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)

Protein C (PC) is an essential blood factor in the human blood coagulation cascade. PC can help achieve blood hemostasis in many deadly disease conditions such as sepsis, cancer, HIV, etc.; reduced oxygen transport due to blood agglutination within the body can cause tissue death and organ failure as a result of low oxygen transport. Our goal is to produce large quantities of low cost zymogen PC for the treatment and prevention of blood clotting resulting from many disease states, as well as provide an effective therapy for PC deficiency. Current studies show that Immobilized Metal Affinity Chromatography (IMAC) has high specificity and can be used for difficult separations among homologous proteins at relatively low cost compared to current methods, such as Immunoaffinity Chromatography. Thus, we are investigating the optimization of IMAC for the separation and purification of PC from Cohn fraction IV-I. Molecular interactions within the chromatography column involve many parameters that include: the use and type of chromatographic gel and buffer solution, the pH, temperature, metal ion, chelator, and the sequence and structure of the protein itself. These parameters all influence the protein's interaction with the column. Experimental equilibrium isotherms show that PC has primary and secondary binding characteristics, demonstrating that the interaction is not just a simple process of one protein binding to one metal ion. Understanding the thermodynamics of interfacial interaction between proteins and surface-bound Cu2+ is essential to optimizing IMAC for PC purification, as well as for separation of other proteins in general. Hence we are undertaking theoretical and experimental studies of IDA-Cu/PC adsorption. The differences in structures of PC and other critical homologous blood factors are examined using the protein visualization program Cn3D. A better understanding of the interfacial phenomena will help determine the most effective conditions to achieve our goal.
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PMID:Protein C production: metal ion/protein interfacial interaction in immobilized metal affinity chromatography. 1659 76

After a coagulation stimulus, the blood clotting cascade amplifies largely unchecked until very high levels of thrombin are generated. Natural anticoagulant mechanisms (for example, the protein C anticoagulant pathway) are amplified to prevent excessive thrombin generation. Thrombin binds to thrombomodulin (TM) and this complex and then activates protein C approximately 1000 times faster than free thrombin. Protein C activation is enhanced approximately 20-fold further by the endothelial cell protein C receptor (EPCR). Activated protein C proteolytically inactivates factor Va (FVa) and FVIIIa, thereby blocking the amplification of the coagulation system, a process that is accelerated by protein S. TM not only accelerates protein C activation, but also decreases endothelial cell activation by blocking high-mobility group protein-B1 inflammatory functions and suppressing both nuclear factor-kappa B nuclear translocation and the mitogen-activated protein kinase pathways. The thrombin-TM complex also activates thrombin-activatable fibrinolysis inhibitor, a procarboxypeptidase that renders fibrin resistant to clot lysis and neutralizes vasoactive molecules such as complement C5a. Activated protein C has a variety of antiinflammatory activities. It suppresses inflammatory cytokine elevation in animal models of severe sepsis, inhibits leukocyte adhesion, decreases leukocyte chemotaxis, reduces endothelial cell apoptosis, helps maintain endothelial cell barrier function through activation of the sphingosine-1 phosphate receptor, and minimizes the decrease in blood pressure associated with severe sepsis. Most of these functions are dependent on binding to EPCR. Overall this pathway is critical to both regulation of the blood coagulation process, and control of the innate inflammatory response and some of its associated downstream pathologies.
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PMID:Inflammation and the activated protein C anticoagulant pathway. 1667 66

The haemostatic system is greatly modified during severe infections. The early activation of coagulation is triggered by tissue factor expression and secondary fibrinolysis impaired by the upregulation of fibrinolysis inhibitors. This imbalance is a major cause of subsequent organ dysfunction. Natural anticoagulants (Tissue factor pathway inhibitor (TFPI), Antithrombin (AT), and Protein C (PC) are consumed or inhibited in this pathological process justifying a therapeutic supplementation with these inhibitors to improve sepsis-induced organ failure and mortality. No effect on the mortality rate could be documented in controlled studies using recombinant TFPI or AT concentrates but a biological interaction with heparin therapy could have biased the results. Treatment with recombinant activated PC was associated with a significant reduction in the mortality rate of severely ill patients. An increase in the rate of hemorrhagic adverse effects was observed with these compounds, justifying a strict observance of contraindications and of patient selection.
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PMID:[Hemostasis disorders in severe infections: state of the art]. 1719 28

The anticoagulant protein C system is a dual function cofactor-dependent system. On one hand, it is designed to regulate coagulation, maintain the fluidity of the vasculature and prevent thrombosis. On the other hand, the protein C pathway provides anti-inflammatory and cytoprotective activities. Protein C, a vitamin K-dependent serine protease zymogen that circulates in plasma, is converted by limited proteolysis to activated protein C (APC) by the thrombin-thrombomodulin-endothelial protein C receptor complex on endothelial surfaces. APC and the cofactors of the protein C pathway exert two major distinct types of activities, namely a well-studied anticoagulant activity and a more recently revealed cytoprotective activity due to direct effects on cells. Because of these pleiotropic properties, APC and the protein C pathway components have important roles in the body's host-defense system and provide opportunities for therapeutic treatment of complex and challenging medical disorders, including thrombosis, severe sepsis and stroke.
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PMID:Protein C anticoagulant activity in relation to anti-inflammatory and anti-apoptotic activities. 1672 Mar 21

Two international multicentre randomised controlled trials of drotrecogin alfa (activated) (DrotAA), the Recombinant Human Activated Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) and Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) trials, have produced inconsistent results. When 28-day mortality data from these trials for patients with severe sepsis and at high risk of death are pooled using a standard random-effects meta-analysis technique, there is no statistically significant survival benefit (for patients with Acute Physiology and Chronic Health Evaluation (APACHE II) scores of 25 or more), or a borderline significant benefit (for patients with multi-organ failure). We argue that two important methodological issues might explain the disparate results between the two trials. These issues centre on early trial stopping, which exaggerates treatment effects, and reliance on subgroup analyses, which for DrotAA yields inconsistent results across different definitions of high risk. These concerns call into question the effectiveness of DrotAA in any patients with severe sepsis. Consequently, further randomised trials of this agent in prospectively defined high-risk patients are required to clarify its role in the management of severe sepsis.
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PMID:Drotrecogin alfa (activated): does current evidence support treatment for any patients with severe sepsis? 1709 91

Protein C is best known for its mild deficiency associated with venous thrombosis risk and severe deficiency associated with neonatal purpura fulminans. Activated protein C (APC) anticoagulant activity involves proteolytic inactivation of factors Va and VIIIa, and APC resistance is often caused by factor V Leiden. Less known is the clinical success of APC in reducing mortality in severe sepsis patients (PROWESS trial) that gave impetus to new directions for basic and preclinical research on APC. This review summarizes insights gleaned from recent in vitro and in vivo studies of the direct cytoprotective effects of APC that include beneficial alterations in gene expression profiles, anti-inflammatory actions, antiapoptotic activities, and stabilization of endothelial barriers. APC's cytoprotection requires its receptor, endothelial cell protein C receptor, and protease-activated receptor-1. Because of its pleiotropic activities, APC has potential roles in the treatment of complex disorders, including sepsis, thrombosis, and ischemic stroke. Although much about molecular mechanisms for APC's effects on cells remains unclear, it is clear that APC's structural features mediating anticoagulant actions and related bleeding risks are distinct from those mediating cytoprotective actions, suggesting the possibility of developing APC variants with an improved profile for the ratio of cytoprotective to anticoagulant actions.
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PMID:The cytoprotective protein C pathway. 1711 Apr 53

Protein C (PC) is a key regulator of blood clotting and inflammation. Its inherited deficiency is associated with venous thromboembolism, and recombinant activated PC is currently used to increase survival in severe sepsis. The molecular basis of inherited PC deficiency is heterogeneous. Due to its multiple physiologic interactions and functions, and its modular structure, natural variants aid in the understanding of the relationship between critical residues and discrete functions. This knowledge has important therapeutic implications in the planning of a recombinant activated PC with a specific therapeutic target and devoid of major collateral effects. A way of predicting important functional consequences of residue variation is the use of molecular modeling and structural interpretation of amino acidic substitutions. A study of 21 out of 32 identified PC gene (PROC) variants is presented. For three of them, localized in the active site, electrostatic potential variation was calculated. For more than half of the studied variants, an explanation for the functional impairment could be derived from computational analysis, allowing a focused choice of which variants it is worthwhile pursuing.
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PMID:Identification and computationally-based structural interpretation of naturally occurring variants of human protein C. 1715 60

The haemostatic system is greatly modified during severe infections. The early activation of coagulation is triggered by tissue factor expression and secondary fibrinolysis impaired by the upregulation of fibrinolysis inhibitors. This imbalance is a major cause of subsequent organ dysfunction. Natural anticoagulants (Tissue factor pathway inhibitor (TFPI), Antithrombin (AT), and Protein C (PC) are consumed or inhibited in this pathological process justifying a therapeutic supplementation with these inhibitors to improve sepsis-induced organ failure and mortality. No effect on the mortality rate could be documented in controlled studies using recombinant TFPI or AT concentrates but a biological interaction with heparin therapy could have biased the results. Treatment with recombinant activated PC was associated with a significant reduction in the mortality rate of severely ill patients. An increase in the rate of hemorrhagic adverse effects was observed with these compounds, justifying a strict observance of contraindications and of patient selection.
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PMID:[Hemostasis disorders in severe infections: State of the art]. 1671 62

Protein C (PC) plays an important role in vascular function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. This study explored the consequences of PC suppression on the kidney in a cecal ligation and puncture model of polymicrobial sepsis. This study shows that a rapid drop in PC after sepsis is strongly associated with an increase in blood urea nitrogen, renal pathology, and expression of known markers of renal injury, including neutrophil gelatinase-associated lipocalin, CXCL1, and CXCL2. The endothelial PC receptor, which is required for the anti-inflammatory and antiapoptotic activity of activated PC (APC), was significantly increased after cecal ligation and puncture as well as in the microvasculature of human kidneys after injury. Treatment of septic animals with APC reduced blood urea nitrogen, renal pathology, and chemokine expression and dramatically reduced the induction of inducible nitric oxide synthase and caspase-3 activation in the kidney. The data demonstrate a clear link between acquired PC deficiency and renal dysfunction in sepsis and suggest a compensatory upregulation of the signaling receptor. Moreover, these data suggest that APC treatment may be effective in reducing inflammatory and apoptotic insult during sepsis-induced acute renal failure.
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PMID:Role of protein C in renal dysfunction after polymicrobial sepsis. 1730 Nov 89

Among numerous non anti-infective treatments proposed in the management of severe sepsis and septic shock, early administration of steroids and recombinant human activated protein C are the most studied and the major source of debate. Patients with functional adrenal insufficiency appear to be the best cases for early treatment with low doses of hydrocortisone. However, definition of adrenal dysfunction, interpretation of cortisol blood concentration and its appropriateness, investigation of the hypothamalo-pituitary-adrenal axis and value of corticotropin stimulation test are matter of discussion. Similarly, recombinant human activated protein C might be beneficial in patients with severe sepsis and septic shock but the results of clinical trials are controversial. Structure of the PROWESS pivotal study, post hoc analyses of numerous subgroups, use of severity scoring system for selection of the patients, unproven mechanisms of action of activated Protein C, interactions with combined treatments represent major sources of confusion and of debate in the analysis of the trials. Non anti-infective treatments should be considered in selected patients when appropriate conventional treatments have been implemented. Use of these new treatments should bring additional improvement in the prognosis in severely ill patients at high risk of death.
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PMID:[Potential benefits of non-anti-infective treatments of septic shock: a critical analysis of literature]. 1739 18


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