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      Coagulation cascade in sepsis: getting from bench to bedside?

      research-article
      1 ,
      Critical Care
      BioMed Central
      blood coagulation factors, protein C, sepsis

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          Abstract

          The relationship between blood coagulation factors and the promotion or inhibition of the anti-inflammatory response continues to be defined through basic research. The potential key role of blood coagulation factors in the response during sepsis provides an exciting potential mechanism(s) for modification through the application of new therapies. The complexity of the potential multiple actions of the proteins, such as protein C, should allow for development of new therapies to minimize the detrimental inflammatory response. However, several gaps in our current understanding must be bridged before the clinician can take the basic knowledge 'to the bedside', where individual patients will benefit.

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          Most cited references5

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          Clinical trials of immunomodulatory therapies in severe sepsis and septic shock.

          Sepsis remains one of the leading causes of mortality in critically ill patients. Increased insight into the complexities of this disease process has resulted in the targeting of various aspects of the inflammatory response as offering potential therapeutic benefits. There have been encouraging results in the past few years. Some of the tested agents have been shown to improve mortality rates in large randomized controlled trials involving patients with severe sepsis. In this article, we discuss the positive and negative results of trials in this field; some of the possible reasons for the negative results are examined, and directions for the future are suggested.
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            Science review: Role of coagulation protease cascades in sepsis

            Cellular signaling by proteases of the blood coagulation cascade through members of the protease-activated receptor (PAR) family can profoundly impact on the inflammatory balance in sepsis. The coagulation initiation reaction on tissue factor expressing cells signals through PAR1 and PAR2, leading to enhanced inflammation. The anticoagulant protein C pathway has potent anti-inflammatory effects, and activated protein C signals through PAR1 upon binding to the endothelial protein C receptor. Activation of the coagulation cascade and the downstream endothelial cell localized anticoagulant pathway thus have opposing effects on systemic inflammation. This dichotomy is of relevance for the interpretation of preclinical and clinical data that document nonuniform responses to anticoagulant strategies in sepsis therapy.
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              New and emerging therapies for sepsis.

              P. Healy (2002)
              To review the recent advances related to the pathophysiology of sepsis and the rationale for recombinant human-activated protein C (drotrecogin alfa) and other antisepsis agents currently in Phase III trials. A MEDLINE (1990-December 2001) search was performed to identify pertinent literature on the pathophysiology of sepsis and treatment strategies. The search was supplemented with AdisInsight (Adis International) using the search terms sepsis, severe sepsis, or septic shock combined with agents in Phase II or higher clinical development. Abstracts presented at infectious diseases and critical care meetings were also reviewed. Clinical efficacy studies were selected for drotrecogin alfa and other Phase III investigational agents. Our current understanding of the pathophysiology of sepsis underscores the contribution of increased coagulation and diminished fibrinolytic activity working in conjunction with an excessive and dysregulated inflammatory response. The loss of homeostatic balance among these systems results in a systemic inflammatory response with generalized coagulopathy, microvascular thrombosis, and, ultimately, acute organ failure and death. As a result of these advances, several compounds are now in various phases of development. A recombinant human form of endogenous activated protein C (drotrecogin alfa) was recently approved by the Food and Drug Administration for severe sepsis in adults who have a high risk of death. It possesses anticoagulant, profibrinolytic, and antiinflammatory properties. Other compounds currently in Phase III trials include tissue-factor pathway inhibitor, tumor-necrosis factor antibody fragment, platelet-activating factor acetylhydrolase, antithrombin III, and pyridoxylated hemoglobin polyoxyethylene. With the recent approval of drotrecogin alfa, there is renewed optimism that we can effectively reduce sepsis-associated mortality.
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                Author and article information

                Journal
                Crit Care
                Critical Care
                BioMed Central (London )
                1364-8535
                1466-609X
                2003
                6 November 2002
                : 7
                : 2
                : 117-118
                Affiliations
                [1 ]Clinical Coordinator, Pharmacy Department, St. Paul's Hospital, Vancouver, British Columbia, Canada
                Article
                cc1842
                10.1186/cc1842
                270606
                12720555
                60e82f56-e8b1-410d-8070-639406fa49b0
                Copyright © 2003 BioMed Central Ltd
                History
                Categories
                Commentary

                Emergency medicine & Trauma
                blood coagulation factors,sepsis,protein c
                Emergency medicine & Trauma
                blood coagulation factors, sepsis, protein c

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