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)

Macrophage (M phi)-mediated fibrin deposition via induction of procoagulant activity (PCA) is an important component of the host response during various infections. While endotoxin (LPS) is a well-known stimulus of PCA, the factors modulating its activity within the inflammatory microenvironment are unknown. The purpose of these studies was to determine the relative roles of two pathways of arachidonic acid metabolism, i.e., the cyclooxygenase (CO) and 5-lipoxygenase (5-LO) pathways, in modulating M phi PCA induction by LPS. Thioglycolate-elicited murine peritoneal M phi were treated with the CO inhibitor indomethacin (INDO), the 5-LO inhibitor nordihydroguaiaretic acid (NDGA), or control vehicle for 15 min prior to a 4-hr exposure to LPS (10 micrograms/ml). The ability of M phi to shorten the clotting time of plasma (i.e., PCA) was measured and clotting times were converted to PCA units via a thromboplastin standard. While CO blockade had no effect on PCA induction by LPS (without INDO 30 microM 446 +/- 131, with INDO 30 microM 546 +/- 193, mU/2 x 10(6) cells, n = 4), NDGA caused a dose-dependent inhibition (IC50 = 3 microM) without affecting cell viability (without NDGA 3 microM 446 +/- 131, with NDGA 3 microM 191 +/- 67, mU/2 x 10(6) cells, n = 6, P less than 0.05). Induction of PCA by Escherichia coli was similarly inhibited (E. coli 10(6) alone = 518 +/- 130; with NDGA 3 microM = 234 +/- 100, n = 2). Combined NDGA/INDO reduced PCA comparable to NDGA alone, ruling out the possibility that NDGA acted through generation of inhibitory prostanoids like PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of macrophage procoagulant activity by arachidonic acid metabolites. 152 29

The cellular basis for the variation in induction of monocyte procoagulant activity (PCA) by murine hepatitis virus strain 3 (MHV-3) was examined using a set of recombinant inbred strains of mice derived from the resistant (A/J) and susceptible C57B1/6J (B) progenitors. Induction of PCA by MHV-3 required live virus and host protein and RNA synthesis. Absolute restriction for induction of PCA was observed at the level of the macrophage. Peritoneal macrophages from resistant parental A/J and RI strains (AXB5) could not be induced to express PCA when stimulated by MHV-3 alone or in the presence of lymphocytes from susceptible and H-2 compatible RI mice (AXB3) although they did respond to endotoxin (LPS). In contrast, macrophages from both susceptible (AXB3) and semisusceptible (AXB1) RI strains of mice expressed a similar increase in PCA after stimulation with MHV-3 in the absence of lymphocytes. The levels of PCA expressed by macrophages in the presence of Thy-1.2+ lymphocytes correlated with susceptibility to disease. Thy-1.2+ lymphocytes from susceptible RI AXB3 mice could induce levels of PCA in macrophages from semisusceptible RI AXB1 mice equivalent to that seen in cultures of macrophages and lymphocytes from susceptible mice. Further subfractionation of Thy-1.2+ cells demonstrated that L3T4+ cells instructed macrophages to produce PCA. Thy-1.2+ cells from MHV-3 immunized resistant AXB5 mice, but not from non-immunized mice, were able to suppress induction of PCA. This suppressor cell activity could be detected 4 days after immunization, reaching maximal activity at day 7 with significant suppression even at 28 days. The PCA was shown to have direct prothrombin cleaving activity (prothrombinase) by ELISA and immunofluorescence staining using the mAb 3D4.3. These results demonstrate that induction of a unique PCA (prothrombinase) is restricted at the level of the macrophage and define a regulatory role for T lymphocytes in its induction.
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PMID:Cellular and metabolic requirements for induction of macrophage procoagulant activity by murine hepatitis virus strain 3 in vitro. 170 94

The mechanisms underlying the superinduction of procoagulant activity by cycloheximide (CHX) on LPS-activated human monocytes have been investigated. Tissue factor (TF) activity of intact, viable cells was quantitated with a plasma recalcification assay and assays using chromogenic substrates specific for thrombin and factor Xa (FXa). TF antigen was measured simultaneously by immunocytochemical staining and immunoblotting with an anti-TF monoclonal antibody (MAb). Peripheral blood mononuclear cells (PBMC) activated with LPS in the presence of low dose CHX expressed more TF activity (approx. 100% increase) than cells activated with LPS alone. However, TF antigen levels were decreased approximately 70% by CHX. This discordant relationship was due primarily to differences in rates of activation of factor X (FX); LPS/CHX-treated PBMC activated nearly twice as much FX as LPS-treated cells (2.19 +/- 0.37 versus 1.10 +/- 0.21 ng FXa/10(6) PBMC/min, respectively). These studies indicate that TF cofactor activity on LPS/CHX-treated monocytes was approximately 7 times greater than that present on LPS-treated cells. Increased TF functional activity may be due to CHX-induced alterations in the type and content of phospholipids (PL) in the cell membrane. Results showed that exogenous mixed PL markedly increased TF activity on LPS-activated monocytes, but not on LPS/CHX-activated cells, without increasing TF antigen levels or altering cell viability. Membrane alterations may occur on monocytes in certain pathological or iatrogenic conditions resulting in a highly active form of TF in vivo.
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PMID:Discordant expression of tissue factor antigen and procoagulant activity on human monocytes activated with LPS and low dose cycloheximide. 180 19

An experimental model incorporating cultured endothelial cells (EC) was used to study the "factor VIII bypassing" activity of prothrombin complex concentrates (PCC), a property exploited in the treatment of hemophiliacs with alloantibodies to factor VIII. Two PCC preparations were ineffective as stimuli of tissue factor expression by EC. However, incubation with a combination of PCC plus endotoxin (lipopolysaccharide, LPS) or tumor necrosis factor (TNF) induced much greater tissue factor expression than was seen in response to either substance alone. PCC expressed an additional direct procoagulant activity at the EC surface, which could not be attributed to either thrombin or factor Xa, and which was diminished by an anti-tissue factor antibody. Therefore factor VIIa, which was detectable in both PCC preparations, likely provided this additional direct procoagulant activity at the EC surface. We also excluded the possibility that coagulation proteases contained in or generated in the presence of PCC are protected from inactivation by AT III. Therefore, PCC can indirectly bypass factor VIII by enhancing induced endothelial tissue factor expression, and also possess direct procoagulant activity, probably mediated by factor VIIa.
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PMID:The factor VIII bypassing activity of prothrombin complex concentrates: the roles of factor VIIa and of endothelial cell tissue factor. 180 20

Macrophage procoagulant activity (PCA) at the site of inflammation may be induced by several stimuli including bacteria and endotoxin (LPS). The local factors controlling PCA induction are poorly defined. The lipid mediator platelet-activating factor (PAF) is ubiquitous to inflammatory sites. To determine the effect of PAF on LPS-induced PCA, thioglycolate-elicited murine peritoneal macrophages were exposed to PAF (10(-7) M) or control medium for 30 min and then stimulated with LPS (10 micrograms/ml) for 2, 4, or 6 hr. The ability of macrophages to shorten the clotting time of plasma (ie., PCA) was then measured and clotting times were converted to PCA units using a thromboplastin standard. Cytosolic calcium ([Ca2+]i) measurements were made using the calcium-sensitive fluorescent dye indo-1. PAF alone did not induce a rise in PCA expression (medium alone, 47 +/- 11 mU/10(6) cells; PAF alone, 49 +/- 12 mU/10(6) cells at t = 4 hr), but PAF treatment prior to LPS exposure resulted in a significant increase in the LPS-stimulated expression of PCA (LPS alone, 190 +/- 29 mU/10(6) cells; PAF/LPS, 329 +/- 57 mU/10(6) cells at t = 4 hr, P less than 0.05). This priming effect was reversed by the PAF antagonist WEB 2086 (WEB/PAF/LPS, 196 +/- 31 mU/2 x 10(6) cells). Stimulation of cells with PAF alone resulted in a rapid rise in [Ca2+]i (resting, 213 +/- 19 nmole; peak, 577 +/- 35 nmole). This effect was also inhibited by WEB 2086. These data suggest that PAF plays an important role in the modulation of PCA production by macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelet-activating factor primes endotoxin-stimulated macrophage procoagulant activity. 203 82

To clarify whether activated platelets play an important role in the occurrence and exacerbation of disseminated intravascular coagulation (DIC), we investigated the effects of 4 anti-platelet drugs, a PGI2 analog (CS-570), a thromboxane synthetase inhibitor (dazoxiben), a thromboxane receptor antagonist (BM-13177), and ticlopidine, in an experimental DIC model in rats. Experimental DIC was induced by a continuous infusion of lipopolysaccharide (LPS derived from E. coli, 055 B5, 25 mg/kg/hr) for 4 hrs. In the time-course determination of the coagulation parameters and prostanoids, an abrupt increase in TxB2 (a stable metabolite of TxA2) and 6-keto-PGF1 alpha (a stable metabolite of PGI2) was followed by a decrease in platelet count, a prolongation of blood coagulation time, and an increase in fibrinogen/fibrin degradation products (FDP). Four hours after the start of LPS infusion, the rats were considered to be in the state of DIC. The effects of the anti-platelet drugs were investigated 4 hrs after the start of LPS infusion. CS-570 and ticlopidine ameliorated DIC in a dose-dependent manner. CS-570 (10 micrograms/kg/min) improved DIC in the platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fbg), and FDP, without affecting TxB2 and 6-keto-PGF1 alpha formation. Ticlopidine (200 mg/kg, i.p.) prevented the exacerbation of DIC in such item parameters as platelet count, APTT, and FDP. Both dazoxiben and BM-13177 (30 mg/kg, i.p.) ameliorated DIC in following parameters as platelet count, APTT and FDP. Dazoxiben, but not BM-13177, significantly inhibited the increase in TxB2 concentration at 4 hr. These observations suggest that drugs which inhibit platelet activation by a TxA2-dependent route are effective in improving DIC induced by LPS, and that drugs which inhibit multiple platelet-activating routes improve DIC in more item parameters than drugs which inhibit only the TxA2-dependent activating route. Consequently, it is concluded that activated platelets might play an important role in the occurrence and exacerbation of DIC induced by LPS, and that one of the roles of TxA2 in DIC is to activate platelets.
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PMID:Role of activated platelets in endotoxin-induced DIC in rats. 208 Apr 92

The purpose of this study was to evaluate the effects of experimentally induced sublethal endotoxaemia in equine neonates. Four foals, between two and five days of age, were infused intravenously with 0.5 microgram/kg bodyweight of Salmonella typhimurium endotoxin (LPS) over a 5 h period. A four-day-old and a five-day-old foal, similarly infused with sterile isotonic saline, served as controls. Clinical signs were monitored, blood samples obtained for evaluation of selected haematological and biochemical parameters; and haemodynamic parameters were recorded hourly during the infusion, as well as 6 and 24 h post infusion. Depression, anorexia, increased rectal temperature, leucopenia followed by leucocytosis, hypoglycaemia, increased prothrombin time, partial thromboplastin time (APTT), pulmonary artery pressure, pulmonary artery wedge pressure, right atrial pressure, pulmonary and systemic vascular resistance and mild hypoxaemia were consistent findings in the foals receiving endotoxin. There was marked variation over time in the above parameters, during the infusion. Shock was not induced, and the foals appeared to be healthy shortly after the infusion was discontinued. The return to baseline values of body temperature (3 of 4 foals), APTT (1 of 4 foals) and neutrophil count (2 of 4 foals), during endotoxin infusion, suggests induction of early tolerance. The control foals remained alert and the temperature, prothrombin time and fibrinogen remained stable during the study. Hyperglycaemia, transient increased APTT and variations in selected haemodynamic parameters were recorded in the control foals during the infusion.
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PMID:Haemodynamic, pathological, haematological and behavioural changes during endotoxin infusion in equine neonates. 240 54

Fibrin deposition is an important histopathologic feature of inflammation and is mediated, in part, by monocyte/macrophage procoagulants. rIFN gamma acted in synergy with suboptimal levels of bacterial LPS by priming thioglycollate-induced mouse peritoneal exudate cells (TG-PEC) to express high levels of surface procoagulant. TFN-alpha beta, TFN-alpha, IL-1, either alone or in combination with LPS or IFN-gamma, had no effect on macrophage procoagulant activity expression. In contrast to the dramatic increases of macrophage procoagulant activity induced by IFN-gamma/LPS, on exudate macrophages, normal peritoneal macrophages, or peripheral blood monocytes were unresponsive suggesting that the state of activation of the macrophage determines reactivity. IFN-gamma induced a Factor VIIa-like activity detected only after cell disruption. Synergy between LPS and IFN-gamma-induced procoagulants may occur as the result of the assembly of the thromboplastin (induced by LPS), Factor VII/VIIa complex on the macrophage surface. RNA synthesis was required for procoagulant induction. Procoagulant expression may, as for other cytokines involved in inflammatory responses, be regulated by short lived repressor proteins as low dose cycloheximide superinduced procoagulant responses to both LPS and IFN-gamma and caused the extracellular expression of procoagulant in response to IFN-gamma. This study suggests an important role for IFN-gamma in the assembly of components of the extrinsic coagulant cascade on the macrophage surface. The synergy between IFN-gamma and LPS may moderate macrophage-initiated fibrin deposition characteristic of inflammatory responses.
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PMID:Recombinant IFN-gamma synergizes with lipopolysaccharide to induce macrophage membrane procoagulants. 245 19

We have evaluated the quantitative relationship between lipopolysaccharide (LPS, endotoxin), fibrinopeptide A (FPA), antithrombin (AT), protein C (PC) and extrinsic pathway inhibitor (EPI) in plasma from 39 consecutively admitted patients with systemic meningococcal disease (SMD). The most severely ill patients with fulminant meningococcal septicemia (n = 13, 6 dead) had significantly (p less than 0.01) higher plasma levels of LPS and FPA and lower levels of PC and AT on admission as compared with the less severe clinical presentations (n = 26, 1 dead). The levels of EPI on admission were significantly (p less than 0.05) higher in nonsurvivors vs survivors with fulminant septicemia. As the disease progressed, the levels of LPS, FPA, AT and PC declined, while the levels of EPI increased. Three of six nonsurviving septicemic patients had levels of EPI greater than 200% within 16 hours of admission vs two of 30 survivors (p = 0.02). The results suggest that increasing levels of LPS in SMD elicit increasing consumption coagulopathy, contributing to the organ pathophysiology. The kinetics of EPI, inhibiting the thromboplastin-FVIIa-FXa complex, differs markedly from the kinetics of AT and PC i.e. increases as opposed to decreases.
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PMID:The quantitative association of plasma endotoxin, antithrombin, protein C, extrinsic pathway inhibitor and fibrinopeptide A in systemic meningococcal disease. 251 Mar 54

Changes were explored in the behavior of circulating monocytes and their potential association with the activation of the coagulation system as assessed following strenuous exercise. Twelve men and nine women from the Norwegian national cross country skiing team and 19 men and six women from a level just below that of the national team were studied before and after ski race competition. Mononuclear cells were isolated after incubation of heparinized blood with lipopolysaccharides (LPS; 3 ng.ml-1) for 2 h. After a 50 km race for men, the specific thromboplastin activity of the stimulated monocytes rose from 3.5 x 10(-3)/10(6) cells to 21.4 x 10(-3)/10(6) cells. This probably reflects the mobilization of a new population of monocytes that are more sensitive to such stimuli. Resting top-athlete skiers had monocytes which were significantly less responsive to the LPS stimulus compared to nontrained people. There was an inverse correlation of plasma factor VII and the monocyte responsiveness to in vitro stimulation (r = 0.814; P less than 0.002) from blood drawn after a race. Furthermore, factor VII was significantly reduced after a 50 km race, and a modest decline in the fibrinogen level was also observed (P less than 0.05). It is concluded that endurance ski racing causes white cell mobilization and more active white cells that may induce activation of the coagulation system and account for the involvement of factor VII and fibrinogen.
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PMID:Effect of strenuous exercise on blood monocytes and their relation to coagulation. 267 88


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