Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipopolysaccharide (LPS) stimulation of human monocytes in heparinized whole blood in vitro as expressed by induced activity of thromboplastin, has been studied. An essential role of arachidonic acid (20:4) release was found. 2,4'-Dibromoacetophenone, a phospholipase A2 inhibitor, totally blocked the induced synthesis of thromboplastin activity. Furthermore, nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, had an effect on the LPS-induced thromboplastin synthesis which varied from no inhibition in individuals insensitive to LPS ('low responders'), up to 80% inhibition in the person with the highest response ('high responder') to LPS. Platelets were found to be partially responsible for this difference. Thus, monocytes from high responders cross-combined with platelets from low responders were much less prone to LPS stimulation than they were in the presence of high responder platelets. Intake of acetylsalicylic acid caused a 50% increment of LPS-induced thromboplastin synthesis, and this effect was mediated by platelets.
 ...
PMID:The role of arachidonic acid release and lipoxygenase pathway in lipopolysaccharide-induced thromboplastin activity in monocytes. 212 91

Human peripheral blood monocytes possessed increased thromboplastin activity when exposed to 10 micrograms/ml of bacterial endotoxin for 2 h. The effects of endotoxin were strongly inhibited by 10-20 microM of several unsaturated fatty acids: arachidonic, dihomo-gamma-linolenic, linoleic, linolenic and oleic acids. Two saturated fatty acids, arachidic and stearic acids, produced minimal inhibition at 20 microM. Three lipoxygenase-derived hydroxyfatty acids were also inhibitory, with IC50 values of 10 microM (5- and 12-hydroxyeicosatetraenoic acids) and 20 microM (15-hydroxyeicosatetraenoic acid). Leukotriene B4, 1 nM to 1 microM, was inactive. None of the fatty acids affected the ability of standard thromboplastin to shorten the clotting time of normal plasma or affected the activity of endotoxin as measured by a Limulus clotting assay.
 ...
PMID:Hydroxyeicosatetraenoic acids and other unsaturated fatty acids inhibit endotoxin-induced thromboplastin activity in human monocytes. 286 54

A remarkable variation in monocyte activation among individuals was observed when blood from different people was incubated with lipopolysaccharides. To elucidate this phenomenon, we studied intracellular signals associated with monocyte activation. This was done by measuring induced thromboplastin synthesis. An inhibitor of phospholipase A2 blocked the lipopolysaccharide induced synthesis of thromboplastin. Thus, release of arachidonic acid (20: 4) seemed to be necessary to activate the monocytes. Nordihydroguaiaretic acid, a lipoxygenase inhibitor, had no effect on the monocyte activation in subjects with a low response to lipopolysaccharides (low responders); this contrasted with nearly 80% inhibition in individuals with very sensitive cells (high responders). Taking aspirin raised monocyte activation by an average of 50%, this was caused by the effect of aspirin on the platelets. Platelets enhanced the lipopolysaccharide activation of monocytes 2-3 fold. The high response phenomenon was partially due to platelets. When platelets in the blood of high responders were substituted with platelets from low responders, the monocyte activation fell by up to 70%. Fatty acids seemed to play a central role in the activation of monocytes. Intake of cod liver resulted in significant reduction of induced thromboplastin synthesis. It is suggested that those who are high responders may be more susceptible to developing atherosclerosis.
 ...
PMID:Fatty acids, platelets and monocytes. Something to do with atherogenesis. 292 3

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.
 ...
PMID:Effects of inhibitors of arachidonic acid metabolism on thromboplastin activity in human monocytes. 642 35

High, low and very low density lipoproteins and lipoprotein (a) were prepared from porcine serum. The apolipoprotein components of the lipoproteins were then isolated and resuspended in soybean lecithin. Apolipoprotein B was also resuspended in lipids more representative of those found in LDL and VLDL. Lipid peroxidation was induced in samples of all the lipoproteins and reconstituted apolipoproteins by incubation with either Cu2+ ions or hedgehog 15-lipoxygenase. Furthermore, aliquots of the samples were incubated with a mixture of lipases. The effect of native preparations and the treated samples on the procoagulant activity of thromboplastin was examined. Native HDL, apo A-II, native LDL, reconstituted LDL and apo B inhibited thromboplastin activity, whereas native VLDL and reconstituted VLDL enhanced this activity. While the ability of HDL and apolipoprotein A-II to inhibit thromboplastin was unaltered by either Cu2+ oxidation, lipoxygenase oxidation or lipolysis, VLDL and particles resembling VLDL, which acted cooperatively with thromboplastin lost their activating potential. On the other hand, LDL and particles resembling LDL changed from being inhibitory to enhancing the thromboplastin activity following oxidation, but not after lipolysis. Apolipoprotein B fragments obtained by mild digestion of this protein, expressed an inhibitory effect towards thromboplastin, while extensive degradation of the protein reduced its inhibitory potential. It is suggested that modifications of lipoproteins in vivo can lead to a hypercoagulable state by modulation of the cofactor activity of thromboplastin to factor VII.
 ...
PMID:The effect of lipid peroxidation and lipolysis on the ability of lipoproteins to influence thromboplastin activity. 759 77

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.
 ...
PMID:Cisplatin-induced platelet activation requires mononuclear cells: role of GMP-140 and modulation of procoagulant activity. 768 17