Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C–deficient mice

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4823-4827 ◽  
Author(s):  
Marcel Levi ◽  
Janine Dörffler-Melly ◽  
Pieter Reitsma ◽  
Harry Büller ◽  
Sandrine Florquin ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Disseminated Intravascular Coagulation ◽  
Protein C ◽  
Activated Protein C ◽  
Intravascular Coagulation ◽  
Cytokine Activation ◽  
Tnf Α ◽  
Single Allele ◽  
Factor Α ◽  
Heterozygous Deficiency

Abstract In the pathogenesis of sepsis and disseminated intravascular coagulation (DIC), dysfunctional anticoagulant pathways are important. The function of the protein C system in DIC is impaired because of low levels of protein C and down-regulation of thrombomodulin. The administration of (activated) protein C results in an improved outcome in experimental and clinical studies of DIC. It is unknown whether congenital deficiencies in the protein C system are associated with more severe DIC. The aim of the present study was to investigate the effect of a heterozygous deficiency of protein C on experimental DIC in mice. Mice with single-allele targeted disruption of the protein C gene (PC+/–) mice and wild-type littermates (PC+/+) were injected with Escherichia coli endotoxin (50 mg/kg) intraperitoneally. PC+/–mice had more severe DIC, as evidenced by a greater decrease in fibrinogen level and a larger drop in platelet count. Histologic examination showed more fibrin deposition in lungs, kidneys, and liver in mice with a heterozygous deficiency of protein C. Interestingly, PC+/– mice had significantly higher levels of proinflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β, indicating an interaction between the protein C system and the inflammatory response. Survival was lower at 12 and 24 hours after endotoxin in the PC+/– mice. These results confirm the important role of the protein C system in the coagulative-inflammatory response on endotoxemia and may suggest that congenital deficiencies in the protein C system are associated with more severe DIC and adverse outcome in sepsis.

The Leiden Mutation and Activated Protein C Resistance as Risk Factors for Disseminated Intravascular Coagulation in Acutely Poisoned Patients

2006 ◽  
Vol 44 (1) ◽  
pp. 53-57
Author(s):  
Mirosław Prazanowski ◽  
Barbara Kur ◽  
Małgorzata Barańska ◽  
Waldemar Lutz ◽  
Bożena Piłacik ◽  
...  
Keyword(s):  
Risk Factors ◽  
Disseminated Intravascular Coagulation ◽  
Protein C ◽  
Activated Protein C ◽  
Activated Protein C Resistance ◽  
Intravascular Coagulation

Disseminated Intravascular Coagulation Is a Frequent Complication of Systemic Inflammatory Response Syndrome

1996 ◽  
Vol 75 (02) ◽  
pp. 224-228 ◽  
Author(s):  
Satoshi Gando ◽  
Takashi Kameue ◽  
Satoshi Nanzaki ◽  
Yoshimi Nakanishi
Keyword(s):  
Systemic Inflammatory Response Syndrome ◽  
Inflammatory Response ◽  
Plasminogen Activator ◽  
Disseminated Intravascular Coagulation ◽  
Protein C ◽  
Plasminogen Activator Inhibitor ◽  
Systemic Inflammatory Response ◽  
Plasminogen Activator Inhibitor 1 ◽  
Intravascular Coagulation ◽  
Activator Inhibitor

SummaryTo evaluate the role of disseminated intravascular coagulation (DIC) and to determine the influence of antithrombin, protein C, and plasminogen activator inhibitor 1 on multiple organ dysfunction syndrome (MODS) and outcome in patients with systemic inflammatory response syndrome (SIRS), we made a prospective cohort study. The study subjects consisted of thirty-five patients who exhibited two or more of the conditions of SIRS for more than three consecutive days. They were classified into subgroups of survivors (n = 13) and nonsurvivors (n = 22). The global coagulation and fibrinolytic markers, antithrombin, protein C, and plasminogen activator inhibitor 1 were measured on the day of the diagnosis of SIRS, and also on the 1st, 3rd, and 5th days. The results of these measurements, demographic data, criteria of severity, incidence of MODS were compared between the subgroups. For prediction of patient’s death, a receiver operating characteristic (ROC) curve analysis was made. DIC was frequently associated with SIRS patients (29/35, 82.9%). A significant decrease in the DIC score was found in the survivors (p = 0.0001). None of them suffered from DIC on the 5th day. In the nonsurvivors, low levels of protein C and antithrombin and markedly high values of plasminogen activator inhibitor 1 continued up to the 5th day, no improvement of the DIC was observed during the study period and the number of the dysfunctioning organs were significantly higher than in the survivors. Plasminogen activator inhibitor 1 on the 5th day had prognostic value for the prediction of death on the SIRS patients. In conclusion, DIC occurs commonly in patients with SIRS and may be the main determinant for the outcome of these patients. Changes in antithrombin, protein C, and plasminogen activator inhibitor 1 are one of the aggravating factors of MODS. Furthermore, plasminogen activator inhibitor 1 is a good predictor of death in these patients.

Recombinant Thrombomodulin and Activated Protein C in the Treatment of Disseminated Intravascular Coagulation

1999 ◽  
Vol 82 (08) ◽  
pp. 718-721 ◽  
Author(s):  
Ikuro Maruyama
Keyword(s):  
Endothelial Cells ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Disseminated Intravascular Coagulation ◽  
Protein C ◽  
Activated Protein C ◽  
Coagulation Cascade ◽  
Regulation System ◽  
Luminal Surface ◽  
Intravascular Coagulation

IntroductionThe blood coagulation cascade is regulated by the luminal surface of the endothelial cell lining.1 Endothelial cells synthesize tissue factor pathway inhibitor (TFPI), which, in part, binds to the cell surface glycosaminoglycans and inhibits factors Xa, VIIa, and tissue factor.2 Endothelial cells also produce and exhibit thrombomodulin (TM) on their luminal surface.3 TM is a kind of thrombin receptor that forms a 1:1 complex with thrombin. In this complex, thrombin activates protein C (PC) more than 1,000-fold more than thrombin alone. TM then loses its procoagulant activities, which include fibrinogen clotting, activation of factors V and VIII, and platelet activation. Thus, TM converts thrombin from a procoagulant protease to an anticoagulant. Pathologic states, such as an endothelial injury or perturbation or continuous rapid coagulation cascade activation, overcomes the endothelial regulating activity, resulting in the development of intravascular coagulation and the induction of disseminated intravascular coagulation (DIC). Theoretically, then, supplementing soluble TM or activated PC (APC) to reconstitute the endothelial coagulation regulation system in the circulation and regulate pathologically-activated blood coagulation could be beneficial. In this chapter, application of soluble TM and APC in the treatment of DIC is reviewed.

Activated Protein C Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production by Inhibiting Activation of both Nuclear Factor-κB and Activator Protein-1 in Human Monocytes

2002 ◽  
Vol 88 (08) ◽  
pp. 267-273 ◽  
Author(s):  
Mehtap Yuksel ◽  
Mitsuhiro Uchiba ◽  
Seikoh Horiuchi ◽  
Hiroaki Okabe ◽  
Kenji Okajima
Keyword(s):  
Protein C ◽  
Tumor Necrosis ◽  
Activated Protein C ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Tnf Α ◽  
Target Sites ◽  
Factor Α ◽  
Necrosis Factor

SummaryActivated protein C (APC), an important natural anticoagulant, inhibits tumor necrosis factor-α (TNF-α) production and attenuates various deleterious events induced by lipopolysaccharide (LPS), contributing thereby to a significant reduction of mortality in patients with severe sepsis. In this study, we investigated the mechanism(s) by which APC inhibits TNF-α production by LPS-stimulated human monocytes in vitro. Although APC inhibited LPS-induced TNF-α production in a concentration-dependent fashion, diisopropyl fluorophosphate-treated APC, an active-site-blocked APC, had no effect. APC inhibited both the binding of nuclear factor-κB (NF-κB) to target sites and the degradation of IκBα. APC also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. These observations strongly suggest that APC inhibited LPS-induced TNF-α production by inhibiting the activation of both NF-κB and AP-1 and that the inhibitory activity of APC might depend on its serine protease activity. These results would at least partly explain the mechanism(s) by which APC reduces the tissue injury seen in animal models of sepsis and in patients with sepsis.

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