The Tissue Factor and Plasminogen Activator Inhibitor Type-1 Response in Pediatric Sepsis-induced Multiple Organ Failure

Green, Jerril; Doughty, Lesley; Kaplan, Sandra S.; Sasser, Howell; Carcillo, Joseph A.

doi:10.1055/s-0037-1612976

Cited by 62 publications

(43 citation statements)

References 19 publications

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“…In a recent study of patients with meningococcemia, TM levels were reduced in dermal microvessels, an effect that would be predicted to yield decreased levels of activated protein C. 42 In a mouse model of endotoxemia, the administration of LPS resulted in reduction in total tissue TM antigen in the lung and brain, but not in the kidney, 41 suggesting that sepsis-associated changes in TM expression may vary between organs. While sepsis is associated with increased levels of PAI-1, 84,97 an endothelial source of PAI-1 has not been established. With few exceptions, 46,47 sepsis studies have consistently failed to demonstrate TF in the intact endothelium.…”

Section: Endothelial Response In Severe Sepsismentioning

confidence: 99%

The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome

Aird

2003

Blood

1,004

815

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Severe sepsis, defined as sepsis with acute organ dysfunction, is associated with high morbidity and mortality rates. The development of novel therapies for sepsis is critically dependent on an understanding of the basic mechanisms of the disease. The pathophysiology of severe sepsis involves a highly complex, integrated response that includes the activation of a number of cell types, inflammatory mediators, and the hemostatic system. Central to this process is an alteration of endothelial cell function. The goals of this article are to (1) provide an overview of sepsis and its complications, IntroductionSepsis is the most common cause of death among hospitalized patients in noncoronary intensive care units. Thus, an important goal in critical care medicine is to develop novel therapeutic strategies that will impact favorably on patient outcome. Unfortunately, the pathophysiology of severe sepsis remains poorly defined. While it is generally accepted that sepsis-associated mortality is related to the host response and involves a multitude of cell types, inflammatory mediators, and coagulation factors, clinical studies have largely failed to identify an effective therapeutic target. Future advances in sepsis therapy will require a better understanding of how the individual components of the host response interact. The endothelium plays a critical role in mediating the sepsis phenotype. This article provides an overview of sepsis and its complications, discusses the role of the endothelium in orchestrating the host response in sepsis, and emphasizes the potential value of the endothelium as a target for sepsis therapy. Overview of the sepsis continuum DefinitionSepsis and its sequelae represent a continuum in clinical-pathologic severity. However, it is one with definable phases that characterize patients at risk for increased mortality. 1 The American College of Chest Physicians and the Society of Critical Care Medicine established a set of definitions to facilitate early detection and treatment of sepsis and to standardize patient requirements for research protocols. 2 Infection is defined as an inflammatory response to microorganisms or the invasion of normally sterile host tissue by those organisms. Sepsis represents the systemic inflammatory response to infection and is manifested by 2 or more of the systemic inflammatory response syndrome (SIRS) criteria (eg, changes in body temperature, tachycardia, tachypnea and/or hyocapnia, and changes in the number and/or immaturity of white blood cells). Severe sepsis is sepsis complicated by organ dysfunction. Septic shock (hypotension despite adequate fluid resuscitation) is a subcategory of severe sepsis. At the end of the spectrum is multiple organ dysfunction syndrome (MODS), defined as the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention. EpidemiologyIn 1990, the Centers for Disease Control and Prevention reported an estimate of 450 000 cases of septicemia per year in the United States, ...

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Section: Endothelial Response In Severe Sepsismentioning

confidence: 99%

The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome

Aird

2003

Blood

1,004

815

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“…[27][28][29][30][31] Tissue factor activates thrombin, and elevated tissue factor expression is associated with thrombosis in atherosclerosis and sepsis. 32,33 Tissue factor expression is inhibited tissue factor endothelial NO ⅐ production. 29 -31 Upregulation of tissue factor may also be facilitated by O 2 ⅐Ϫ .…”

Section: Our Data Indicate That the Increase In Omentioning

confidence: 99%

Atrial Fibrillation Increases Production of Superoxide by the Left Atrium and Left Atrial Appendage

et al. 2005

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Background— Atrial fibrillation (AF) is associated with an increased risk of stroke due almost exclusively to emboli from left atrial appendage (LAA) thrombi. Recently, we reported that AF was associated with endocardial dysfunction, limited to the left atrium (LA) and LAA and manifest as reduced nitric oxide (NO · ) production and increased expression of plasminogen activator inhibitor-1. We hypothesized that reduced LAA NO · levels observed in AF may be associated with increased superoxide (O 2 ·− ) production. Methods and Results— After a week of AF induced by rapid atrial pacing in pigs, O 2 ·− production from acutely isolated heart tissue was measured by 2 independent techniques, electron spin resonance and superoxide dismutase–inhibitable cytochrome C reduction assays. Compared with control animals with equivalent ventricular heart rates, basal O 2 ·− production was increased 2.7-fold ( P <0.01) and 3.0-fold ( P <0.02) in the LA and LAA, respectively. A similar 3.0-fold ( P <0.01) increase in LAA O 2 ·− production was observed using a cytochrome C reduction assay. The increases could not be explained by changes in atrial total superoxide dismutase activity. Addition of either apocyanin or oxypurinol reduced LAA O 2 ·− , implying that NADPH and xanthine oxidases both contributed to increased O 2 ·− production in AF. Enzyme assays of atrial tissue homogenates confirmed increases in LAA NAD(P)H oxidase ( P =0.04) and xanthine oxidase ( P =0.01) activities. Although there were no changes in expression of the NADPH oxidase subunits, the increase in superoxide production was accompanied by an increase in GTP-loaded Rac1, an activator of the NADPH oxidase. Conclusions— AF increased O 2 ·− production in both the LA and LAA. Increased NAD(P)H oxidase and xanthine oxidase activities contributed to the observed increase in LAA O 2 ·− production. This increase in O 2 ·− and its reactive metabolites may contribute to the pathological consequences of AF such as thrombosis, inflammation, and tissue remodeling.

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“…A procoagulant glycoprotein TF may be released by endothelial and subendothelial cells, and a dysregulated balance of tissue-type plasminogen activator (TPA) and plasminogen activator inhibitor-1 (PAI-1) would lead to increased coagulation and suppressed fibrinolytic activity. Despite increased levels of PAI-1 in sepsis (Mavrommatis et al, 2001;Green et al, 2002), however, an endothelial source of PAI-1 has not been established. Furthermore, sepsis studies with few exceptions (Drake et al, 1993;Todoroki et al, 2000) have consistently failed to demonstrate TF in the intact endothelium.…”

Section: Abnormal Coagulation and Fibrinolysismentioning

confidence: 99%

Vascular biology in sepsis: pathophysiological and therapeutic significance of vascular dysfunction

Matsuda

Hattori

2007

J Smooth Muscle Res

116

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Sepsis is the leading cause of mortality in critically ill patients. In this pathological syndrome, septic shock and sequential multiple organ failure correlate with poor outcome. The pathophysiology of sepsis with acute organ dysfunction involves a highly complex, integrated response that includes activation of number of cell types, inflammatory mediators, and the hemostatic system. Central to this process may be alterations in vascular functions. This review article provides a growing body of evidence for the potential impact of vascular dysfunction on sepsis pathophysiology with a major emphasis on the endothelium. Furthermore, the role of apoptotic signaling molecules in the mechanisms underlying endothelial cell injury and death during sepsis and its potential value as a target for sepsis therapy will be discussed, which may help in the assessment of ongoing therapeutic strategies.

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The Tissue Factor and Plasminogen Activator Inhibitor Type-1 Response in Pediatric Sepsis-induced Multiple Organ Failure

Cited by 62 publications

References 19 publications

The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome

The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome

Atrial Fibrillation Increases Production of Superoxide by the Left Atrium and Left Atrial Appendage

Vascular biology in sepsis: pathophysiological and therapeutic significance of vascular dysfunction

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