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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Widespread intravascular coagulation is common in patients with sepsis. Coagulation abnormalities may result from exposure to endotoxin, from tumor necrosis factor alpha or interleukin 1 release, or from the actions of a more specific mediator, such as vascular permeability factor. The result is marked activation of the contact and coagulation systems; simultaneously, there is decreased fibrinolysis and depressed levels of the inhibitors of the contact and coagulation systems. Multiple agents are being studied to correct these abnormalities. Antithrombin III holds promise because it inhibits a number of factors important in contact and coagulation activation, not just thrombin. Plasminogen activators may prove helpful in increasing fibrinolysis during sepsis; because they have been associated with rebound thrombin generation, however, plasminogen activators may be most effective if used in conjunction with hirudin or a synthetic hirudin analogue. Bradykinin may offset hypotension in sepsis. Protein C may inhibit thrombin formation and also complex with plasminogen activator inhibitor 1, thereby promoting fibrinolysis. Other agents that may prove effective include alpha 1-antitrypsin Pittsburgh, C1-esterase inhibitor, monoclonal antibodies to contact factors, soybean trypsin inhibitors, thrombomodulin, prostaglandin I2, and aprotinin. There are no data to support the use of heparin or fibronectin, except in limited circumstances.
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PMID:Modulators of coagulation. A critical appraisal of their role in sepsis. 162 18

Tumor necrosis factor (TNF) may be involved in the disturbance of the procoagulant-fibrinolytic balance in septicemia, leading to microvascular thrombosis. To assess the dynamics of the fibrinolytic response to TNF in humans, we performed a crossover saline-controlled study in six healthy men, investigating the effects of a bolus intravenous injection of recombinant human TNF (50 micrograms/m2) on the stimulation and inhibition of plasminogen activation as well as on plasmin activity and inhibition. TNF induced a brief fourfold increase in the overall plasma plasminogen activator (PA) activity peaking after 1 h (p less than 0.0001), which was associated with rises in the antigenic levels of urokinase-type plasminogen activator (p less than 0.0001) and tissue-type plasminogen activator (p less than 0.0001). Plasminogen activator inhibitor type I antigen remained unchanged in the first hour, but showed a rapid eightfold increase thereafter (p less than 0.0001), which coincided with the decrease in PA activity. Generation of plasmin activity in the first hour was signified by an 11-fold rise in D-dimer levels (p less than 0.0001); inhibition of plasmin was reflected by a 36-fold rise in plasmin-alpha 2 antiplasmin complexes (p less than 0.0001), as well as by a transient 16% decrease in alpha 2-antiplasmin activity (p less than 0.01). In conclusion, TNF induced an early activation of the fibrinolytic system becoming maximal in 1 h, with a rapid inhibition thereafter. Earlier observations in the same subjects showed sustained coagulation activation for 6-12 h. The observed disbalance between the procoagulant and fibrinolytic mechanisms after TNF injection confirms the in vivo relevance of the effects of TNF on vascular endothelium in vitro and may explain the tendency towards microvascular thrombosis in septicemia.
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PMID:Fibrinolytic response to tumor necrosis factor in healthy subjects. 171 36

Trauma causes more years of lost life than any other cause of death. Traumatic shock and sepsis are the most common late causes of death following trauma. Traumatic shock and sepsis cause multiple organ failure. The most common organ to fail is the lung, which develops Adult Respiratory Distress Syndrome (ARDS). ARDS can be caused by Disseminated Intravascular Coagulation (DIC) with microscopic clots in the lungs. Trauma causes hemolysis and the red cell stroma may initiate DIC. Plasminogen activators, which causes lysis of blood clot, can lyse pulmonary microthrombi and prevent the onset of ARDS even when given several hours after the trauma.
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PMID:A new treatment for traumatic shock and ARDS. 215 24

In the present study treatment of sepsis in 18 surgical patients, 9 survivors and 9 fatal cases, were evaluated by determining components of the plasma proteolytic enzyme systems using chromogenic peptide substrate assays. During persistent sepsis, continuous low values for prekallikrein, plasminogen and antithrombin III were found until death. At autopsy a septic focus was found in all but one of the fatal cases. Very low levels of prekallikrein during sepsis and reduced functional inhibition of plasma kallikrein in septic shock indicated a poor prognosis. In the survivors all parameters returned towards normal range upon successful therapy. Plasminogen and antithrombin III were most rapidly normalized. It is concluded that determination of components of the plasma protease systems using chromogenic peptide substrate assays, gives valuable information about course and prognosis in surgical sepsis, and that they are suitable for practical clinical use.
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PMID:Treatment of sepsis in the surgical patient evaluated by means of chromogenic peptide substrate assays. 618 46

1. Disseminated intravascular coagulation frequently accompanies Gram-negative sepsis and may contribute to widespread deposition of microthrombi. Besides the endotoxin-induced activation of coagulation, an important role for the fibrinolytic system has been postulated. The precise mechanisms underlying these fibrinolytic changes during endotoxaemia are not known but have been suggested to be mediated directly by cytokines or secondary to thrombin generation. 2. In the present study we have delineated in detail the fibrinolytic response to a bolus injection of endotoxin in non-human primates and analysed the contribution of cytokines and thrombin generation to the endotoxin-induced release of tissue-type plasminogen activator and plasminogen activator inhibitor 1. Chimpanzees received a bolus injection of endotoxin alone or in combination with blocking monoclonal antibodies directed against tumour necrosis factor or interleukin 6 or in combination with pentoxifylline. Furthermore, to assess the effect of coagulation activation on the activation of fibrinolysis, another group of chimpanzees received endotoxin in combination with either anti-tissue factor antibodies or recombinant hirudin. 3. Infusion of endotoxin induced a rapid increase in plasminogen activator activity and tissue-type plasminogen activator antigen levels and subsequent plasmin generation, reaching peak levels 2h after endotoxin administration. Plasminogen activator inhibitor 1 levels remained constant for the first 2 h, after which time a steep increase was observed. Plasminogen activator activity and plasmin generation decreased simultaneously with the rise in plasminogen activator inhibitor 1 levels. Fibrinolytic activity remained suppressed during the remainder of the study owing to sustained increased levels of plasminogen activator inhibitor 1. The administration of pentoxifylline strongly attenuated the release of tissue-type plasminogen activator and plasminogen activator inhibitor 1, whereas the antitumour necrosis factor antibodies blocked the fibrinolytic response entirely. In contrast, interleukin 6-neutralizing antibodies did not affect the fibrinolytic response. Although endotoxin-induced generation of thrombin was completely prevented by the administration of tissue factor-neutralizing antibodies or by hirudin, no effect on the fibrinolytic response was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades. 761 18

The vascular endothelium plays a central role in the regulation of extrinsic fibrinolysis and thus maintains vascular patency through clot dissolution. Plasminogen activation provides an important source of localized proteolytic activity not only during fibrinolysis but also during a variety of other physiological and pathological processes. Numerous studies have indicated that human endothelial cells can directly synthesize and secrete plasminogen activators (PA) and inhibitors of these activators. PAs specifically hydrolyse a single arginine-valine bond in plasminogen, an abundant and widely distributed plasma zymogen, to form the broad spectrum serine protease, plasmin. Tissue type-PA (t-PA) and urokinase type PA (u-PA) forms of PA have been described in endothelial cells, although t-PA production and secretion is elevated most frequently. The tPA form of PA functions predominantly in endothelial cell mediated fibrinolysis, while uPA is involved in tissue remodeling. During inflammatory reactions activated mononuclear phagocytes produce a variety of cytokines which may influence the phenotype of the endothelium through a process termed "endothelial cell activation". Tumor necrosis factor alpha (TNF alpha), a mononuclear cytokine, is a distinct polypeptide of Mr 17,000 and has been implicated as a mediator of gram negative induced sepsis as well as angiogenesis. TNF alpha is known to interact with specific endothelial cell receptors and to alter endothelial coagulant and anticoagulant properties implying that cytokines may be potent modulators of hemostasis. Recent observations have indicated that TNF alpha and lymphotoxin (TNF beta) can promote the expression, synthesis and secretion of urokinase plasminogen activator (uPA) in human endothelial cells. The upregulation of uPA results in an alteration in the fibrinolytic capacity of endothelial cells and allows cells the selective ability to degrade and invade underlying subendothelial extracellular matrix (ECM). Endothelial cells treated with TNF alpha also display, in an in vitro angiogenic assay, the ability to invade Matrigel and reorganize into tube-like structures, unlike control cultures. The effects of TNF alpha on the PA proteolytic system of endothelial cells, the biological significance of this event and potential in vivo consequences will be discussed. In addition, the influence of cytokine regulatory control systems will be described, since it is becoming increasingly clear that cytokines do not act in isolation. The vascular endothelium serves as a widely distributed anatomical interface between the blood and tissue with diverse capabilities, performing distinctive biologic functions at different sites and within specific organs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cytokine regulation of endothelial cell extracellular proteolysis. 835 23

Leucocytes, both polymorphs and mononuclear cells, play a variety of roles in the evolution of human response to sepsis, both local and generalised. In this study, inhibitors of plasminogen activator were measured in leucocytes from normal and septic patients. Plasminogen activator inhibitor-1 (PAI-1) was identified in polymorphs from normal individuals and levels rose significantly in polymorphs from septic patients: neutrophils from normal subjects did not contain PAI-2 but this protein was detectable in significant quantities in polymorph preparations from septic patients. In contrast, mononuclear cells from normal and septic patients contained no detectable quantities of PAI-1. Significant amounts of PAI-2 were present in normal mononuclear cells, and the levels rose significantly in monocytes from septic patients. PAI-2 is thus here identified in human subjects, distinct from those with pregnancy or malignancy, as playing a role in a pathological process. The increased levels of both inhibitors produced by leucocytes may clearly contribute directly to the persistence of fibrin, a characteristic feature of the response to infection, local or general; they may thus participate in successful localisation of infections (abscess formation etc.) and in the evolution of the major systemic complications of disseminated sepsis characterised by microvascular occlusion by fibrin such as renal failure, shock lung or digital ischaemia.
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PMID:Inhibitors of plasminogen activator in neutrophils and mononuclear cells from septic patients. 877 32

Lipopolysaccharide-containing outer membrane vesicles (OMV-LPS) which are spontaneously released from Neisseria meningitidis during logarithmic growth were studied for their ability to induce procoagulant (tissue factor), profibrinolytic (urokinase-type plasminogen activator) and antifibrinolytic (plasminogen activator inhibitor-2) factors in purified human monocytes. Cell-associated tissue factor was 5.0-fold (n=5) increased, peaking after 8 h, in the presence of OMV-LPS (1 microg/ml, final concentration). Plasminogen activator inhibitor-2 release from monocytes was maximal after 24 h OMV-LPS (1 microg/ml) stimulation and 13.7-fold (n=5) increased compared to controls; whereas urokinase-type plasminogen activator antigen in culture medium remained uninfluenced by OMV-LPS. In conclusion, these OMV-induced imbalances favor fibrin deposition in the monocyte microenvironment and is probably of great importance in the development of disseminated intravascular coagulation, microthrombosis and organ dysfunction related to fulminant meningococcal septicemia.
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PMID:Outer membrane vesicles from Neisseria meningitidis: effects on tissue factor and plasminogen activator inhibitor-2 production in human monocytes. 1136 30

Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of plasminogen activation and likely plays important roles in coronary thrombosis and arteriosclerosis. Tumor necrosis factor-alpha (TNFalpha) is one of many recognized physiological regulators of PAI-1 expression and may contribute to elevated plasma PAI-1 levels in sepsis and obesity. Although TNFalpha is a potent inducer of PAI-1 expression in vitro and in vivo, the precise location of the TNFalpha response site in the PAI-1 promoter has yet to be determined. Transient transfection studies using luciferase reporter constructs containing PAI-1 promoter sequence up to 6.4 kb failed to detect a response to TNFalpha. Moreover, TNFalpha failed to induce expression of enhanced green fluorescent protein under the control of a 2.9-kb human PAI-1 promoter in transgenic mice, although endogenous murine PAI-1 was strongly induced. These data suggested that the TNFalpha response element in the PAI-1 gene is remote from the proximal promoter region. In this study, seven candidate regulatory regions were identified using cross-species sequence homology analysis as well as DNase I-hypersensitive site analysis. We identified a 5' distal TNFalpha-responsive enhancer of the PAI-1 gene located 15 kb upstream of the transcription start site containing a conserved NFkappaB-binding site that mediates the response to TNFalpha. This newly recognized site is fully capable of binding NFkappaB subunits p50 and p65, whereas overexpression of the NFkappaB inhibitor IkappaB prevents TNFalpha-induced activation of this enhancer element.
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PMID:Tumor necrosis factor alpha activates the human plasminogen activator inhibitor-1 gene through a distal nuclear factor kappaB site. 1496 43

Plasminogen activator inhibitor-1 (PAI-1), a 45-kDa serine proteinase inhibitor with reactive site peptide bond Arg345-Met346, is the main physiological plasminogen activator inhibitor. It occurs in human plasma at an antigen concentration of about 20 ng mL(-1). Besides the active inhibitory form of PAI-1 that spontaneously converts to a latent form, also a substrate form exists that is cleaved at the P1-P1' site by its target enzymes, but does not form stable complexes. Besides its role in regulating hemostasis, PAI-1 plays a role in several biological processes dependent on plasminogen activator or plasmin activity. Studies with transgenic mice have revealed a functional role for PAI-1 in wound healing, atherosclerosis, metabolic disturbances such as obesity and insulin resistance, tumor angiogenesis, chronic stress, bone remodeling, asthma, rheumatoid arthritis, fibrosis, glomerulonephritis and sepsis. It is not always clear if these functions depend on the antiproteolytic activity of PAI-1, on its binding to vitronectin or on its intereference with cellular migration or matrix binding.
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PMID:Pleiotropic functions of plasminogen activator inhibitor-1. 1563 64


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