Relationship Between the Inflammation and Coagulation Pathways in Patients with Severe Sepsis

Morris, Peter E.; Hite, R. Duncan; Ohl, Christopher

doi:10.2165/00063030-200216060-00002

Cited by 7 publications

(2 citation statements)

References 84 publications

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“…Besides the ability of APC to inhibit thrombinmediated inflammatory activities [6], and to regulate both the coagulation and inflammation pathways [7], a blocked expression of downstream nuclear factorkappaB (NFkappaB) regulated genes has been suggested [8]. This includes dose-dependent suppression of cell adhesion expression and functional binding of intracellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin [8].…”

Section: Introductionmentioning

confidence: 99%

Effect of Drotrecogin alfa (activated) on platelet receptor expressionin vitro

et al. 2007

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Thrombocytopenia is a common problem in critically ill patients, which is associated with increased mortality. Recently, Drotrecogin alfa (activated) (recombinant human activated protein C (APC)) was shown to reduce mortality in patients with severe sepsis. Only minimal effect of APC on coagulation markers was demonstrated. Nevertheless, low platelet count was identified as a risk factor for bleeding with use of this drug. We conducted this study to evaluate possible influence of APC on in vitro expression of platelet receptors at therapeutic and supra-therapeutic concentrations. Blood samples of volunteers and patients with severe sepsis were adjusted with APC to final concentrations of 0.045 microg mL(-1) APC (APC-45, therapeutic dose) and 0.225 microg mL(-1) APC (APC-225, five-fold therapeutic dose), respectively. The activation of platelets was mediated by two different agonists. APC had no significant influence on platelet activation, with or without stimulation at both concentrations. In group APC-225, CD62P showed a non-significant decrease. This in vitro study demonstrates that therapeutic plasma concentrations of Drotrecogin alfa (activated) have neither influence on expression of platelet activation markers nor on platelet-granulocyte complexes in blood of volunteers and patients with severe sepsis. Thus, a direct drug-platelet interaction seems unlikely.

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Section: Introductionmentioning

confidence: 99%

Effect of Drotrecogin alfa (activated) on platelet receptor expressionin vitro

et al. 2007

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“…Thrombin may also affect the production of inflammatory cytokines by binding to protease-activated receptors (PARs) in mononuclear cells [ 3 ]. Secondly, rhAPC may inhibit the action of plasminogen activator inhibitor type I (PAI-I), thereby restoring the suppressed fibrinolytic state during sepsis [ 4 ]. Thirdly, binding of rhAPC to the endothelial protein C receptor (EPCR) may influence gene expression profiles of cells by blocking nuclear factor kappa B nuclear translocation, which is required for increases in proinflammatory cytokines and adhesion molecules [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Recombinant human activated protein C resets thrombin generation in patients with severe sepsis – a case control study

et al. 2005

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IntroductionRecombinant human activated protein C (rhAPC) is the first drug for which a reduction of mortality in severe sepsis has been demonstrated. However, the mechanism by which this reduction in mortality is achieved is still not clearly defined. The aim of the present study was to evaluate the dynamics of the anticoagulant, anti-inflammatory and pro-fibrinolytic action of rhAPC in patients with severe sepsis, by comparing rhAPC-treated patients with case controls.MethodsIn this prospectively designed multicenter case control study, 12 patients who were participating in the ENHANCE study, an open-label study of rhAPC in severe sepsis, were treated intravenously with rhAPC at a constant rate of 24 μg/kg/h for a total of 96 h. Twelve controls with severe sepsis matching the inclusion criteria received standard therapy. The treatment was started within 48 h after the onset of organ failure. Blood samples were taken before the start of the infusion and at 4, 8, 24, 48, 96 and 168 h, for determination of parameters of coagulation and inflammation.ResultsSepsis-induced thrombin generation as measured by thrombin-antithrombin complexes and prothrombin fragment F1+2, was reset by rhAPC within the first 8 h of infusion. The administration of rhAPC did not influence parameters of fibrinolysis and inflammation. There was no difference in outcome or occurrence of serious adverse events between the treatment group and the control group.ConclusionSepsis-induced thrombin generation in severely septic patients is reset by rhAPC within the first 8 h of infusion without influencing parameters of fibrinolysis and inflammation.

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Sepsis

Scott

Conrad

2006

Wiley Encyclopedia of Biomedical Engineering

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Sepsis is a state of systemic inflammation resulting from an unregulated and dysfunctional response of the innate immune system to an infectious stimulus. The sepsis response is initiated through cell surface signaling receptors that recognize specific microbial antigens, such as lipopolysaccharide, from gram‐negative bacteria. The signaling pathway activation results in increased activity of transcription factors in the cytoplasm, in particular nuclear factor κ B, followed by translocation to the nucleus and promotion of transcription of several early phase (proximal) inflammatory mediators, such as tumor necrosis factor‐ α and interleukin‐1 β . A number of later phase (distal) mediators are upregulated, producing activation of inflammation, anti‐inflammation, coagulation, and apoptotic pathways, with the endothelial cell playing a central role. This response is intended to function at a local level to contain the pathogenic process; however, systemic activation results in a systemic inflammatory response. Therapies targeting single mediators of the sepsis response based on linear, reductionist approaches to sepsis pathophysiology have been largely ineffectual. The sepsis response is perhaps best approached as a nonlinear, redundant complex network. Mathematical models based on this approach are being developed and hold promise for better understanding of the sepsis response and for developing therapeutic targets. Recently described models include a mechanistic model based on ordinary differential equations describing the behavior of populations of cells and mediators, and an agent‐based model in which agents represent individual cells associated with the inflammatory response. Both of these models show promise in reproducing particular components of the sepsis response. Future successes in the treatment of sepsis will depend on improvements in modeling that will enable a better understanding of this complex process.

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Relationship Between the Inflammation and Coagulation Pathways in Patients with Severe Sepsis

Cited by 7 publications

References 84 publications

Effect of Drotrecogin alfa (activated) on platelet receptor expressionin vitro

Effect of Drotrecogin alfa (activated) on platelet receptor expressionin vitro

Recombinant human activated protein C resets thrombin generation in patients with severe sepsis – a case control study

Sepsis

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