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

Membrane assembly of the C5b-9 proteins on gel-filtered human platelets has been shown to initiate the nonlytic release of alpha-granule contents and expression of membrane prothrombinase sites, suggesting cellular activation by these ostensibly cytolytic plasma proteins (Wiedmer, T., Esmon, C. T., and Sims, P. J. (1986) J. Biol. Chem. 261, 14587-14592). We now examine the mechanism of the C5b-9-induced release reaction. The release of alpha-granule contents upon C5b-9 assembly is accompanied by expression of alpha-granule membrane glycoprotein 140 on the platelet surface, confirming that the complement-mediated release reaction occurs by secretory fusion of the alpha-granule with the plasma membrane. C5b-9 binding initiates the phosphorylation of both 40- and 20-kDa platelet proteins, indicative of activation of protein kinase C and myosin light chain kinase, respectively. Activation of cellular protein kinases under these conditions was not accompanied by the formation of inositol phosphates and was found to strictly depend upon extracellular Ca2+, suggesting that the platelet's secretory response to the C5b-9 proteins is triggered directly by the influx of Ca2+ across the plasma membrane. measurement of intracellular Ca2+ confirmed that elevation of this ion in the cytosol was strictly dependent upon increased plasma membrane permeability due to C5b-9 assembly and was not accompanied by mobilization of this ion from internal storage pools. The C5b-9-mediated secretory response was blocked by sphingosine, a potent inhibitor of protein kinase C, but was unaffected by the cyclooxygenase inhibitor indomethacin, suggesting that feedback (receptor-linked) by thromboxane is not required for platelet activation after C5b-9 insertion.
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PMID:Complement C5b-9-stimulated platelet secretion is associated with a Ca2+-initiated activation of cellular protein kinases. 311 83

Human isolated monocytes possess low levels of procoagulant activity, which was stimulated 10-30 fold by brief (2 hr) exposure to 10 micrograms/ml endotoxin. This activity was expressed in normal or factor XII-deficient plasma, but lost in plasma deficient in factors X or VII, indicating that it was due to thromboplastin. The stimulation of monocyte thromboplastin by endotoxin was inhibited in a dose-dependent manner by two phospholipase A2 inhibitors, 4-bromophenacyl bromide and quinacrine, and by two lipoxygenase inhibitors, eicosatetraynoic acid and nordihydroguaiaretic acid. Two cyclooxygenase inhibitors, aspirin and indomethacin, prevented endotoxin-induced increases in thromboxane B2 production but had no effect on thromboplastin production. These results suggest that a component in the sequence of lipid deacylation, arachidonic acid release, and metabolism via lipoxygenase may mediate the stimulation of monocyte thromboplastin activity by endotoxin.
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PMID:Effects of inhibitors of arachidonic acid metabolism on thromboplastin activity in human monocytes. 642 35

N (7-carboxyheptyl) imidazole is an inhibitor of platelet thromboxane synthetase that has no effect on the cyclooxygenase activity. An oral dose of the substance to rats (10 mg/kg) prolonged tail bleeding time from 170 +/- 13 sec to 284 +/- 22 sec. This oral dose also inhibited platelet thromboxane B2 production induced by collagen ex vivo but had little effect on the aggregation dose response curve. There was no effect on thrombin-induced aggregation. Neither the thrombocytopenia induced by the Arthus reaction nor thrombus formation on an implanted cotton thread were inhibited by oral doses of carboxyheptylimidazole up to 30 mg/kg. Similarly neither the prothrombin nor activated partial thromboplastin time were affected. It is postulated that this thromboxane synthetase inhibitor prolongs bleeding time nor by inhibiting platelet aggregation or blood coagulation but rather by preventing the vasoconstriction which would normally be caused by thromboxane A2.
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PMID:Prolongation of rat tail bleeding time caused by oral doses of a thromboxane synthetase inhibitor which have little effect on platelet aggregation. 646 44

Factor V, a plasma protein cofactor necessary for optimal conversion of prothrombin to thrombin, is also present in considerable concentration in blood platelets (9.9 units per 10(9) platelets). Subcellular fractionation by two methods has localized factor V in the alpha granules of unstimulated platelets. ADP and epinephrine cause release of 4.6% and 6.4%, respectively, of the total factor V, a process completely inhibited by cyclooxygenase alkylation by aspirin. In contrast, collagen causes release of 25% of platelet factor V, a process only partially suppressed by aspirin. Secretion of factor V depends on the availability of metabolic energy, because antimycin A, an inhibitor of aerobic metabolism, and 2-deoxyglucose, an inhibitor of anaerobic glycolysis, together almost totally inhibited the secretion of factor V induced by collagen. The data establish that factor V is not normally available on unstimulated platelets but can be secreted from alpha granules upon stimulation with physiological agents such as ADP, epinephrine, and collagen. Because factor V is known to serve as a receptor for factor Xa, the exposure of factor V on platelets consequent to release would accelerate the process of blood coagulation.
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PMID:Subcellular localization and secretion of factor V from human platelets. 694 65

Cytotoxic drugs may potentiate the thrombotic complications in patients with malignancies and platelet function abnormalities have been reported after initiation of cisplatin therapy. This report describes a prolonged activation of platelets over 6-24 h co-culture with peripheral blood mononuclear cells (PBM) by pharmacological doses of cisplatin. Cisplatin had no direct effect on platelets and depended on PBM to produce aggregation which was apparently not mediated by products of the cyclooxygenase or lipoxygenase pathways, by platelet activation factor (PAF) or by thrombin. Although platelet aggregation normally involves the binding of fibrinogen to the beta 3 integrin, GP IIb-IIIa, on activated platelets, the cisplatin-dependent platelet aggregation observed in the co-culture experiments was not inhibited by an anti-GP IIb-IIIa monoclonal antibody which blocks fibrinogen-dependent aggregation nor by an adhesive peptide containing the RGDS integrin recognition sequence. Rather, aggregation appeared to involve a novel 140 kD granule membrane protein (GMP-140) mediated mechanism since aggregation was almost completely blocked by Fab fragments of an antibody to GMP-140 and was inhibited by fluid-phase GMP-140. At concentrations of cisplatin, adriamycin, and LPS that induced equivalent levels of tissue factor of blood monocytes, prothrombinase activity was significantly greater in cultures containing cisplatin. Prothrombinase activity was dependent on the presence of platelets and the rate of thrombin formation was enhanced by factor Xa generated by the tissue factor-factor VIIa complex. These studies suggest that the vascular and thrombotic complications associated with cisplatin therapy are mediated, at least in part, by platelet activation and aggregation and monocyte procoagulant activity.
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PMID:Cisplatin-induced platelet activation requires mononuclear cells: role of GMP-140 and modulation of procoagulant activity. 768 17

Tepoxalin [5- (4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole -3-propanamide] is an orally active anti-inflammatory agent, which inhibits both cyclooxygenase and 5-lipoxygenase activities. The oral toxicity of tepoxalin was evaluated in 1- and 6-month rat (up to 50 mg/kg/day) and dog (up to 150 mg/kg bid) studies. In rats, increased liver weight, centrilobular hypertrophy, and hepatic necrosis were observed at dosages >/=20 mg/kg/day. Renal changes indicative of analgesic nephropathy syndrome (i.e., papillary edema or necrosis, cortical tubular dilatation) were seen at >/=15 mg/kg. In rats treated for 1 month, these hepatic and renal effects were largely reversible after a 1-month recovery period. Gastrointestinal erosions and ulcers were seen in female rats given 40 mg/kg/day for 6 months. Changes in clinical pathology parameters included decreases in red blood cell count, hemoglobin, and hematocrit mean values; elevation in platelet counts; and an increase in prothrombin and activated partial thromboplastin times. Mild increases in alanine aminotransferase, aspartate aminotransferase, and cholesterol were also noted in rats. Decreased erythrocyte parameters, increased leukocyte counts, and decreased total protein, albumin, and/or calcium were noted in some dogs in the 300 mg/kg/day group following 6 months of dosing. Small pyloric ulcerations were seen at 100 and 300 mg/kg/day dosages for up to 6 months. In both rats and dogs, no accumulation of tepoxalin or its carboxylic acid metabolite was detected in plasma following multiple dosing over a range of 5 to 50 mg/kg/day for rats and 20 to 300 mg/kg/day for dogs. Plasma concentrations of the carboxylic acid metabolite were severalfold higher than those of the parent compound. The no-effect dosages in rats (5 mg/kg/day) and dogs (20 mg/kg/day) were approximately one and six times the ED50 (3.5 mg/kg), respectively, for inhibition of inflammatory effects in the adjuvant arthritic rat without gastric mucosal damage. In terms of severity, the relative lack of gastrointestinal side effects, within the estimated therapeutic dose range, distinguishes tepoxalin from most marketed anti-inflammatory drugs.
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PMID:Preclinical toxicity evaluation of tepoxalin, a dual inhibitor of cyclooxygenase and 5-lipoxygenase, in Sprague-Dawley rats and beagle dogs. 881 16

A double-blind, placebo-controlled clinical trial comparing the effect on hemostasis of nabumetone (Relafen) to placebo in patients who were about to undergo forefoot surgery was performed. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are reported to inhibit platelet cyclooxygenase activity, resulting in altered platelet function and thus potentially enhanced bleeding. Nabumetone has been reported to have no effect on platelet aggregation and bleeding time in normal volunteers and in patients who have undergone knee arthroscopy. After fulfilling the inclusion criteria and after a 1-week washout period (acetaminophen controlled), 15 patients were enrolled in the nabumetone group and 15 patients were randomized in the placebo group. Hemostatic parameters [prothrombin time (PT), partial thromboplastin time (PTT), and Ivy bleeding time (IBT)] were assessed at baseline, visit 2, visit 3, and final visit. No meaningful differences were observed between treatment groups in any of the measured hemostatic parameters. No significant adverse events were reported. There was no significant change from baseline for PT, PTT, and IBT in the nabumetone group (PT, p < .06; PTT, p < .64; IBT, p < .17) versus the placebo group (PT, p < .61; PTT, p < .63; IBT, p < .25). The lack of bleeding diathesis and significant prolongation of PT, PTT, or IBT in this study suggests that nabumetone in dosages up to 1000 mg/day can be administered safely in the immediate preoperative period to patients undergoing forefoot surgery.
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PMID:A double-blind study of the effect on hemostasis of nabumetone (Relafen) compared to placebo. 1086 88

This study was conducted to determine which isoform of cyclooxygenase (COX) is more significantly involved in the anti-thrombin (AT)-induced increase in prostaglandin production in the liver of rats, subjected to hepatic ischemia/reperfusion (I/R). Hepatic tissue levels of 6-keto-PGF(1alpha), a stable metabolite of prostacyclin (PGI(2)), and PGE(2) were transiently increased 1 hour after reperfusion. Thereafter, hepatic PGE2 levels were gradually increased until 6 hours after reperfusion, while hepatic 6-keto-PGF(1alpha) levels were decreased to the pre-ischemia levels at 6 hours after reperfusion. AT significantly enhanced increases in hepatic tissue levels of 6-keto-PGF(1alpha) and PGE(2) seen 1 hour after reperfusion, while it inhibited increases in hepatic PGE(2) levels seen 6 h after reperfusion. Neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp(49)-modified AT which lacks affinity for heparin, showed any effects on these changes. Pretreatment with indomethacin (IM), a non-selective inhibitor of COX, inhibited AT-induced increases in hepatic tissue levels of 6-keto-PGF(1alpha) and PGE(2) seen 1 hour after reperfusion, whereas pretreatment with NS-398, a selective inhibitor of COX-2, did not. The increase in hepatic tissue blood flow and inhibition of hepatic inflammatory responses seen in animals given AT were reversed by pretreatment with IM, but were not affected by pretreatment with NS-398. Administration of ilo-prost, a stable analog of PGI(2), and PGE(2) produced effects similar to those induced by AT. Increases in hepatic tissue levels of PGE(2) 6 hours after reperfusion were inhibited by pretreatment with NS-398. Although AT did not affect COX-1 mRNA levels 1 hour after reperfusion, it inhibited the I/R-induced increases in hepatic tissue levels of both PGE(2) and COX-2 mRNA 6 hours after reperfusion. These observations strongly suggested that AT might reduce the I/R-induced liver injury by increasing the production of PGI2 and PGE2 through activation of COX-1. Furthermore, since TNF-alpha is capable of inducing COX-2, inhibition of TNF-alpha production by AT might inhibit COX-2-mediated PGE(2) production. These effects induced by AT might contribute to its anti-inflammatory activity.
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PMID:Antithrombin reduces ischemia/reperfusion-induced liver injury in rats by activation of cyclooxygenase-1. 1535 51

The conventional management of thrombotic and cardiovascular disorders is based on the use of heparin, oral anticoagulants, and aspirin. Despite remarkable progress in life sciences, these drugs still remain a challenge and a mystery to us, and their use is far from optimized. The development of low-molecular-weight heparins and the synthesis of heparinomimetics, such as the chemically synthesized pentasaccharide, represent a refined use of heparin. Additional drugs from this knowledge will continue to develop; however, none of these drugs will ever match the polypharmacology of heparin. Aspirin still remains the leading drug in the management of thrombotic and cardiovascular disorders. The newer antiplatelet drugs such as adenosine diphosphate receptor inhibitors, glycoprotein IIb/IIIa inhibitors, and other specific inhibitors have limited effects and have been tested in patients who have already been treated with aspirin. Warfarin provides a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. The optimized use of these drugs still remains as the approach of choice to manage thrombotic disorders. The new anticoagulant targets, including specific sites in the hemostatic network such as tissue factor, individual clotting factors (IIa, VIIa, IXa, Xa, XIIa, and XIIIa), recombinant forms of serpins (antithrombin, heparin cofactor II, and tissue factor pathway inhibitors), recombinant activated protein C, thrombomodulin, and site-specific serine protease inhibitor complexes have also been developed. There is a major thrust on the development of orally bioavailable anticoagulant drugs (anti-Xa and anti-IIa agents), which are slated to replace oral anticoagulants. Both the anti-factor Xa and antithrombin agents have been developed for oral use and have provided impressive clinical outcomes in sponsor trials for the postsurgical prophylaxis of venous thrombosis; however, safety concerns related to liver enzyme elevations and thrombosis rebound have been reported with their use. For these reasons, the U.S. Food and Drug Administration did not approve the orally active antithrombin agent ximelagatran for several indications. The synthetic pentasaccharide (fondaparinux) has undergone an aggressive clinical development. Unexpectedly, fondaparinux also produced major bleeding problems at minimal dosages. Fondaparinux represents only one of the multiple pharmacologic effects of heparins. Thus, its therapeutic index will be proportionately narrower. The newer antiplatelet drugs have added a new dimension in the management of thrombotic disorders. The favorable clinical outcomes with aspirin and clopidogrel have validated cyclooxygenase (COX)-1 and P2Y (12) receptors as targets for new drug development. Prasugrel, a novel thienopyridine, cangrelor, and AZD 6140 represent newer P2Y (12) antagonists. Cangrelor and AZD 6140 are direct inhibitors, whereas prasugrel requires metabolic activation. Though clinically effective, recent results have prompted a closure of a large clinical trial with prasugrel due to bleeding. The newer anticoagulant and antiplatelet drugs are attractive for several reasons; however, none of these are expected to replace the conventional drugs in polytherapeutic approaches. Heparins, warfarin, and aspirin will continue to play a major role in the management of thrombotic and cardiovascular disorders beyond 2010.
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PMID:Survival of heparins, oral anticoagulants, and aspirin after the year 2010. 1839 43


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