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

Thrombin is a multifunctional protein, with procoagulant, inflammatory and anticoagulant effects. Binding of thrombin to thrombomodulin results in activation of Protein C and initiation of the Activated Protein C anticoagulant pathway, a process that is augmented by the endothelial cell Protein C receptor (EPCR). Activated Protein C has demonstrated antithrombotic, anti-inflammatory, and profibrinolytic properties. Its antithrombotic activity is particularly important in the microcirculation, and Protein C deficiency is associated with microvascular thrombosis. Activated Protein C has also been shown to modulate inflammation. When the level of thrombomodulin or Protein C is reduced in sepsis there is a vicious cycle of coagulation and inflammation, with potentially lethal consequences. In vitro studies and animal models have shown that Activated Protein C blunts the inflammatory and coagulant response to sepsis through a variety of mechanisms.
 ...
PMID:The normal role of Activated Protein C in maintaining homeostasis and its relevance to critical illness. 1137 86

It is becoming increasingly clear that coagulation augments inflammation and that anticoagulants, particularly natural anticoagulants, can limit the coagulation induced increases in the inflammatory response. The latter control mechanisms appear to involve not only the inhibition of the coagulation proteases, but interactions with the cells that either generate anti-inflammatory substances, such as prostacyclin, or limit cell activation. Recent studies have demonstrated a variety of mechanisms by which coagulation, particularly the generation of thrombin, factor Xa and the tissue factor-factor VIIa complex, can augment acute inflammatory responses. Many of these responses are due to the activation of one or more of the protease activated receptors. Activation of these receptors on endothelium can lead to the expression of adhesion molecules and platelet activating factor, thereby facilitating leukocyte activation. Therefore, anticoagulants that inhibit any of these factors would be expected to dampen the inflammatory response. The three major natural anticoagulant mechanisms seem to exert a further inhibition of these processes by impacting cellular responses. Antithrombin has been shown in vitro to increase prostacyclin responses and activated protein C has been shown to inhibit a variety of cellular responses including endotoxin induced calcium fluxes in monocytes and the nuclear translocation of NFKB, a key step in the generation of the inflammatory response. In some, but not all, in vivo models, these natural anticoagulants have been able to inhibit endotoxin/E. coli-mediated leukocyte activation and to diminish cytokine elaboration (TNF, IL-6 and IL-8). Phase III clinical studies for treatment of patients with severe sepsis have been completed for APC, which was successful (1), and for antithrombin, which was not (2). A phase III trial with tissue factor pathway inhibitor is in progress. In this review, the mechanisms by which the different natural anticoagulants are thought to function will be reviewed.
 ...
PMID:Role of coagulation inhibitors in inflammation. 1148 41

The 26th Congress of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine took place in the state-of-the art Tromso University Hospital. There were over 500 participants, and approximately 300 oral and poster presentations highlighted the latest progress in diverse areas. Much interest focused on activated protein C (APC) and other ways forward in sepsis treatment, pain management, novel markers of neurotrauma and antioxidants in bypass surgery. The meeting continues to be the leading anaesthesiology and intensive care conference in the region.
 ...
PMID:The 26th Congress of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine, Tromso, Norway, 13-17 June 2001. 1151 33

Mutations in the gene encoding thrombomodulin (TM), a thrombin regulator, are suspected risk factors for venous and arterial thrombotic disease. We have previously described the generation of TM(Pro/Pro) mice carrying a TM gene mutation that disrupts the TM-dependent activation of protein C. Here, it is shown that inbred C57BL/6J TM(Pro/Pro) mice exhibit a hypercoagulable state and an increased susceptibility to thrombosis and sepsis. Platelet thrombus growth after FeCl(3)-induced acute endothelial injury was accelerated in mutant mice. Vascular stasis after permanent ligation of the carotid artery precipitated thrombosis in mutant but not in normal mice. Mutant mice showed increased mortality after exposure to high doses of endotoxin and demonstrated altered cytokine production in response to low-dose endotoxin. The severity of the hypercoagulable state and chronic microvascular thrombosis caused by the TM(Pro) mutation is profoundly influenced by mouse strain-specific genetic differences between C57BL/6 and 129SvPas mice. These data demonstrate that in mice, TM is a physiologically relevant regulator of platelet- and coagulation-driven large-vessel thrombosis and modifies the response to endotoxin-induced inflammation. The phenotypic penetrance of the TM(Pro) mutation is determined by as-yet-uncharacterized genetic modifiers of thrombosis other than TM.
 ...
PMID:Characterization of a mouse model for thrombomodulin deficiency. 1155 84

During the past 15 years, several anti-inflammatory treatments have failed to reduce mortality in patients with severe sepsis. However, recent evidence indicates that coagulation abnormalities in sepsis may play a major role in the pathogenesis of multiple organ failure and the high mortality rate in patients with severe sepsis. Interestingly, blockade of the coagulant pathway can inhibit both procoagulant and proinflammatory pathways in sepsis. Protein C, a natural anticoagulant, interrupts several of the pathophysiologic pathways in sepsis. Acquired protein C deficiency is present in the majority of septic patients and is associated with unfavorable outcomes. Protein C replacement therapy was effective in preclinical animal models of sepsis in reducing end-organ damage and mortality. Recent clinical trials of protein C replacement in human meningococcemia resulted in a markedly decreased morbidity and mortality. And, most importantly, in a recently completed large, randomized trial of activated protein C treatment in severe sepsis, mortality was reduced from 30.8% in the placebo group to 24.7% in the treatment group at 28 days. Thus, there is new evidence that mortality can be reduced among patients with severe sepsis through the use of a new therapy that inhibits the procoagulant and the inflammatory cascades.
 ...
PMID:The Role of Protein C in Sepsis. 1155 61

Adjuvant therapy for severe sepsis and shock can be divided into 4 groups. The first group comprises those compounds with proven efficacy in human studies (activated protein C and recombinant bacterial permeability-increasing protein). The second group includes compounds with potential efficacy (heparin), while the third group represents those with no demonstrated efficacy in randomised clinical trials (tumour necrosis factor and interleukin-1 antibodies and receptor antagonists). The fourth group includes those drugs which have been found to be potentially effective in animal studies, but which have not yet been evaluated in humans (i.e., tyrosine kinase inhibitors, selective inducible nitric oxide synthase inhibitors, polyadenosine-diphosphate-ribose-polymerase and caspase III (apoptosis) inhibitors). Formal clinical comparisons between the various treatment options are necessary to assist the clinician in selecting the appropriate form of therapy.
 ...
PMID:[Adjuvant therapies for sepsis and shock: which are more effective?]. 1157 77

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.
 ...
PMID:[Idiopathic purpura fulminans with transient protein S deficiency]. 1157 47

Many sequelae associated with endotoxaemic-induced shock result from excessive production of the cytokine mediators, tumour necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1) and IL-6 from lipopolysaccharide (LPS)-activated monocytes. Protein C (PC)/activated protein C (APC) has potent cytokine-modifying properties and is protective in animal models and human clinical trials of sepsis. The precise mechanism by which this anti-inflammatory response is achieved remains unknown; however, the recently described endothelial protein C receptor (EPCR) appears to be essential for this function. The pivotal role that monocytes play in the pathophysiology of septic shock led us to investigate the possible expression of a protein C receptor on the monocyte membrane. We used similarity algorithms to screen human sequence databases for paralogues of the EPCR but found none. However, using reverse transcription-polymerase chain reaction (RT-PCR), we detected an mRNA transcribed in primary human monocytes and THP1 cells that was identical to human EPCR mRNA. We also used immunocytochemical analysis to demonstrate the expression of a protein C receptor on the surface of monocytes encoded by the same gene as EPCR. These results confirm a new member of the protein C pathway involving primary monocytes. Further characterization will be necessary to compare and contrast its biological properties with those of EPCR.
 ...
PMID:Characterization of protein C receptor expression in monocytes. 1170 43

Sepsis remains a major cause of death in hospitalized patients. Despite a massive research effort over the past 2 decades to identify innovative therapies for sepsis, current treatment strategies consist primarily of antiinfective agents and a variety of supportive measures. Activated protein C, an endogenous protein that inhibits thrombosis and inflammation while promoting fibrinolysis, plays an important role in the pathogenesis of sepsis. Recombinant human activated protein C, drotrecogin alfa (activated), when compared with placebo in a randomized, double-blind study of 1690 patients with severe sepsis (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis [PROWESS] trial), decreased the relative risk of death at 28 days by 19.4% (95% confidence interval 6.6-30.5%, p=0.005), although there was a trend for more serious bleeding (3.5% vs 2.0%, p=0.06) with its use. Drotrecogin alfa is the first antisepsis drug found to have a mortality benefit. It should be administered only to patients with severe sepsis who meet the PROWESS study inclusion criteria and should be avoided when risk factors for bleeding are present. Ongoing research will help determine the cost-effectiveness of drotrecogin alfa, as well as its role in critically ill populations not studied in the PROWESS trial.
 ...
PMID:Recombinant human activated protein C, drotrecogin alfa (activated): a novel therapy for severe sepsis. 1171 12

At the 2001 Toronto Critical Care Medicine Symposium, exciting new research results were presented, including a randomized trial of peri-operative pulmonary-artery catheter use and evidence-based guidelines for the prevention of ventilator-acquired pneumonia. Presenters reviewed other important recent critical care developments such as (1) activated protein C and low-dose steroids in sepsis, (2) prone positioning and long-term outcomes in patients with adult respiratory distress syndrome, and (3) medical errors in the critical care unit. Along with these new findings, another theme emerged during the symposium. This theme emphasized that research breakthroughs are not sufficient in themselves: outcome studies are needed to learn how new research is applied on a large-scale basis within actual clinical practice. Furthermore, additional study is needed for an understanding of how physicians implement new research findings. Successful methods of enhancing the widespread adoption of new research require further study.
 ...
PMID:Toronto Critical Care Medicine Symposium, 18-20 October 2001, Canada: research breakthroughs are not enough. 1173 21


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>