Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objective of this study was to evaluate and compare the derangement of body homeostatis and the inflammatory response after different types of traumatological operations in patients with multiple injuries. These were determined in a total of 60 operations. The procedures comprised osteosynthesis of the femur (n = 28), the pelvic girdle (n = 11) the spine (n = 8), and facial and basal skull reconstructions (n = 13). Specific and unspecific parameters of the inflammatory response were determined on the morning of the operation, immediately after the procedure, every 6 h on the 1st day and 48 h after the end of surgery. After all types of operations (pelvis, femur, spine, face/basal skull) significant alterations were observed for neutrophil elastase, C-reactive protein, interleukin 6, interleukin 8, antithrombin III, partial thromboplastin time and other parameters. The degree of postoperative changes differed significantly (Kruskal-Wallis test, P < 0.05) among the four types of operations for lactate, heart rate, PO2/FiO2 ratio and nitrogen excretion and showed a strong discriminating tendency for neutrophil elastase and C-reactive protein. The changes were most pronounced after operations on the pelvic girdle, followed by procedures in the femoral, spinal, and facial/basal skull regions. We conclude that a considerable inflammatory response and pronounced disturbance of body homeostasis follow traumatological operative procedures, varying in severity with the type of surgery. Several parameters allow quantitation of the surgical trauma and differentiation between different operations/regions. Further research should focus on the interrelationship between pre-existing preoperative inflammation and the additional trauma inflicted by surgery in patients with severe injuries.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Postoperative homeostatic imbalance after trauma surgical interventions of various degrees in polytrauma]. 748 29

Human GRO alpha, GRO beta, and GRO gamma are neutrophil chemoattractants structurally related to IL-8 and compete with IL-8 for binding to IL-8 receptors on neutrophils. These proteins are part of a large superfamily of chemotactic cytokines, the "chemokines," members of which share striking structural similarities. We have expressed GRO cDNA's in Escherichia coli as fusions to the MalE gene product, maltose-binding protein (MBP), in a way that allows separation of GRO and MBP moieties by factor Xa cleavage. GRO beta and GRO gamma expressed in bacteria were active in in vitro chemotaxis assays and were as effective as IL-8 in inducing chemotactic migration of neutrophils. Recombinant GRO beta was chemotactic rather than chemokinetic when tested by checkerboard analysis while GRO gamma showed evidence of chemokinetic as well as chemotactic activity. The activities of GRO beta and GRO gamma were not species-specific as both proteins were active on rat as well as human neutrophils and were inhibitable by antibodies raised against CINC, the rat GRO homolog. These data indicate that the MBP fusion protein expression system provides a rapid and simple method for obtaining large quantities of members of the chemokine protein family for biological uses.
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PMID:Expression of active human GRO beta and GRO gamma neutrophil chemotactic proteins in E. coli. 795 Mar 80

Fusion proteins of the human 55-kDa TNF receptor extracellular domain with hinge and C2/C3 constant domains of human IgG1 or IgG3 heavy chains were tested in a primate sepsis model. Twenty-four baboons received 4.6, or 0.2 mg/kg of TNFR5-G1,3, or placebo, before the administration of a lethal dose of live Escherichia coli. Treatment with TNFR5-G1,3 decreased 5-day mortality from 88% in the placebo group to 12% in the TNFR5-G1,3-treated animals (p < 0.01 by Fisher's exact test). Treatments with TNR5-G1 and TNFR5-G3 in doses from 0.2 to 4.6 mg/kg were efficacious. Free plasma TNF was neutralized by all treatments, but inactive TNF/TNFR5-G1,3 complexes remained in circulation for prolonged periods. TNFR5-1,3 treatments attenuated the hemodynamic disturbances, reduced fluid requirements, and decreased the systemic IL-1 beta, IL-6, and IL-8 responses. In addition, TNFR5-G1,3 treatment shortened the granulocytopenia and reduced the loss of cellular TNF receptors from granulocytes. The decrease in fibrinogen concentrations and increase in prothrombin and partial thromboplastin times were significantly attenuated by TNFR5-G1,3 treatment. TNFR5-G1,3 treatment markedly attenuated the rise in plasma lactate concentration. Histologic studies of TNFR5-G1,3 revealed dose-dependent protection against tissue injury by Escherichia coli administration.
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PMID:Protection against lethal Escherichia coli bacteremia in baboons (Papio anubis) by pretreatment with a 55-kDa TNF receptor (CD120a)-Ig fusion protein, Ro 45-2081. 869 Sep 12

Antitissue factor antibody attenuated the coagulopathic and lethal responses to LD100 Escherichia coli, whereas active site inhibited factor Xa inhibited only the coagulopathic response. In this study, we wished to determine: (1) whether active site inhibited factor VIIa blocks the coagulopathic and/or attenuates the lethal effects of LD100 E coli and (2) whether these effects are accompanied by attenuation of the inflammatory cytokine response to LD100 E coli. Eight baboons infused for 2 hours with LD100 E coli also were given five bolus infusions of DEGR VIIa of 280 microg/kg at T = -10 minutes, +2, 4, 6, and 8 hours and observed for changes in vital signs, and the concentrations of hemostatic components (fibrinogen, platelets, fibrin degradation products) and inflammatory mediators (tumor necrosis factor [TNF], interleukin-6 [IL-6], IL-8) at T = 0, 1, 2, 4, 6, and 8 hours. Eight control baboons were also infused with LD100 E coli alone and followed as described above. Four of the eight baboons treated with DEGR VIIa were permanent 7-day survivors versus none in the control group. The mean survival times for the treated and control groups were 116 +/- 22 and 26 +/- 8 hours, respectively. These values differed significantly from each other, (P = .0008). The decrease in platelet and fibrinogen concentrations and the increase in fibrin degradation products observed in the control group were significantly attenuated in the treated group, as was thrombosis of renal glomerular capillaries. Treatment with DEGR VIIa showed no effect on the peak TNF response to LD100 E coli at T = 2 hours (170 +/- 32 v 120 +/- 35 ng/mL). DEGR VIIa, however, did attenuate the IL-6 and IL-8 responses at T = 8 hours (ie, the IL-6 concentrations were 81 +/- 10 for treated and 1,256 +/- 236 for the control groups and the IL-8 concentrations were 28 +/- 3.9 for the treated and 60 +/- 8.2 for the control group). These values for IL-6 and IL-8 differed significantly from each other between the treated and control groups (P = .0001 and .0074, respectively). It should be noted that the initial responses of IL-6 and IL-8 up to T = 4 hours were not attenuated. We concluded that DEGR VIIa treatment attenuates inflammatory, as well as hemostatic system responses to LD100 E coli. We hypothesize that this occurs through interference with the assembly and/or interactions of tissue factor/VIIa complexes.
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PMID:Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and interleukin-6 and -8, but not tumor necrosis factor, responses of the baboon to LD100 Escherichia coli. 947 26

Proinflammatory effects induced by the serine protease factor Xa were investigated in HUVEC. Exposure of cells to factor Xa (5-80 nM) concentration dependently stimulated the production of IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) and the expression of E-selectin, ICAM-1, and VCAM-1, which was accompanied by polymorphonuclear leukocyte adhesion. The effects of factor Xa were blocked by antithrombin III, but not by the thrombin-specific inhibitor hirudin, suggesting that factor Xa elicits these responses directly and not via thrombin. IL-1alpha and TNF-alpha were not implicated, since neither the IL-1 receptor antagonist nor a TNF-neutralizing Ab could suppress the factor Xa responses. Active site-inhibited factor Xa and factor Xa depleted from gamma-carboxyglutamic acid residues were completely inactive. The effector cell protease receptor-1 (EPR-1) seems not to be involved since anti-EPR-1 Abs failed to inhibit cytokine production. Moreover, neither the factor X peptide Leu83-Leu88, representing the inter-epidermal growth factor sequence in factor Xa that mediates ligand binding to EPR-1, nor the peptide AG1, corresponding to the EPR-1 sequence Ser123-Pro137 implicated in factor Xa binding, inhibited the factor Xa-induced cytokine production. In conclusion, these findings indicate that factor Xa evokes a proinflammatory response in endothelial cells, which requires both its catalytic and gamma-carboxyglutamic acid-containing domain. The receptor system involved in these responses induced by factor Xa remains to be established.
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PMID:Factor Xa induces cytokine production and expression of adhesion molecules by human umbilical vein endothelial cells. 978 Feb 8

The chemokine RANTES (regulated on activation, normal T cell expressed and secreted) is a potent regulator of leukocyte trafficking. RANTES preferentially attracts mature CD4 cells as well as macrophages and eosinophils, but not neutrophils. In total, 128 children with meningococcal disease were prospectively studied, and the role of RANTES in the pathophysiology of meningococcal disease was assessed. Plasma RANTES, interleukin (IL)-8, IL-6, IL-1 receptor agonist, and tumor necrosis factor-alpha were measured at admission. Severity of disease was stratified by the Glasgow meningococcal septicemia prognostic score (GMSPS). RANTES levels correlated significantly with IL-8 levels, admission lactate levels, platelets, prothrombin time, and activated partial thromboplastin time. RANTES levels were lower in children with severe disease (GMSPS>/=8; P=.001), in those with septic shock (P<.0005), and in nonsurvivors (P=.048; Mann-Whitney test). RANTES is a potential mediator in the pathophysiology of meningococcal disease.
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PMID:The role of RANTES in meningococcal disease. 1088 26

The spontaneous loss of normal karyotype embryos may be initiated or prevented by the maternal immune system. In mice, loss between the time of implantation (day 4.5) and formation of a vascularized placenta (day 9.5) when the embryo is too large to survive by diffusion alone, is analogous to occult pregnancy failure in humans. They are called occult because usually the woman does not know she is pregnant. From studies in mice, these early losses have a different mechanism than abortion of a vascularized placenta (analogous to clinically evident human spontaneous miscarriage). The latter depend on the activation of the novel prothrombinase fgl2 on the fetal trophoblast and in maternal decidua by the T helper-1 (Th1) type cytokines TNF- alpha+gamma -interferon that arise from NK cells and NK gammadelta T cells; conversion of prothrombin to thrombin which in turn generates IL8 that activates polymorphonuclear leukocytes leads to embryonic death. These inflammatory processes are counteracted by Th2/3-type cytokines that arise in part from V gamma 1 delta 6 T cells reacting to, as yet, unidentified trophoblast antigens in the presence of the 'tolerance signaling molecule' OX-2. By contrast, peri-implantation losses (between implantation and formation of a vascularized placenta, analogous to occult losses in humans) appear to be dependent upon perforin(+)cells, complement activation, and products of alphabeta T and NK alphabeta T cells, but not on TNF- alpha or procoagulant activation. Similarities and differences between findings in the mouse and human, and the potential evolutionary significance of mechanisms affecting reproductive success are reviewed.
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PMID:Procoagulants in fetus rejection: the role of the OX-2 (CD200) tolerance signal. 1143 33

It is becoming increasingly clear that coagulation augments inflammation and that anticoagulants, particularly natural anticoagulants, can limit the coagulation induced increases in the inflammatory response. The latter control mechanisms appear to involve not only the inhibition of the coagulation proteases, but interactions with the cells that either generate anti-inflammatory substances, such as prostacyclin, or limit cell activation. Recent studies have demonstrated a variety of mechanisms by which coagulation, particularly the generation of thrombin, factor Xa and the tissue factor-factor VIIa complex, can augment acute inflammatory responses. Many of these responses are due to the activation of one or more of the protease activated receptors. Activation of these receptors on endothelium can lead to the expression of adhesion molecules and platelet activating factor, thereby facilitating leukocyte activation. Therefore, anticoagulants that inhibit any of these factors would be expected to dampen the inflammatory response. The three major natural anticoagulant mechanisms seem to exert a further inhibition of these processes by impacting cellular responses. Antithrombin has been shown in vitro to increase prostacyclin responses and activated protein C has been shown to inhibit a variety of cellular responses including endotoxin induced calcium fluxes in monocytes and the nuclear translocation of NFKB, a key step in the generation of the inflammatory response. In some, but not all, in vivo models, these natural anticoagulants have been able to inhibit endotoxin/E. coli-mediated leukocyte activation and to diminish cytokine elaboration (TNF, IL-6 and IL-8). Phase III clinical studies for treatment of patients with severe sepsis have been completed for APC, which was successful (1), and for antithrombin, which was not (2). A phase III trial with tissue factor pathway inhibitor is in progress. In this review, the mechanisms by which the different natural anticoagulants are thought to function will be reviewed.
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PMID:Role of coagulation inhibitors in inflammation. 1148 41

Endothelial cells react to factor Xa and thrombin by proinflammatory responses. It is unclear how these cells respond under physiological conditions, where the serine proteases factor VIIa, factor Xa and thrombin are all simultaneously generated, as in tissue factor-driven blood coagulation. We studied the Ca(2+) signaling and downstream release of interleukins (ILs), induced by these proteases in monolayers of human umbilical vein endothelial cells. In single cells, factor Xa, but not factor VIIa, complexed with tissue factor, evoked a greatly delayed, oscillatory Ca(2+) response, which relied on its catalytic activity and resembled that of SLIGRL, a peptide specifically activating the protease-activated receptor 2 (PAR2). Thrombin even at low concentrations evoked a rapid, mostly non-oscillating Ca(2+) response through activation of PAR1, which reinforced the factor Xa response. The additive Ca(2+) signals persisted, when factor X and prothrombin were activated in situ, or in the presence of plasma that was triggered to coagulate with tissue factor. Further, thrombin reinforced the factor Xa-induced production of IL-8, but not of IL-6. Both interleukins were produced in the presence of coagulating plasma. In conclusion, under coagulant conditions, factor Xa and thrombin appear to contribute in different and additive ways to the Ca(2+)-mobilizing and proinflammatory reactions of endothelial cells. These data provide first evidence that these serine proteases trigger distinct signaling modules in endothelium that is activated by plasma coagulation.
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PMID:Factor Xa and thrombin evoke additive calcium and proinflammatory responses in endothelial cells subjected to coagulation. 1676 66

Recent clinical studies have shown a sex dimorphism of morbidity and mortality due to shock, trauma, and sepsis, with females tolerating these insults better than males. Experimental animal studies have suggested that sex hormones have a pivotal role in this dimorphism. In the present investigation, a prospective cohort study at a university level-1 trauma center was conducted to evaluate the association between sex hormones and alterations in coagulation and inflammation. Patients with an admission to the intensive care unit, injury severity score (ISS) greater than 4, and obtainable consent were included in the study. In addition to routine clinical laboratories and patient outcomes, plasma TNF-[alpha], IL-6, IL-8, estradiol, progesterone, and testosterone were measured. Sixty-two patients (71% men, 29% women) met criteria for entry. Mean age was 42 +/- 17 years, and mean ISS was 23 +/- 13, with no statistical difference in age or ISS between sexes. Estradiol levels were positively correlated with ISS (P < 0.05) and negatively correlated with TNF-[alpha] (P < 0.01). Initial estradiol levels were higher in patients who developed an infection (P < 0.05). Testosterone was negatively correlated with age (P < 0.01) and was higher in patients who developed acute respiratory distress syndrome (P < 0.05) and in patients who did not survive (P < 0.05). The estradiol-to-progesterone ratio (E2-Pr) was higher in the survivors (P < 0.05). The E2-Pr had positive correlations with fibrinogen levels, rate of fibrin deposition and cross-linking, and overall clot strength (P < 0.05). Estradiol-to-progesterone ratio was negatively correlated with partial thromboplastin times (P < 0.01). In men, the E2-Pr was also negatively correlated with the time to onset of clot formation (P = 0.03). Sex hormone levels (or their ratios) were not correlated to platelet count or international normalized ratios. These findings provide evidence that sex hormone levels in the early posttraumatic period are significantly associated with alterations in the hemostatic and inflammatory response to trauma.
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PMID:The influence of sex hormones on coagulation and inflammation in the trauma patient. 1843 14


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