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)

The pathogenesis of disseminated intravascular coagulation (DIC) has, in part, been attributed to the impairment of the natural anticoagulant protein C/protein S pathway. DIC, which frequently occurs during sepsis, has been linked to cytokines that can induce or modulate procoagulant activity. Three of these cytokines, IL-1 alpha, IL-6, and TNF-alpha have been reported to be increased in the early stages of sepsis. In the present study, we have stimulated HepG-2 hepatoma cell cultures with recombinant human IL-1 alpha, IL-6, TNF-alpha, and oncostatin M (OSM). The results demonstrated that TNF-alpha, and to a lesser degree, IL-1 alpha, could significantly suppress IL-6 upregulation of protein S, whereas the effects of OSM was only suppressed by the combination of IL-1 alpha and TNF-alpha. The combination of IL-1 alpha and TNF-alpha also suppressed protein S production below that of control or basal levels. These results indicate that IL-1 alpha and TNF-alpha may play important regulatory roles in coagulation.
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PMID:TNF-alpha suppresses IL-6 upregulation of protein S in HepG-2 hepatoma cells. 892 89

Purpura fulminans is associated with homozygous protein C and homozygous protein S deficiency or may follow bacterial or viral infections. We present 2 children from 2 unrelated Arab families with purpura fulminans who were double heterozygotes for factor V Leiden inherited from their fathers and protein S deficiency inherited from their mothers. No previous thrombotic events have occurred in either patient or their respective family members. In one patient sepsis accompanied by disseminated intravascular coagulation appeared to be the trigger of purpura fulminans. In the other patient varicella infection preceded purpura fulminans and was also associated with disseminated intravascular coagulation. This report emphasizes the need for evaluation of hereditary defects in the inhibitory mechanisms of blood coagulation in patients with purpura fulminans at any age.
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PMID:Purpura fulminans induced by disseminated intravascular coagulation following infection in 2 unrelated children with double heterozygosity for factor V Leiden and protein S deficiency. 924 37

In patients with sepsis and septic shock, both coagulation and fibrinolysis are activated frequently leading to the syndrome of diffuse intravascular coagulation (DIC). The different mechanisms leading to abnormalities in coagulation and fibrinolysis are discussed in detail. The coagulation and fibrinolytic system appear to be influenced by the septic process largely independently, leading to a procoagulant imbalance between these systems. Coagulation is initiated by mediator-induced expression of tissue factor and is associated with consumption of the natural coagulation inhibitors antithrombin III, protein C, and protein S. As a result, high plasma levels of thrombin-antithrombin complex (TAT) can be found. The effects on fibrinolysis are dominated by (highly) increased levels of plasminogen activator inhibitor type 1 (PAI-1), leading to inadequate fibrinolysis. Although levels of plasminogen activator antigen are increased, its activity is almost completely inhibited by PAI-1. The resulting effects predispose to a procoagulant state, with widespread fibrin deposition, which may be an important mechanism contributing to multiple organ failure. A thorough understanding of the pathophysiological mechanisms underlying the DIC-syndrome is a prerequisite for a rational approach and future therapy for this severe complication of sepsis.
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PMID:Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. 951 78

An 11-y-old girl who presented with cellulitis and clinical signs of deep vein thrombosis (DVT) is reported here. She developed staphylococcal sepsis, recurrent septic emboli and a large vegetation on the tricuspid valve. The patient was found to be heterozygous for the Arg506Gln mutation in factor Va and had low levels of protein C and protein S during the sepsis. The coexistence of the two thrombophilic states may explain the severe thromboembolic manifestations.
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PMID:Coexistence of acquired protein S and protein C deficiency and the Arg506Gln mutation in factor Va in a child with severe thromboembolic disease. 956 48

The protein C anticoagulant pathway converts the coagulation signal generated by thrombin into an anticoagulant response through the activation of protein C by the thrombin-thrombomodulin (TM) complex. The activated protein C (APC) thus formed interacts with protein S to inactivate two critical coagulation cofactors, factors Va and VIIIa, thereby dampening further thrombin generation. The proposed mechanisms by which TM switches the specificity of thrombin include conformational changes in thrombin, blocking access of normal substrates to thrombin and providing a binding site for protein C. The function of protein S appears to be to alter the cleavage site preferences of APC in factor Va, probably by changing the distance of the active site of APC relative to the membrane surface. The clinical relevance of this pathway is now established through the identification of deficient individuals with severe thrombotic complications and through the analysis of families with partial deficiencies in these components and an increased thrombotic tendency. One possible reason that even partial deficiencies are a thrombotic risk is that the function of the pathway can be down-regulated by inflammatory mediators. For instance, clinical studies have shown that the extent to which protein C levels decrease in patients with septic shock is predictive of a negative outcome. Initial clinical studies suggest that supplementation with protein C may be useful in the treatment of acute inflammatory diseases such as sepsis.
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PMID:Regulation of blood coagulation. 1070 69

Activated protein C (APC) is a natural anticoagulant that plays a pivotal role in coagulation homeostasis. Severe inherited or acquired deficiency results in a clinical syndrome called purpura fulminans. In addition, APC also appears to have potent cytokine-modifying properties and is protective in animal models of sepsis. The dual functional properties of APC are particularly relevant to severe meningococcemia, where acquired PC deficiency is accompanied by multiorgan failure and purpura fulminans. The authors conducted an open-label prospective study assessing the efficacy of PC replacement therapy in patients with severe meningococcal septicemia, purpura fulminans, and multiorgan failure. The morbidity and mortality were compared with predicted morbidity using the Glasgow Meningococcal Septicemia Prognostic Score. Thirty-six patients with a mean age of 12 years (range 3 months to 72 years) were enrolled in the study. The mean +/- SD for plasma PC was 18 +/- 7 IU/mL. PC was significantly lower than antithrombin or protein S and was also significantly lower than PC levels in a cohort of patients who developed meningococcemia without multiorgan failure and purpura fulminans. A total of 3 of 36 (8%) patients died, which compares favorably with predicted mortality of 18 of 36 (50%). Amputations were required in 4 of 33 (12%) survivors and in 2 of 31 (6.5%) patients who received PC within 24 hours of admission into the hospital, in comparison with the predicted amputation rate of 11 of 33 (30%). In conclusion, PC replacement therapy in severe meningococcal septicemia was associated with a reduction in predicted morbidity and mortality. The beneficial effect of PC replacement may reflect both the anticoagulant and anti-inflammatory properties of the PC pathway. (Blood. 2000;96:3719-3724)
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PMID:An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. 1109 52

Idiopathic purpura fulminans produces rapidly progressive hemorrhagic necrosis of the skin with disseminated intravascular coagulation in individuals without known abnormalities of the protein C pathway or acute infections. The disease mainly affects children and in 90 % of cases is preceded by a benign infection. Its pathogenesis involves a temporary autoimmune protein S deficiency that provokes a state of hypercoagulability. We present the case of a previously healthy 2-year-old boy with hemorrhagic skin lesions characteristic of purpura fulminans and disseminated intravascular coagulation without sepsis. Severe, temporary protein S deficiency was confirmed. The patient received daily replacement therapy with fresh frozen plasma for 12 days and anticoagulation with heparin for 3 months. Evolution was favorable. Although the other parameters returned to normal, protein S remained low for 50 days despite treatment. The patient has made a complete recovery.
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PMID:[Idiopathic purpura fulminans with transient protein S deficiency]. 1157 47

The role of activated protein C (APC) in coagulation, inflammation, and fibrinolysis and the pharmacology, pharmacokinetics, and trials of recombinant human activated protein C (rhAPC), or drotrecogin alfa (activated), in sepsis are described. Protein C, a naturally occurring vitamin K-dependent serine protease in the blood, remains inactive until exposed to the thrombin-thrombomodulin complex. This change between the inactive and active forms occurs constantly in humans and serves to balance the coagulation cascade. APC functions in concert with protein S as an anticoagulant, a fibrinolytic agent, and an antiinflammatory agent. In response to serious infection, a procoagulant process is activated leading to thrombin and fibrin deposition in small vessels that results in decreased blood flow, decreased oxygen delivery, and organ failure. The body's natural defense during severe sepsis is to activate protein C through the thrombin-thrombomodulin complex in an attempt to restore the imbalance of the hemostatic systems. However, APC has a short half-life, and the pool of circulating protein C is rapidly depleted in severe sepsis. Low protein C levels have been correlated with poor outcome in patients with severe sepsis and in animal models. These observations led to a Phase III safety and efficacy trial of drotrecogin alfa (activated) that demonstrated a significant improvement in mortality compared with placebo (24.7% versus 30.8%). This 6.1% absolute difference in mortality translates to a 19.4% reduction in relative risk of death in the treated patients. The proper use of drotrecogin alfa (activated) will require careful consideration of appropriate patients to treat and further studies in patient populations that were excluded from the Phase III trial, as well as possible modification of dosing schemes on the basis of patient response.
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PMID:Recombinant human activated protein C in severe sepsis. 1188 9

Inter-alpha inhibitor protein (IalphaIp) is an endogenous serine protease inhibitor in human plasma. Circulating IalphaIp levels were lower in 51 patients with severe sepsis than in healthy volunteers. Mean levels were 688+/-295 mg/L in patients with severe sepsis who survived (n=32), 486+/-193 mg/L in patients with sepsis who died (n=19), and 872+/-234 mg/L in control subjects (n=25). IalphaIp levels were lower in patients with shock versus those without (540+/-246 [n=33] vs. 746+/-290 [n=18] mg/L; P=.0102). IalphaIp levels were inversely correlated with 28-day mortality rates and Acute Physiology and Chronic Health Evaluation II scores and directly correlated with antithrombin III, protein C, and protein S levels. The administration of IalphaIp (30 mg/kg body weight intravenously) increased the 50% lethal dose in mice by 100-fold after an intravenous challenge of Escherichia coli. Thus, human IalphaIp may be a useful predictive marker and potential therapeutic agent in sepsis.
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PMID:Correlation between mortality and the levels of inter-alpha inhibitors in the plasma of patients with severe sepsis. 1296 25

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


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