Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0012739 (disseminated intravascular coagulation)
 8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Perfluorotributylamine/Pluronic F68 Stem-Emulsion (FC43se), which is a blood substitute, was assessed for its effectiveness on disseminated intravascular coagulation (DIC) in the rat model. Rats were infused intravenously with 2.5 mg/kg of Escherichia coli lipopolysaccharide (Escherichia coli 055:B5 lipopolysaccharide B) for four hours. At the same time, FC43se or normal physiological saline was infused at 2.5 ml/kg/hr. The white blood cell and platelet counts, prothrombin time (PT), activated partial thromboplastin time (APTT), and the plasma levels of interleukin-1 beta (IL-1 beta), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor alpha (TNF alpha) were determined at 4 hr. The infusion of FC43se markedly prevented a decrease in platelet counts (p = 0.0004) and a prolongation of both PT and APTT (p < 0.05 and p < 0.03 each). The serum level of IL-1 beta and IL-4 showed no significant change. The serum level of IL-6, IL-10 and TNF alpha increased significantly (p = 0.0007, p = 0.0004 and p < 0.05 each) with infusion of FC43se in rats treated with bacterial endotoxin. FC43se has beneficial effects on endotoxin-induced DIC as an anticoagulant and anti-inflammatory cytokine induced agent.
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PMID:Effect of FC43se on endotoxin-induced disseminated intravascular coagulation in rats. 1043 77

Endotoxic lipopolysaccharide (LPS) is a proinflammatory agonist produced by gram-negative bacteria and a contributor to the majority of the 400,000 septic shock cases recorded annually in US hospitals. The primary target cells for LPS are monocytes and macrophages. Their response consists of massive production of proinflammatory cytokines, reactive oxygen- and nitrogen-intermediates, procoagulants, and cell adhesion molecules. In turn, expression of these LPS-responsive factors contributes to collapse of the circulatory system, to disseminated intravascular coagulation, and to a 30% mortality rate. A common intracellular mechanism responsible for the expression of septic shock genes in monocytes and macrophages involves the activation of NF-kappaB. This transcription factor is regulated by a family of structurally related inhibitors including IkappaBalpha, IkappaBbeta, and IkappaBepsilon, which trap NF-kappaB in the cytoplasm. In this report, the investigators show that LPS derived from different gram-negative bacteria activates cytokine-responsive IkappaB kinases containing catalytic subunits termed IKKalpha (IKK1) and IKKbeta (IKK2). The kinetics of IKKalpha and IKKbeta activation in LPS-stimulated human monocytic cells differ from that recorded on their stimulation with tumor necrosis factor-alpha, thereby implying a distinct activation mechanism. LPS-activated IKK complexes phosphorylate all 3 inhibitors of NF-kappaB: IkappaBalpha, IkappaBbeta, and IkappaBepsilon. Moreover, LPS activates IKKbeta preferentially, relative to IKKalpha. Thus, IKK complex constitutes the main intracellular target for LPS-induced NF-kappaB signaling to the nucleus in human monocytic cells to activate genes responsible for septic shock.
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PMID:IkappaB kinase complex is an intracellular target for endotoxic lipopolysaccharide in human monocytic cells. 1047 96

In order to determine whether prednisolone has a protective effect against the development of disseminated intravascular coagulation (DIC), we measured the effect of prednisolone on changes in hemostatic parameters and plasma levels of inflammatory cytokines in endotoxin-treated rats. Decreases in platelet count and fibrinogen levels, prolongation of prothrombin time, and increases in the plasma fibrin degradation products and levels of thrombin-antithrombin III (TAT) complex following the administration of endotoxin, all of which are associated with DIC, were significantly suppressed by the administration of prednisolone. Heparin administration significantly suppressed changes in all these parameters except for the decrease in platelet count. The combination of prednisolone and heparin was more effective than either treatment alone. In order to determine whether these effects of prednisolone are correlated with the suppression of inflammatory cytokine production, we examined the relationship between changes in plasma levels of cytokine, the hemostatic parameters listed above, and mortality using a number of intervention regimens designed to alter events of the experimentally induced DIC. Changes in hemostatic parameters associated with DIC following 30 mg/kg per 4 h of endotoxin infusion were significantly suppressed by treatment with 1 mg/kg prednisolone 30 min before beginning endotoxin infusion, followed by administration of 250 U/kg heparin 2 h after the start of endotoxin infusion (prednisolone-endotoxin-heparin regimen). The heparin and prednisolone were administrated subcutaneously. The administration of prednisolone and heparin in the reverse order (i.e. heparin first and prednisolone second: heparin-endotoxin-prednisolone regimen) also suppressed changes in hemostatic parameters, albeit to a smaller degree. Cytokine production was also significantly suppressed by the first treatment, but was not affected by the regimen in which heparin was administered first. Administration of prednisolone alone or heparin alone 30 min before endotoxin significantly reduced the number of renal glomeruli with fibrin thrombi. Plasma levels of creatinine and alanine transferase were reduced only by prednisolone. Increased plasma levels of interleukin-1beta, tissue necrosis factor-alpha and interleukin-6 were suppressed by prednisolone but not by heparin, and there were significant correlations between plasma levels of TAT and cytokines. Prednisolone was more effective than heparin in reducing mortality at 24 h after 100 mg/kg over 4 h of endotoxin infusion (four of 20 versus 15 of 20 deaths for prednisolone and heparin, respectively). These findings suggest that prednisolone inhibits the development of endotoxin-induced DIC and reduces mortality by a different mechanism than heparin, possibly through suppressing the production of inflammatory cytokines. Prednisolone may be efficacious in preventing DIC and multiple organ dysfunction caused by endotoxin.
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PMID:Prednisolone inhibits endotoxin-induced disseminated intravascular coagulation and improves mortality in rats: importance of inflammatory cytokine suppression. 1049 13

Although morbidity following cryotherapy is usually minor, a syndrome of multiorgan failure and disseminated intravascular coagulation (DIC) has been described and referred to as the cryoshock phenomenon. We hypothesized that mediators similar to those in septic shock may be involved in this syndrome. In this study we aimed to assess the plasma concentrations of the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) following hepatic cryotherapy and to relate them to the duration and volume of freezing and to hepatocellular injury. Between April and December 1997 blood samples were taken preoperatively and at different times postoperatively from patients undergoing hepatic artery catheter-insertion (HAC) (n = 15), cryotherapy (n = 5), liver resection (n = 9), liver resection and edge cryotherapy (n = 7), or liver resection and cryotherapy of additional lesions (n = 9). They were analyzed for serum aspartate transaminase (AST) and plasma TNF-alpha and IL-6 levels. There was a significant association (Pearson correlation) of serum AST levels 1 hour postoperatively with plasma TNF-alpha and IL-6 levels at the end of the procedure. In patients undergoing cryotherapy or resection with cryotherapy of additional lesions (n = 14), the volume and duration of hepatic freezing were significantly associated with postoperative serum AST and plasma TNF-alpha and IL-6 levels at various postoperative times. Hepatic cryotherapy is followed by cytokine release, with postoperative plasma TNF-alpha and IL-6 levels associated with the degree of hepatic cryotrauma. These mediators may be involved in the occurrence of cryoshock following large-volume hepatic freezing.
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PMID:Interleukin-6 and tumor necrosis factor-alpha levels following hepatic cryotherapy: association with volume and duration of freezing. 1051 41

Hemophagocytic syndrome (HPS) is a syndrome presenting with signs of persistent remittent fever, hepatosplenomegaly, pancytopenia, hepatic dysfunction, and disseminated intravascular coagulation (DIC) due to hypercytokinemia caused by activated T lymphocytes and macrophages. The mortality in adults is high and a small number of complicated cases during pregnancy have been reported. We report one HPS case that developed a remittent fever, leukocytopenia, and thrombocytopenia in the 2st week of pregnancy, and abnormal blood coagulation, hepatic dysfunction, and hypercytokinemia were found. Antibiotics and immunoglobulin were given but failed to improve clinical and laboratory findings. At the 24th week, the patient was diagnosed with DIC, and antithrombin (AT) concentrate was given. With the increase in plasma levels of AT, improvements were seen in both clinical signs and laboratory findings. Bone marrow biopsies were carried out, and a diagnosis of HPS was made. Preeclampsia developed in the 27th week and it became severe. Cesarean section was performed in the 29th week because of severe preeclampsia, intrauterine growth retardation (IUGR), and fetal distress. The courses of mother and newborn were uneventful. We discuss the mechanism of AT in the treatment of this syndrome and the association between this syndrome and severe preeclampsia. In conclusion, AT concentrate was very effective in suppressing cytokine production, and the possibility that severe preeclampsia developed because of hypercytokinemia, which may be one of the pathogeneses of severe preeclampsia and IUGR, was suggested.
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PMID:Association of hypercytokinemia in the development of severe preeclampsia in a case of hemophagocytic syndrome. 1062 4

Disseminated intravascular coagulation (DIC) is a complex disorder, with pathophysiology being variable and highly dependent upon the triggering event(s), host response(s) and comorbid conditions. As a result of these complicated interactions, the clinical expression and laboratory findings are varied, thereby affecting the specifics of diagnosis and therapeutic approaches. The highly complex and variable pathophysiology of DIC often results in a lack of uniformity in clinical manifestations, a lack of consensus in the specific appropriate laboratory criteria of diagnosis, and a lack of specific therapeutic modalities. Indeed, recommendations for therapy are often difficult because the morbidity and survival is more dependent on the specific cause of DIC and because the generally used specific therapeutic approaches, which include for example heparin, low-molecular-weight-heparin antithrombin concentrate and protein C concentrate, have never been subjected to objective prospective randomized trials, except antithrombin concentrates. An analysis of the complex and varied pathophysiological events in DIC provide objective guidelines and criteria for the clinical diagnosis, the laboratory diagnosis, and the definition of severity. These data compounded by an understanding of complex and varied pathophysiology can be used for objective evaluation of therapeutic responses and results. DIC is an intermediary mechanism of disease usually seen in association with well-defined clinical disorders. The pathophysiology of DIC serves as an intermediary mechanism in many disease processes, which sometimes remain organ specific. This catastrophic syndrome spans all areas of medicine and presents a broad clinical spectrum that is confusing to many. Most physicians consider DIC to be a systemic hemorrhagic syndrome; however, this is only because hemorrhage is evident and often impressive. Less commonly appreciated is the profound microvascular thrombosis and sometimes, large vessel thrombosis. The hemorrhage is often simple to contend with in patients with fulminant DIC, but it is the small- and large-vessel thrombosis, with impairment in blood flow, ischemia, and associated end-organ damage that usually leads to irreversible morbidity and mortality. In conclusion, the pathophysiological mechanisms, clinical, and laboratory manifestations of DIC are complex in part due to interrelationships within the hemostasis system. Only by clearly understanding these extraordinarily complex pathophysiological interrelationships can the clinician and laboratory scientist appreciate the divergent and wide spectrum of often confusing clinical and laboratory findings in patients with DIC. Many therapeutic decisions to be made are controversial and lack validation. Nevertheless, newer antithrombotic agents, and agents which can block, blunt or modify cytokine activity and the activity of vasoactive substances appear to be of value. The complexity and variable degree of clinical expression suggests that therapy should be individualized depending on the nature of DIC, age, etiology of DIC, site and severity of hemorrhage or thrombosis and hemodynamics and other appropriate clinical parameters.
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PMID:Disseminated intravascular coagulation. clinical and pathophysiological mechanisms and manifestations. 1062 92

Administration of lipopolysaccharide (LPS) induces inflammation and tissue injuries that occasionally results in disseminated intravascular coagulation (DIC). This process is believed to be mediated by vasoactive molecules such as kinins and leads to endothelial damage and obstruction of the microcirculation. In this study, we evaluated the involvement of T-kininogen and macrophage migration inhibitory factor (MIF) in endotoxin-induced systemic inflammation. T-Kininogen is a protein unique to the rat and known as an acute-phase protein in response to endotoxins. Similarly, MIF functions as a proinflammatory cytokine and glucocorticoid-induced immunoregulator. First, we examined the effects of anti-MIF antibody on Wistar King male rats (ca 400 g) treated with intraperitoneal injection of LPS. At 6 hours after LPS injection (5 mg/kg), the platelet counts had decreased from 85 +/- 12.8 (x 10(4)/microL) to 8.8 +/- 2.6 (x 10(4)/microL). We treated these rats with the anti-rat MIF antibody (5 mg gamma G immunoglobulin [IgG] fraction/kg) 2 hours prior to LPS injection. This treatment prevented the decrease in platelet counts (45.6 +/- 5.6 [x 10(4)/microL]). Next, we examined the potential of MIF for production of T-kininogen. Intraperitoneal injection of rat MIF significantly upregulated the serum content of T-kininogen at the dose of 500 microg MIF/head. These results imply that MIF and T-kininogen might function in concert in the event of endotoxin-induced inflammation.
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PMID:Induction of T-kininogen and tumor necrosis factor-alpha by macrophage migration inhibitory factor in vivo. 1063 78

During sepsis toxins released from, e.g., bacteria induce reactions of various cascade systems that may cause progression of the patient into septic shock, disseminated intravascular coagulation, multiorgan dysfunction syndrome and subsequent death. The use of conventional treatments using antibiotics, fluid substitution, inotropic drugs, respiration aid and dialysis is not enough to reverse the serious prognosis. The addition of various other drugs such as antibodies against various cytokines and cytokine receptors, pentoxiphylline, immunoglobulins or high doses of steroids is usually without benefit for the prognosis of the patient. Another possibility to reduce the extent of toxins and other harmful compounds in the circulation is the use of apheresis (removal by technical devices). This can be done either in a nonselective way (plasma exchange, plasmapheresis) or more selectively using various adsorbers such as polymyxin B. The survival in studies varies between 50 and 80%. Besides the use of nonselective apheresis, the development of various selective adsorption techniques may be one approach to improve survival of these severely ill patients.
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PMID:Is there a future for adsorption techniques in sepsis? 1102 91

Recently, basic and clinical advances have provided insights into the molecular events that link inflammation with blood coagulation and thrombosis. At least in cell culture, the inflammatory cytokines, especially tumour necrosis factor alpha (TNF) and interleukin 1-beta (IL-1), are major mediators that can elicit changes in cell phenotype. With respect to coagulation, one of the clot-promoting and one of the inhibitory pathways seem especially prone to modulation by these cytokines. Whenever Tissue Factor contacts the blood, coagulation is initiated rapidly. These cytokines can elicit Tissue Factor production on endothelium and monocytes. Thus, the cytokines elaborate Tissue Factor formation intravascularly. This contrasts with the normal situation in which Tissue Factor is located exclusively in the extravascular space, largely on fibroblasts, where it is expressed constitutively. Furthermore, cytokines, especially interleukin 6 (IL-6), can stimulate new platelet formation, and the new platelets responding to IL-6 have increased sensitivity to thrombin activation and increased procoagulant activity. Regulating the clotting process are a large number of anticoagulant and fibrinolytic mechanisms. The three major anticoagulant mechanisms appear to involve antithrombin-heparin, Tissue Factor pathway inhibitor (TFPI) and the Protein C pathway. Of these, the Protein C pathway appears to be the primary target for cytokine action. The Protein C pathway is initiated when thrombin binds to thrombomodulin (TM). TM is expressed constitutively on endothelium. In tissue culture, TNF, IL-1 or endotoxin lead to a slow loss of TM and endothelial cell Protein C receptor (EPCR) from the cell surface. In addition, Protein S levels decrease in patients with disseminated intravascular coagulation (DIC). Taken together, these results suggest that cytokines should elicit massive thrombotic responses when administered systemically. At near toxic levels, TNF fails to elicit an overt DIC or thrombotic response in patients, although sensitive markers of coagulation do detect changes in coagulation in response to TNF. In baboons, very high levels of TNF also fail to elicit fibrinogen or platelet consumption. However, if the Protein C pathway is blocked, these cytokines can elicit either DIC or deep-vein thrombosis, depending on the conditions. Thrombus formation is potently potentiated by impeding flow and/or by catheterization. DIC is facilitated by providing membrane surfaces, possibly mimicking complement mediated platelet activation/damage that occurs in shock. Thus, available evidence suggests important roles for inflammatory cytokines in DIC and thrombosis, but they seem insufficient by themselves to elicit overt thrombotic responses without secondary stimuli. Current data suggest that anti-inflammatory drugs are a viable candidate to blocking DIC or thrombosis without impairing the haemostatic balance.
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PMID:Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis. 1085 74

Sepsis is often associated with a downward spiral through a spectrum of systemic inflammatory response syndrome (SIRS) culminating in organ failure and death. Here we present a 3-year-old girl with Hemophilus influenzae septic meningitis who developed SIRS and acute renal failure. In the initial stage, the patient showed uremia, cytopenia, disseminated intravascular coagulation, elevation of tissue enzyme and ferritin values, hemophagocytosis and overproduction of nitric oxide. The serum cytokine profile revealed increased levels of soluble interleukin (IL)-2 receptor, IL-6, IL-10 and tumor necrosis factor alpha. The patient responded positively to early and intensive interventions including antibiotics, repeated exchange transfusions, dexamethasone and high-dose gamma-globulin. The above laboratory abnormalities almost normalized with clinical improvement. We consider that SIRS was probably responsible for the sequence of events resulting in renal failure in this case, and suggest that renal failure should be included among the serious complications of SIRS associated with Hemophilus influenzae septic meningitis.
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PMID:Systemic inflammatory response syndrome and acute renal failure associated with Hemophilus influenzae septic meningitis. 1087 2


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