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Jean-françois Dhainaut - One of the best experts on this subject based on the ideXlab platform.
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Protein C/aCtivated Protein C pathway: overview of CliniCal trial results in severe sepsis.
Critical Care Medicine, 2004Co-Authors: Jean-françois Dhainaut, S Betty Yan, Yann-erick ClaessensAbstract:ObjeCtive: To review the results from CliniCal trials of treatments for severe sepsis involving the Protein C/aCtivated Protein C pathway. Data SourCe: Published researCh and review artiCles (PubMed, from 1985 to 2003) relating to CliniCal trials of Compounds involving the Protein C pathway. Data ExtraCtion and Synthesis: Protein C is Converted to aCtivated Protein C when thrombin Complexes with thrombomodulin. Sepsis is assoCiated with rapid depletion of Protein C and blunted endogenous Protein C aCtivation. Treatment with Protein C ConCentrate is followed by inCreased aCtivated Protein C plasma levels and a dose-dependent deCrease in D-dimer levels in Children with purpura fulminans. This supplementation is safe. A phase III trial of reCombinant human aCtivated Protein C (drotreCogin alfa [aCtivated]) in severe sepsis demonstrated a 6.1% absolute reduCtion in 28-day mortality Compared with plaCebo. The short- and long-term survival rates assoCiated with drotreCogin alfa (aCtivated) were better in patients at high risk of death assoCiated with a better Cost/effeCtiveness ratio. Treatment with drotreCogin alfa (aCtivated) was assoCiated with an inCreased risk of serious bleeding Compared with plaCebo during the 28-day study period (3.5% vs. 2.0%). ConClusions: Treatment with Protein C ConCentrate is followed by an improvement of the Coagulopathy and is safe in Children with purpura fulminans; however, a large trial involving a high dose is required to determine its effeCt on mortality and morbidity. Treatment with drotreCogin alfa (aCtivated) leads to substantial reduCtion in mortality and has an aCCeptable risk/benefit ratio in septiC patients at high risk of death.
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Protein C/aCtivated Protein C pathway: overview of CliniCal trial results in severe sepsis.
Critical care medicine, 2004Co-Authors: Jean-françois Dhainaut, S Betty Yan, Yann-erick ClaessensAbstract:To review the results from CliniCal trials of treatments for severe sepsis involving the Protein C/aCtivated Protein C pathway. Published researCh and review artiCles (PubMed, from 1985 to 2003) relating to CliniCal trials of Compounds involving the Protein C pathway. Protein C is Converted to aCtivated Protein C when thrombin Complexes with thrombomodulin. Sepsis is assoCiated with rapid depletion of Protein C and blunted endogenous Protein C aCtivation. Treatment with Protein C ConCentrate is followed by inCreased aCtivated Protein C plasma levels and a dose-dependent deCrease in d-dimer levels in Children with purpura fulminans. This supplementation is safe. A phase III trial of reCombinant human aCtivated Protein C (drotreCogin alfa [aCtivated]) in severe sepsis demonstrated a 6.1% absolute reduCtion in 28-day mortality Compared with plaCebo. The short- and long-term survival rates assoCiated with drotreCogin alfa (aCtivated) were better in patients at high risk of death assoCiated with a better Cost/effeCtiveness ratio. Treatment with drotreCogin alfa (aCtivated) was assoCiated with an inCreased risk of serious bleeding Compared with plaCebo during the 28-day study period (3.5% vs. 2.0%). Treatment with Protein C ConCentrate is followed by an improvement of the Coagulopathy and is safe in Children with purpura fulminans; however, a large trial involving a high dose is required to determine its effeCt on mortality and morbidity. Treatment with drotreCogin alfa (aCtivated) leads to substantial reduCtion in mortality and has an aCCeptable risk/benefit ratio in septiC patients at high risk of death.
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Soluble thrombomodulin, plasma-derived unaCtivated Protein C, and reCombinant human aCtivated Protein C in sepsis.
Critical Care Medicine, 2002Co-Authors: Jean-françois Dhainaut, S Betty Yan, Alain Cariou, Jean-paul MiraAbstract:ObjeCtive: To review the physiologiC and bioChemiCal meChanisms and the rationale for the use of soluble thrombomodulin, plasma-derived Protein C, and reCombinant human aCtivated Protein C in sepsis. Data SourCes and Study SeleCtion: ResearCh and review artiCles related to the Protein C pathway published in English from 1960 to present. Data ExtraCtion and Synthesis: The Protein C antiCoagulant pathway plays a major role in Controlling miCrovasCular Coagulation and inflammation. Protein C is the zymogen of the vitamin K-dependent serine protease aCtivated Protein C. Protein C is Converted to aCtivated Protein C when thrombin Complexes with thrombomodulin, an endothelial surfaCe transmembrane glyCoProtein. ACtivated Protein C inaCtivates faCtors Va and VIIIa and effeCtively limits further thrombin generation. This Protein also enhanCes endogenous fibrinolytiC aCtivity and modulates the inflammatory response. A rapid depletion of Protein C oCCurs in sepsis, whiCh Contributes to sepsis-induCed Coagulopathy and Correlates with a poor prognosis. The deCrease in tissue levels of thrombomodulin in patients with meningoCoCCemia suggests that the ability to Convert Protein C to aCtivated Protein C may also be Compromised. The ability of soluble thrombomodulin to bloCk fibrinogen Clotting and Cell aCtivation, to aCtivate Protein C, and to promote thrombin inhibition in different animal models suggests that soluble thrombomodulin Could be a useful therapeutiC agent in sepsis. However, soluble thrombomodulin is less effeCtive in bloCking fibrinogen and platelet aCtivation and in promoting thrombin inhibition than endothelial surfaCe membrane-bound thrombomodulin. Only aCtivated Protein C, and not Protein C, has Clearly shown a reduCtion in mortality in experimental animal models of sepsis and in humans. ConClusions: The multipotent pharmaCodynamiC effeCts (antithrombotiC, profibrinolytiC, and anti-inflammatory) of aCtivated Protein C may explain why reCombinantly derived human aCtivated Protein C is the first experimental agent to demonstrate a signifiCant survival benefit in patients with severe sepsis.
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Soluble thrombomodulin, plasma-derived unaCtivated Protein C, and reCombinant human aCtivated Protein C in sepsis.
Critical care medicine, 2002Co-Authors: Jean-françois Dhainaut, S Betty Yan, Alain Cariou, Jean-paul MiraAbstract:To review the physiologiC and bioChemiCal meChanisms and the rationale for the use of soluble thrombomodulin, plasma-derived Protein C, and reCombinant human aCtivated Protein C in sepsis. ResearCh and review artiCles related to the Protein C pathway published in English from 1960 to present. The Protein C antiCoagulant pathway plays a major role in Controlling miCrovasCular Coagulation and inflammation. Protein C is the zymogen of the vitamin K-dependent serine protease aCtivated Protein C. Protein C is Converted to aCtivated Protein C when thrombin Complexes with thrombomodulin, an endothelial surfaCe transmembrane glyCoProtein. ACtivated Protein C inaCtivates faCtors Va and VIIIa and effeCtively limits further thrombin generation. This Protein also enhanCes endogenous fibrinolytiC aCtivity and modulates the inflammatory response. A rapid depletion of Protein C oCCurs in sepsis, whiCh Contributes to sepsis-induCed Coagulopathy and Correlates with a poor prognosis. The deCrease in tissue levels of thrombomodulin in patients with meningoCoCCemia suggests that the ability to Convert Protein C to aCtivated Protein C may also be Compromised. The ability of soluble thrombomodulin to bloCk fibrinogen Clotting and Cell aCtivation, to aCtivate Protein C, and to promote thrombin inhibition in different animal models suggests that soluble thrombomodulin Could be a useful therapeutiC agent in sepsis. However, soluble thrombomodulin is less effeCtive in bloCking fibrinogen and platelet aCtivation and in promoting thrombin inhibition than endothelial surfaCe membrane-bound thrombomodulin. Only aCtivated Protein C, and not Protein C, has Clearly shown a reduCtion in mortality in experimental animal models of sepsis and in humans. The multipotent pharmaCodynamiC effeCts (antithrombotiC, profibrinolytiC, and anti-inflammatory) of aCtivated Protein C may explain why reCombinantly derived human aCtivated Protein C is the first experimental agent to demonstrate a signifiCant survival benefit in patients with severe sepsis.
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ACtivated Protein C versus Protein C in severe sepsis.
Critical care medicine, 2001Co-Authors: Sau-chi B. Yan, Jean-françois DhainautAbstract:ObjeCtive: To delineate CritiCal differenCes between aCtivated Protein C (APC) and its preCursor, Protein C, with regard to plasma levels in health and in severe sepsis, and to disCuss the impliCations of these differenCes as they relate to treatment strategies in patients with severe sepsis. Data SourCe/Study SeleCtion: Published literature inCluding s, manusCripts, and review artiCles reporting studies in both experimental animal models and humans that provide an understanding of the relationship and the CritiCal differenCes between CirCulating levels of APC and Protein C. Data ExtraCtion and Synthesis: The Protein C pathway represents one of the major regulatory systems of hemostasis, exhibiting antithrombotiC, profibrinolytiC and anti-inflammatory properties. This pathway also plays a CritiCal role in the pathophysiology of severe sepsis. Central to this pathway is the vitamin K-dependent serine protease, APC, and its preCursor, Protein C. The Conversion of Protein C to APC is dependent on the Complex of thrombin and thrombomodulin, an integral endothelial surfaCe reCeptor. The Conversion of Protein C to APC is further augmented by another endothelial surfaCe Protein, the endothelial Protein C reCeptor. There are limited published data on APC levels in health and disease, probably due to the Complexity of the assay methodology for measuring APC and the absenCe of CommerCially available diagnostiC kits. In animals and humans with normal funCtioning endothelium, CirCulating levels of APC (1-3 ng/mL) are positively Correlated with Protein C (4000-5000 ng/mL) ConCentration and the amount of thrombin generated. In patients with severe sepsis, there is a generalized endothelial dysfunCtion, Contributing to multiple organ failure with inCreased morbidity and mortality. Persistently low Protein C levels are related to poor prognosis. Key to understanding the treatment strategy with APC or Protein C is knowledge of the funCtional status of the endothelium and, speCifiCally, whether the miCrovasCulature in patients with severe sepsis Can support the Conversion of Protein C to APC. To date, only APC (drotreCogin alfa [aCtivated]) has been shown to reduCe mortality in severe sepsis in a large, phase 3, plaCebo-Controlled, double-blind international trial. In Contrast, no data, other than open-label Case studies, are available for evaluation of the effeCts of Protein C in the treatment of severe sepsis. ConClusion: The limited data available indiCate that lower levels of Protein C in sepsis oCCur in the absenCe of appreCiable Conversion to APC. These observations indiCate that treatment with APC may be more effiCaCious than Protein C in severe sepsis, where generalized endothelial dysfunCtion may impair Conversion of Protein C to APC. Additional researCh is required to Confirm these observations.
Charles T. Esmon - One of the best experts on this subject based on the ideXlab platform.
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The endothelial Protein C reCeptor.
Current opinion in hematology, 2006Co-Authors: Charles T. EsmonAbstract:Purpose of review The endothelial Cell Protein C reCeptor is known to be CritiCal for the regulation of natural antiCoagulant funCtions and some anti-inflammatory and anti-apoptotiC funCtions of aCtivated Protein C. This leads to the prediCtion that abnormalities in endothelial Cell Protein C reCeptor might be assoCiated with altered thrombotiC tendenCies and hyperinflammatory responses to infeCtious agents. This review Covers the most reCent evidenCe that relatively Common genetiC and aCquired abnormalities of endothelial Cell Protein C reCeptor do Contribute to pathophysiologiCal disease proCesses. ReCent findings In miCe, inCreases and deCreases in endothelial Cell Protein C reCeptor expression are shown to modulate the Coagulation and inflammatory proCeses. GenetiC polymorphisms are assoCiated with alterations in Protein expression and familial and aCquired thrombotiC disease. Summary The emerging CliniCal evidenCe of endothelial Cell Protein C reCeptor involvement in thrombotiC disease suggests that the understanding of endothelial Cell Protein C reCeptor genotype and the knowledge of auto-antibodies may aid in diagnosing the risk of thrombotiC events in patients.
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Protein C in murine neonatal sepsis
Critical Care, 2005Co-Authors: Eva-maria Muchitsch, Charles T. Esmon, Hans Peter Schwarz, Katalin Varadi, Giuseppe Mancuso, Giuseppe TetiAbstract:Neonatal sepsis is frequently assoCiated with aCtivation of the Coagulation system. Generally, Protein C levels are markedly reduCed in the majority of septiC patients, being assoCiated with an inCreased risk of death. There is an aCtivated Protein C ConCentrate liCensed for the treatment of severe sepsis in adults. However, the risk of severe bleeding may limit its use in neonates. SinCe the likelihood to induCe bleeding with the zymogen form of Protein C may be reduCed, we therefore assessed both human and reCombinant murine Protein C zymogen in a murine neonatal sepsis model. In this model neonatal miCe were Challenged with viable group B streptoCoCCi (GBS). The impaCt of this septiC Condition on endogenous Protein C levels was evaluated and the effeCt of treatment with either reCombinant murine Protein C or human plasma-derived (non-aCtivated) Protein C (Ceprotin®) investigated. During severe GBS sepsis murine endogenous Protein C levels deCreased over time in neonatal miCe, resulting in a maximum deCrease of 30% at 16 hours after GBS Challenge and returned towards baseline at 30 hours. ConComitantly, there was an inCrease in endogenous Protein C aCtivation up to 59% at 6 hours after GBS Challenge, returning to baseline levels at 16 hours. BloCking endogenous murine Protein C with an anti-mouse monoClonal antibody inCreased the mortality rate signifiCantly from 62% to 91%. Treatment of neonatal septiC miCe (n = 36) with 300 U/kg murine Protein C subCutaneously 4 hours before GBS Challenge deCreases the mortality rate signifiCantly in severe sepsis (LD90) to 64% (P = 0.002). Similarly, pretreatment with human plasma-derived Protein C (200 U/kg) 4 hours before GBS Challenge inCreased the survival rate signifiCantly in severe septiC miCe. Human plasma derived Protein C at the dose of 200 IU/kg was even effeCtive given 18 hours after GBS Challenge, leading to a deCrease of the mortality rate in severe sepsis from 87.5% to 48%. Despite the speCies differenCes human Protein C zymogen was aCtivated to aCtivated Protein C and was deteCtable in the CirCulation of miCe, showing a slow and low in vivo reCovery, possibly due to the subCutaneous route of administration. This is the first preCliniCal study where a benefiCial effeCt of a non-aCtivated Protein C Could be shown in an animal model of severe neonatal sepsis.
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EffeCt of Human Plasma-Derived Protein C and Murine ReCombinant Protein C on Severe Neonatal Sepsis in MiCe.
Blood, 2004Co-Authors: Eva-maria Muchitsch, Charles T. Esmon, Hans Peter Schwarz, Katalin Varadi, Giuseppe Mancuso, Giuseppe TetiAbstract:Neonatal sepsis is a leading Cause of infant morbidity and mortality frequently assoCiated with aCtivation of the Coagulation system. ReduCed levels of Protein C are found in the majority of patients with sepsis and are assoCiated with an inCreased risk of death. Although aCtivated Protein C is indiCated for the treatment of severe sepsis in adults, the risk of severe bleeding may limit its use in neonates. BeCause the likelihood of induCing bleeding with the zymogen form of Protein C is reduCed we assessed both human and murine Protein C zymogen in a murine neonatal sepsis model. In this model neonatal miCe were Challenged with viable group B streptoCoCCi (GBS). The effeCt of this septiC Condition on endogenous Protein C levels was evaluated and the effeCt of treatment with either reCombinant murine Protein C or human plasma-derived (non-aCtivated) Protein C (Ceprotin) investigated. During severe GBS sepsis murine endogenous Protein C levels deCreased over time in neonatal miCe, resulting in a maximum deCrease of −30 % at 16 hours after GBS Challenge and returned towards baseline at 30 hours. ConComitantly, there was an inCrease in endogenous Protein C aCtivation up to 59 % at 6 hours after GBS Challenge, returning to baseline levels at 16 hours. BloCking endogenous murine Protein C with an anti-mouse monoClonal antibody inCreased the mortality rate signifiCantly from 62 to 91 %. Treatment of neonatal septiC miCe (n=36) with 300 U/kg murine Protein C subCutaneously 4 hours before GBS Challenge deCreased the mortality rate signifiCantly in severe sepsis (LD90) to 64 % (p=0.002). Similarly pretreatment with human plasma-derived Protein C (200 IU/kg) 4 hours before GBS Challenge inCreased survival rate signifiCantly in severe septiC miCe. Treatment with 200 IU/kg (Ceprotin) was even effeCtive given 18 hours after GBS Challenge, leading to a deCrease in the mortality rate in severe sepsis from 87.5 to 48 %. Despite this speCies differenCe and the septiC Condition, human Protein C zymogen was aCtivated to aCtivated Protein C and deteCtable in the CirCulation of miCe. This is the first preCliniCal study were a benefiCial effeCt of a non-aCtivated Protein C Could be shown in an animal model of severe neonatal sepsis.
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The Protein C Pathway
Chest, 2003Co-Authors: Charles T. EsmonAbstract: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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Protein C pathway in sepsis.
Annals of medicine, 2002Co-Authors: Charles T. EsmonAbstract:The goals of this Chapter are to provide a brief review of the biology of the Protein C pathway and some of the features of the pathway that make it uniquely positioned to Control miCrovasCular Coagulation and Control the aCute inflammatory response. ACtivated Protein C works as an antithrombotiC agent by inaCtivating faCtors Va and VIIIa. It is partiCularly effeCtive at preventing miCrovasCular thrombosis. Platelets may provide a margin of safety for aCtivated Protein C as an antithrombotiC. Approximately 25% of the faCtor V/Va in plasma is Contained within the platelet and henCe resistant to time dependent inaCtivation by aCtivated Protein C. In addition, faCtor Va bound to the platelet surfaCe is relatively resistant to inaCtivation by aCtivated Protein C. ACtivated Protein C also faCilitates Clot lysis by inhibiting plasminogen aCtivator inhibitor 1, a proCess that is aCCelerated markedly by vitroneCtin. Inflammatory Cytokines like tumor neCrosis faCtor alpha (TNFalpha) and interleukin-1beta (IL-1beta) downregulate two key Components of the Protein C aCtivation Complex, thrombomodulin and the endothelial Cell Protein C reCeptor resulting in deCreased Protein C aCtivation. ACtivated Protein C in turn has been shown in several animal models and in vitro to inhibit TNF elaboration in response to endotoxin. This inhibition appears to be due to diminished nuClear faCtor kappaB (NF kappaB) expression and nuClear transloCation. ACtivated Protein C has been shown to reduCe the rate of death due to severe sepsis. This reduCtion may be due to both the antiCoagulant effeCts as demonstrated by a reduCtion in D-dimer and inflammatory effeCts as demonstrated by a reduCtion in interleukin 6.
Jean-paul Mira - One of the best experts on this subject based on the ideXlab platform.
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Soluble thrombomodulin, plasma-derived unaCtivated Protein C, and reCombinant human aCtivated Protein C in sepsis.
Critical Care Medicine, 2002Co-Authors: Jean-françois Dhainaut, S Betty Yan, Alain Cariou, Jean-paul MiraAbstract:ObjeCtive: To review the physiologiC and bioChemiCal meChanisms and the rationale for the use of soluble thrombomodulin, plasma-derived Protein C, and reCombinant human aCtivated Protein C in sepsis. Data SourCes and Study SeleCtion: ResearCh and review artiCles related to the Protein C pathway published in English from 1960 to present. Data ExtraCtion and Synthesis: The Protein C antiCoagulant pathway plays a major role in Controlling miCrovasCular Coagulation and inflammation. Protein C is the zymogen of the vitamin K-dependent serine protease aCtivated Protein C. Protein C is Converted to aCtivated Protein C when thrombin Complexes with thrombomodulin, an endothelial surfaCe transmembrane glyCoProtein. ACtivated Protein C inaCtivates faCtors Va and VIIIa and effeCtively limits further thrombin generation. This Protein also enhanCes endogenous fibrinolytiC aCtivity and modulates the inflammatory response. A rapid depletion of Protein C oCCurs in sepsis, whiCh Contributes to sepsis-induCed Coagulopathy and Correlates with a poor prognosis. The deCrease in tissue levels of thrombomodulin in patients with meningoCoCCemia suggests that the ability to Convert Protein C to aCtivated Protein C may also be Compromised. The ability of soluble thrombomodulin to bloCk fibrinogen Clotting and Cell aCtivation, to aCtivate Protein C, and to promote thrombin inhibition in different animal models suggests that soluble thrombomodulin Could be a useful therapeutiC agent in sepsis. However, soluble thrombomodulin is less effeCtive in bloCking fibrinogen and platelet aCtivation and in promoting thrombin inhibition than endothelial surfaCe membrane-bound thrombomodulin. Only aCtivated Protein C, and not Protein C, has Clearly shown a reduCtion in mortality in experimental animal models of sepsis and in humans. ConClusions: The multipotent pharmaCodynamiC effeCts (antithrombotiC, profibrinolytiC, and anti-inflammatory) of aCtivated Protein C may explain why reCombinantly derived human aCtivated Protein C is the first experimental agent to demonstrate a signifiCant survival benefit in patients with severe sepsis.
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Soluble thrombomodulin, plasma-derived unaCtivated Protein C, and reCombinant human aCtivated Protein C in sepsis.
Critical care medicine, 2002Co-Authors: Jean-françois Dhainaut, S Betty Yan, Alain Cariou, Jean-paul MiraAbstract:To review the physiologiC and bioChemiCal meChanisms and the rationale for the use of soluble thrombomodulin, plasma-derived Protein C, and reCombinant human aCtivated Protein C in sepsis. ResearCh and review artiCles related to the Protein C pathway published in English from 1960 to present. The Protein C antiCoagulant pathway plays a major role in Controlling miCrovasCular Coagulation and inflammation. Protein C is the zymogen of the vitamin K-dependent serine protease aCtivated Protein C. Protein C is Converted to aCtivated Protein C when thrombin Complexes with thrombomodulin, an endothelial surfaCe transmembrane glyCoProtein. ACtivated Protein C inaCtivates faCtors Va and VIIIa and effeCtively limits further thrombin generation. This Protein also enhanCes endogenous fibrinolytiC aCtivity and modulates the inflammatory response. A rapid depletion of Protein C oCCurs in sepsis, whiCh Contributes to sepsis-induCed Coagulopathy and Correlates with a poor prognosis. The deCrease in tissue levels of thrombomodulin in patients with meningoCoCCemia suggests that the ability to Convert Protein C to aCtivated Protein C may also be Compromised. The ability of soluble thrombomodulin to bloCk fibrinogen Clotting and Cell aCtivation, to aCtivate Protein C, and to promote thrombin inhibition in different animal models suggests that soluble thrombomodulin Could be a useful therapeutiC agent in sepsis. However, soluble thrombomodulin is less effeCtive in bloCking fibrinogen and platelet aCtivation and in promoting thrombin inhibition than endothelial surfaCe membrane-bound thrombomodulin. Only aCtivated Protein C, and not Protein C, has Clearly shown a reduCtion in mortality in experimental animal models of sepsis and in humans. The multipotent pharmaCodynamiC effeCts (antithrombotiC, profibrinolytiC, and anti-inflammatory) of aCtivated Protein C may explain why reCombinantly derived human aCtivated Protein C is the first experimental agent to demonstrate a signifiCant survival benefit in patients with severe sepsis.
S Betty Yan - One of the best experts on this subject based on the ideXlab platform.
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Protein C/aCtivated Protein C pathway: overview of CliniCal trial results in severe sepsis.
Critical Care Medicine, 2004Co-Authors: Jean-françois Dhainaut, S Betty Yan, Yann-erick ClaessensAbstract:ObjeCtive: To review the results from CliniCal trials of treatments for severe sepsis involving the Protein C/aCtivated Protein C pathway. Data SourCe: Published researCh and review artiCles (PubMed, from 1985 to 2003) relating to CliniCal trials of Compounds involving the Protein C pathway. Data ExtraCtion and Synthesis: Protein C is Converted to aCtivated Protein C when thrombin Complexes with thrombomodulin. Sepsis is assoCiated with rapid depletion of Protein C and blunted endogenous Protein C aCtivation. Treatment with Protein C ConCentrate is followed by inCreased aCtivated Protein C plasma levels and a dose-dependent deCrease in D-dimer levels in Children with purpura fulminans. This supplementation is safe. A phase III trial of reCombinant human aCtivated Protein C (drotreCogin alfa [aCtivated]) in severe sepsis demonstrated a 6.1% absolute reduCtion in 28-day mortality Compared with plaCebo. The short- and long-term survival rates assoCiated with drotreCogin alfa (aCtivated) were better in patients at high risk of death assoCiated with a better Cost/effeCtiveness ratio. Treatment with drotreCogin alfa (aCtivated) was assoCiated with an inCreased risk of serious bleeding Compared with plaCebo during the 28-day study period (3.5% vs. 2.0%). ConClusions: Treatment with Protein C ConCentrate is followed by an improvement of the Coagulopathy and is safe in Children with purpura fulminans; however, a large trial involving a high dose is required to determine its effeCt on mortality and morbidity. Treatment with drotreCogin alfa (aCtivated) leads to substantial reduCtion in mortality and has an aCCeptable risk/benefit ratio in septiC patients at high risk of death.
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Protein C/aCtivated Protein C pathway: overview of CliniCal trial results in severe sepsis.
Critical care medicine, 2004Co-Authors: Jean-françois Dhainaut, S Betty Yan, Yann-erick ClaessensAbstract:To review the results from CliniCal trials of treatments for severe sepsis involving the Protein C/aCtivated Protein C pathway. Published researCh and review artiCles (PubMed, from 1985 to 2003) relating to CliniCal trials of Compounds involving the Protein C pathway. Protein C is Converted to aCtivated Protein C when thrombin Complexes with thrombomodulin. Sepsis is assoCiated with rapid depletion of Protein C and blunted endogenous Protein C aCtivation. Treatment with Protein C ConCentrate is followed by inCreased aCtivated Protein C plasma levels and a dose-dependent deCrease in d-dimer levels in Children with purpura fulminans. This supplementation is safe. A phase III trial of reCombinant human aCtivated Protein C (drotreCogin alfa [aCtivated]) in severe sepsis demonstrated a 6.1% absolute reduCtion in 28-day mortality Compared with plaCebo. The short- and long-term survival rates assoCiated with drotreCogin alfa (aCtivated) were better in patients at high risk of death assoCiated with a better Cost/effeCtiveness ratio. Treatment with drotreCogin alfa (aCtivated) was assoCiated with an inCreased risk of serious bleeding Compared with plaCebo during the 28-day study period (3.5% vs. 2.0%). Treatment with Protein C ConCentrate is followed by an improvement of the Coagulopathy and is safe in Children with purpura fulminans; however, a large trial involving a high dose is required to determine its effeCt on mortality and morbidity. Treatment with drotreCogin alfa (aCtivated) leads to substantial reduCtion in mortality and has an aCCeptable risk/benefit ratio in septiC patients at high risk of death.
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Soluble thrombomodulin, plasma-derived unaCtivated Protein C, and reCombinant human aCtivated Protein C in sepsis.
Critical Care Medicine, 2002Co-Authors: Jean-françois Dhainaut, S Betty Yan, Alain Cariou, Jean-paul MiraAbstract:ObjeCtive: To review the physiologiC and bioChemiCal meChanisms and the rationale for the use of soluble thrombomodulin, plasma-derived Protein C, and reCombinant human aCtivated Protein C in sepsis. Data SourCes and Study SeleCtion: ResearCh and review artiCles related to the Protein C pathway published in English from 1960 to present. Data ExtraCtion and Synthesis: The Protein C antiCoagulant pathway plays a major role in Controlling miCrovasCular Coagulation and inflammation. Protein C is the zymogen of the vitamin K-dependent serine protease aCtivated Protein C. Protein C is Converted to aCtivated Protein C when thrombin Complexes with thrombomodulin, an endothelial surfaCe transmembrane glyCoProtein. ACtivated Protein C inaCtivates faCtors Va and VIIIa and effeCtively limits further thrombin generation. This Protein also enhanCes endogenous fibrinolytiC aCtivity and modulates the inflammatory response. A rapid depletion of Protein C oCCurs in sepsis, whiCh Contributes to sepsis-induCed Coagulopathy and Correlates with a poor prognosis. The deCrease in tissue levels of thrombomodulin in patients with meningoCoCCemia suggests that the ability to Convert Protein C to aCtivated Protein C may also be Compromised. The ability of soluble thrombomodulin to bloCk fibrinogen Clotting and Cell aCtivation, to aCtivate Protein C, and to promote thrombin inhibition in different animal models suggests that soluble thrombomodulin Could be a useful therapeutiC agent in sepsis. However, soluble thrombomodulin is less effeCtive in bloCking fibrinogen and platelet aCtivation and in promoting thrombin inhibition than endothelial surfaCe membrane-bound thrombomodulin. Only aCtivated Protein C, and not Protein C, has Clearly shown a reduCtion in mortality in experimental animal models of sepsis and in humans. ConClusions: The multipotent pharmaCodynamiC effeCts (antithrombotiC, profibrinolytiC, and anti-inflammatory) of aCtivated Protein C may explain why reCombinantly derived human aCtivated Protein C is the first experimental agent to demonstrate a signifiCant survival benefit in patients with severe sepsis.
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Soluble thrombomodulin, plasma-derived unaCtivated Protein C, and reCombinant human aCtivated Protein C in sepsis.
Critical care medicine, 2002Co-Authors: Jean-françois Dhainaut, S Betty Yan, Alain Cariou, Jean-paul MiraAbstract:To review the physiologiC and bioChemiCal meChanisms and the rationale for the use of soluble thrombomodulin, plasma-derived Protein C, and reCombinant human aCtivated Protein C in sepsis. ResearCh and review artiCles related to the Protein C pathway published in English from 1960 to present. The Protein C antiCoagulant pathway plays a major role in Controlling miCrovasCular Coagulation and inflammation. Protein C is the zymogen of the vitamin K-dependent serine protease aCtivated Protein C. Protein C is Converted to aCtivated Protein C when thrombin Complexes with thrombomodulin, an endothelial surfaCe transmembrane glyCoProtein. ACtivated Protein C inaCtivates faCtors Va and VIIIa and effeCtively limits further thrombin generation. This Protein also enhanCes endogenous fibrinolytiC aCtivity and modulates the inflammatory response. A rapid depletion of Protein C oCCurs in sepsis, whiCh Contributes to sepsis-induCed Coagulopathy and Correlates with a poor prognosis. The deCrease in tissue levels of thrombomodulin in patients with meningoCoCCemia suggests that the ability to Convert Protein C to aCtivated Protein C may also be Compromised. The ability of soluble thrombomodulin to bloCk fibrinogen Clotting and Cell aCtivation, to aCtivate Protein C, and to promote thrombin inhibition in different animal models suggests that soluble thrombomodulin Could be a useful therapeutiC agent in sepsis. However, soluble thrombomodulin is less effeCtive in bloCking fibrinogen and platelet aCtivation and in promoting thrombin inhibition than endothelial surfaCe membrane-bound thrombomodulin. Only aCtivated Protein C, and not Protein C, has Clearly shown a reduCtion in mortality in experimental animal models of sepsis and in humans. The multipotent pharmaCodynamiC effeCts (antithrombotiC, profibrinolytiC, and anti-inflammatory) of aCtivated Protein C may explain why reCombinantly derived human aCtivated Protein C is the first experimental agent to demonstrate a signifiCant survival benefit in patients with severe sepsis.
Alain Cariou - One of the best experts on this subject based on the ideXlab platform.
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Soluble thrombomodulin, plasma-derived unaCtivated Protein C, and reCombinant human aCtivated Protein C in sepsis.
Critical Care Medicine, 2002Co-Authors: Jean-françois Dhainaut, S Betty Yan, Alain Cariou, Jean-paul MiraAbstract:ObjeCtive: To review the physiologiC and bioChemiCal meChanisms and the rationale for the use of soluble thrombomodulin, plasma-derived Protein C, and reCombinant human aCtivated Protein C in sepsis. Data SourCes and Study SeleCtion: ResearCh and review artiCles related to the Protein C pathway published in English from 1960 to present. Data ExtraCtion and Synthesis: The Protein C antiCoagulant pathway plays a major role in Controlling miCrovasCular Coagulation and inflammation. Protein C is the zymogen of the vitamin K-dependent serine protease aCtivated Protein C. Protein C is Converted to aCtivated Protein C when thrombin Complexes with thrombomodulin, an endothelial surfaCe transmembrane glyCoProtein. ACtivated Protein C inaCtivates faCtors Va and VIIIa and effeCtively limits further thrombin generation. This Protein also enhanCes endogenous fibrinolytiC aCtivity and modulates the inflammatory response. A rapid depletion of Protein C oCCurs in sepsis, whiCh Contributes to sepsis-induCed Coagulopathy and Correlates with a poor prognosis. The deCrease in tissue levels of thrombomodulin in patients with meningoCoCCemia suggests that the ability to Convert Protein C to aCtivated Protein C may also be Compromised. The ability of soluble thrombomodulin to bloCk fibrinogen Clotting and Cell aCtivation, to aCtivate Protein C, and to promote thrombin inhibition in different animal models suggests that soluble thrombomodulin Could be a useful therapeutiC agent in sepsis. However, soluble thrombomodulin is less effeCtive in bloCking fibrinogen and platelet aCtivation and in promoting thrombin inhibition than endothelial surfaCe membrane-bound thrombomodulin. Only aCtivated Protein C, and not Protein C, has Clearly shown a reduCtion in mortality in experimental animal models of sepsis and in humans. ConClusions: The multipotent pharmaCodynamiC effeCts (antithrombotiC, profibrinolytiC, and anti-inflammatory) of aCtivated Protein C may explain why reCombinantly derived human aCtivated Protein C is the first experimental agent to demonstrate a signifiCant survival benefit in patients with severe sepsis.
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Soluble thrombomodulin, plasma-derived unaCtivated Protein C, and reCombinant human aCtivated Protein C in sepsis.
Critical care medicine, 2002Co-Authors: Jean-françois Dhainaut, S Betty Yan, Alain Cariou, Jean-paul MiraAbstract:To review the physiologiC and bioChemiCal meChanisms and the rationale for the use of soluble thrombomodulin, plasma-derived Protein C, and reCombinant human aCtivated Protein C in sepsis. ResearCh and review artiCles related to the Protein C pathway published in English from 1960 to present. The Protein C antiCoagulant pathway plays a major role in Controlling miCrovasCular Coagulation and inflammation. Protein C is the zymogen of the vitamin K-dependent serine protease aCtivated Protein C. Protein C is Converted to aCtivated Protein C when thrombin Complexes with thrombomodulin, an endothelial surfaCe transmembrane glyCoProtein. ACtivated Protein C inaCtivates faCtors Va and VIIIa and effeCtively limits further thrombin generation. This Protein also enhanCes endogenous fibrinolytiC aCtivity and modulates the inflammatory response. A rapid depletion of Protein C oCCurs in sepsis, whiCh Contributes to sepsis-induCed Coagulopathy and Correlates with a poor prognosis. The deCrease in tissue levels of thrombomodulin in patients with meningoCoCCemia suggests that the ability to Convert Protein C to aCtivated Protein C may also be Compromised. The ability of soluble thrombomodulin to bloCk fibrinogen Clotting and Cell aCtivation, to aCtivate Protein C, and to promote thrombin inhibition in different animal models suggests that soluble thrombomodulin Could be a useful therapeutiC agent in sepsis. However, soluble thrombomodulin is less effeCtive in bloCking fibrinogen and platelet aCtivation and in promoting thrombin inhibition than endothelial surfaCe membrane-bound thrombomodulin. Only aCtivated Protein C, and not Protein C, has Clearly shown a reduCtion in mortality in experimental animal models of sepsis and in humans. The multipotent pharmaCodynamiC effeCts (antithrombotiC, profibrinolytiC, and anti-inflammatory) of aCtivated Protein C may explain why reCombinantly derived human aCtivated Protein C is the first experimental agent to demonstrate a signifiCant survival benefit in patients with severe sepsis.
