and were maintained under PC replacement therapy. Improving or even normalizing global hemostatic parameters were assessed in all patients. Markedly elevated plasminogen activator inhibitor type 1 (PAI-1) levels prior to treatment, reflecting a reduced fibrinolytic potential, decreased rapidly under PC substitution. Concomitantly improving signs of purpura fulminans reflected by decreasing size of skin lesions, demonstrated a restoring microcirculation. Six of the eight patients survived. One patient required limb amputation; two patients died because of multiorgan failure. Both presented with a severely low plasma PC activity of 0.02 IU/mL on admission to the hospital. No adverse effects were observed with the PC concentrate administration. It can be concluded that the administration of PC concentrate had a marked benefit on the deranged coagulation status of patients with purpura fulminans and meningococcal septicemia. Normalization or even partial correction of hemostasis as well as improvement of microcirculation accompanied by improving signs of purpura fulminans were demonstrated in all patients.
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PMID:Replacement therapy with protein C concentrate in infants and adolescents with meningococcal sepsis and purpura fulminans. 1063 75

Proteins influencing plasminogen activation to plasmin, namely plasminogen activators tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) and their principal inhibitors, plasminogen activator inhibitor 1 (PAI-1) and PAI-2, were measured in the plasma, the polymorph and mononuclear cell fractions taken from patients with major sepsis who were entering a general intensive care unit. The purpose of this study was to elucidate the factors favouring the persistence of fibrin in the microvasculature and thus contributing to multiple organ failure. Levels of u-PA antigen in plasma rose in sepsis and u-PA activity, not detectable in normal plasma, appeared. Levels of u-PA antigen in the cell fractions fell concomitantly. t-PA antigen in plasma and in the mononuclear cell fraction rose in sepsis, but t-PA activity was not detectable. Plasma PAI-1 antigen levels were strikingly raised in sepsis, presumably accounting for the complete neutralization of t-PA activity. PAI-2 antigen, not normally detected in plasma, appeared in the plasma of some patients, whereas it disappeared from the cellular fractions. Appearance of PAI-2 in plasma was associated with non-survival of the patient. The observations indicate that all the agents involved in plasminogen activation are released into the plasma in major sepsis. The levels of PAI-1 reached were quantitatively sufficient to suppress all activity of the released t-PA, but the inhibitors did not prevent expression of u-PA activity in the circulation. Circulating active u-PA and PAI-2 in the plasma of patients with severe sepsis may represent material originating from leucocytes. Leucocyte release of these agents within fibrin deposits may influence the persistence of fibrin and thus the development of multiple organ failure.
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PMID:Plasminogen activator inhibitor 2 and urokinase-type plasminogen activator in plasma and leucocytes in patients with severe sepsis. 1084 22

Monocytes play a pivotal role in various human infectious and inflammatory diseases. To reveal a whole picture of pathophysiologic function of activated human monocytes, this study used the serial analysis of gene expression (SAGE) procedure in lipopolysaccharide (LPS)-stimulated human monocytes. A total of 35 874 tags corresponding to more than 12 000 different transcripts were sequenced. Comparison of gene expression profile with that of resting monocytes revealed the LPS-inducible gene expression profile. Many cytokines and chemokines, including interleukin (IL)-6, IL-1alpha, IL-1beta, tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1beta, MIP-2beta, MIP-2alpha, liver and activation-regulated chemokine (LARC), MIP-1alpha, thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), regulated on activation, normal T cell expressed and secreted (RANTES), growth-regulated oncogene (GRO) alpha, and IL-8, were observed in the highest inducible transcripts. Other genes encoding plasminogen activator inhibitor type 2 (PAI-2), Hc-gp39, apolipoproteins, malate dehydrogenase, matrix metalloproteinase-9 (MMP-9), and cyclooxygenase (COX2) were also highly elevated in LPS-stimulated monocytes. Moreover, up-regulation of Naf1beta, IL-7 receptor, adenosine receptor A2a, and many novel genes was newly identified. These results suggest that the LPS-inducible gene products may be involved in cell activation and migration, angiogenesis, tissue remodeling, and metabolism, and thus may orchestrate the inflammatory reactions. On the other hand, the expression of numerous sets of novel genes was discovered to be down-regulated on LPS stimulation. This study represents the first comprehensive analysis of LPS-inducible gene expression in human monocytes and provides tremendous novel information for the function of LPS-activated monocytes and targets for diagnosing, monitoring, and treating sepsis and various human infectious and inflammatory diseases.
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PMID:Comprehensive gene expression profile of LPS-stimulated human monocytes by SAGE. 1100 15

Endothelial damage plays a central role in the development of an SIRS-related Multiple Organ Dysfunction Syndrome (MODS) as a consequence of the establishment of a hemostatic imbalance between coagulation and fibrinolysis systems. Until now, sepsis is the SIRS model that has been most studied. The aim of this study was to assess the endothelial damage and the hemostatic imbalance in early stages of an SIRS of different origins, and to study if there are any differences in these disturbances between infectious and noninfectious SIRS. The endothelial damage and hemostatic changes were studied in 40 patients with SIRS (with less than 12 h of evolution) and an acute renal failure. Infectious SIRS was diagnosed in 19 cases and noninfectious SIRS in the remaining 21 patients. Patients with SIRS presented significantly higher values (p<0.001) for factors related to endothelial damage [von Willebrand factor (vWF), thrombomodulin, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor type 1 (PAI-1) antigen], hypercoagulability [prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complexes (TAT)], and fibrinolysis (D-dimer and PAI activity) with respect to the control group. However, although the group with infectious SIRS presented higher values for all the factors except for the t-PA and D-dimer with respect to SIRS of other origins, none of these differences reached statistical significance (p>0.05). Our data show that patients with SIRS and associated acute renal failure, irrespective of the origin (infectious or noninfectious), show signs of intense endothelial damage and hypercoagulability throughout the process.
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PMID:Hemostatic disturbances in patients with systemic inflammatory response syndrome (SIRS) and associated acute renal failure (ARF). 1105 12

During the past 20 years several treatments designed to reduce inflammatory responses to sepsis have been unsuccessful. Sepsis results from a generalised inflammatory and procoagulant response to an infection. Activated protein C, a component of the anticoagulant system, is an anti-thrombotic serine protease with anti-inflammatory properties. A recently published study reported the results of a large clinical trial in which recombinant human activated protein C significantly reduced mortality in patients with severe sepsis. Treatment with activated protein C also reduced circulating D-dimer and IL-6 levels, which are markers of coagulation activation and inflammation. There are several reasons why activated protein C could be effective in sepsis. Firstly, reduced levels of protein C are found during sepsis and are associated with an increased risk of death. Secondly, activated protein C can directly inhibit factors Va and VIIIa, resulting in decreased thrombin formation. Finally, activated protein C can reduce plasminogen activator inhibitor I, thereby stimulating fibrinolysis. In addition to these effects on thrombin formation, activated protein C directly reduces pro-inflammatory responses by as yet unknown mechanisms.
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PMID:[Activated protein C, coagulation, inflammation, and treatment of severe sepsis]. 1143 70

In this study, we examined changes in the plasma levels of total plasminogen activator inhibitor-I (PAI-I) and tissue-type plasminogen activator (tPA)/PAI-I complex in patients with disseminated intravascular coagulation (DIC) and in those with thrombotic thrombocytopenic purpura (TTP) to investigate the fibrinolytic function and its relation to organ failure. The plasma levels of total PAI-1 and tPA/PAI-I complex were significantly higher in patients with DIC, pre-DIC, and TTP than in those with non-DIC. The plasma levels of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), D-dimer, thrombomodulin (TM), total PAI-I, and tPA/PAI-I complex were significantly higher in patients with organ failure than in those without organ failure. The plasma levels of total PAI-I and tPA/PAI-I complex were markedly increased in patients with acute leukemia. The plasma levels of total PAI-I, but not those of tPA/PAI-I complex, were significantly increased in patients with sepsis or with solid cancer. In all cases, total PAI-I or tPA/PAI-I complex was not significantly correlated with any hemostatic marker. Measurement of total PAI-I and tPA/PAI-I complex may be useful in the diagnosis of DIC.
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PMID:Plasma levels of total plasminogen activator inhibitor-I (PAI-I) and tPA/PAI-1 complex in patients with disseminated intravascular coagulation and thrombotic thrombocytopenic purpura. 1144 85

Despite significant progress in intensive care medicine, the mortality of septic shock has not changed in recent years. Early recognition of subtle signs in favor of meningococcal sepsis, early antibiotic treatment, and aggressive hemodynamic support remains the cornerstone of therapy of severe meningococcal shock in children. Recent work has emphasized the role of genetic polymorphisms in various systems to explain the most severe cases: anti-inflammatory cytokine profile IL-10/TNF-alpha, elevated levels of plasminogen activator inhibitor type-1, variants of the gene for mannose-binding lectin complement pathway. This may explain the disillusionment of pediatric intensivists, and the general failure of immunotherapy for sepsis. Reasonable hope lies upon new meningococcal vaccines.
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PMID:[Meningococcal purpura fulminans: untoward result of genetic polymorphism?]. 1152 16

Studies in experimental models for sepsis, the most common cause of disseminated intravascular coagulation (DIC), have put forward the concept of a procoagulant state that is characterized by thrombin generation exceeding that of plasmin. Convincing evidence indicates that this imbalance between coagulation and fibrinolysis is due to increased levels of plasminogen activator inhibitor type 1 (PAI-1). Levels of this fibrinolysis inhibitor indeed correlate with outcome and severity of multiple organ failure in patients with sepsis, as well as in patients with DIC from other causes. Hence we suggest that PAI-1 constitutes an important target for therapy in patients with DIC.
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PMID:Fibrinolysis in disseminated intravascular coagulation. 1174 Jun 86

Sepsis and trauma are the two most common causes of disseminated intravascular coagulation and multiple organ dysfunction syndrome. Both disseminated intravascular coagulation and the systemic inflammatory response syndrome often lead to multiple organ dysfunction syndrome. The current studies have evaluated the relationship between the anaphylatoxin, C5a, and changes in the coagulation/fibrinolytic systems during the cecal ligation and puncture (CLP) model of sepsis in rats. CLP animals treated with anti-C5a had a much improved number of survivors (63%) compared to rats treated with pre-immune IgG (31%). In CLP rats treated with pre-immune IgG there was clearly increased procoagulant activity with prolongation of the activated partial thromboplastin time and prothrombin time, reduced platelet counts, and increased levels of plasma fibrinogen. Evidence for thrombin formation was indicated by early consumption of factor VII:C, subsequent consumption of factors XI:C and IX:C and anti-thrombin and increased levels of the thrombin-anti-thrombin complex and D-dimer. Limited activation of fibrinolysis was indicated by reduced plasma levels of plasminogen and increased levels of tissue plasminogen activator and plasminogen activator inhibitor. Most of these parameters were reversed in CLP rats that had been treated with anti-C5a. Production of C5a during sepsis may directly or indirectly cause hemostatic defects that can be reduced by blockade of C5a.
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PMID:Anti-c5a ameliorates coagulation/fibrinolytic protein changes in a rat model of sepsis. 1200 Jul 38

Systemic inflammation because of sepsis results in endothelial cell activation and microvascular injury. High-mobility group protein-1 (HMGB1), a novel inflammatory molecule, is a late mediator of endotoxin shock and is present in the blood of septic patients. The receptor for advanced glycation end products (RAGE) is expressed on endothelium and is a receptor for HMGB1. Here we examine the effects of HMGB1 on human endothelial cell function. Recombinant human HMGB1 (rhHMGB1) was cloned and expressed in Escherichia coli and incubated with human microvascular endothelium. rhHMGB1 caused a dose- and time-dependent increase in the expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and RAGE. rhHMGB1 induced the secretion of tumor necrosis factor-alpha (TNFalpha), interleukin 8 (IL-8), monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), and tissue plasminogen activator (tPA) (P <.01). rhHMGB1 stimulation resulted in transient phosphorylation of mitogen-activated protein (MAP) kinases, extracellular signal-related kinase (ERK), Jun N-terminal kinase (JNK), and p38, and in nuclear translocation of transcription factors NF-kappaB and Sp1. These effects are partially mediated by TNFalpha autocrine stimulation, as anti-TNFalpha antibodies significantly decrease chemokine and adhesion molecule responses (P </=.002). Thus, rhHMGB1 elicits proinflammatory responses on endothelial cells and may contribute to alterations in endothelial cell function in human inflammation.
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PMID:Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. 1245 6


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