Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cells are responsible for the secretion or surface expression of a wide variety of mediators involved in the control of thrombosis. These include von Willebrand factor, prostacyclin, nitric oxide, thrombomodulin, tissue-type plasminogen activator and its inhibitor, tissue factor and the tissue factor pathway inhibitor. The production of each of these can be modulated; in some cases very rapidly in response to external stimuli, in other cases more slowly. Thrombin is a key stimulus, which affects the production of almost all of these mediators. In addition, several cytokines and bacterial endotoxins shift the balance of endothelial mediator secretion from the basal anticoagulant profile towards a procoagulant profile.
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PMID:Vessel wall interactions regulating thrombosis. 780 30

Thrombin, the final product of blood coagulation cascade, shows several effect on the vessel-wall cells. However the effects may be regulated by several thrombin receptors on the endothelium. They include thrombomodulin (TM), protease-Nexin, heparin-like molecule-antithrombin III complex. These binding sites do not transduce the signal of thrombin. Especially TM converts thrombin from a procoagulant protease to an anticoagulant. Recently new thrombin receptor was identified on the endothelium and platelets. Through this receptor, thrombin induces activations both on platelet end-endothelium. In brief platelets aggregate and release several factors including serotonin, PDGF, platelet factor4, beta-thromboglobulin on the stimulation by thrombin. The endothelium release t-PA inhibitor; PAI-1, prostacyclin and endothelin. Thus the activations of these cells by thrombin is a key events in hemostasis, wound healing, inflammation, atherosclerosis and restenosis of coronary artery after PTCA.
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PMID:[Regulation of the endothelial function by thrombomodulin and/or thrombin receptor]. 815 41

The roles for the fibrinolytic activation and disorder of coagulation in formation of gastric ulcer induced by microvascular derangement were investigated. The rat stomach was exposed and repeated electrical stimuli (RES) were applied on the small arterial wall close to the lesser curvature to induce mucosal microcirculatory disturbances. The level of tissue-type plasminogen activator (t-PA), a key enzyme for fibrinolytic activity, in the regional blood of the stomach was significantly elevated immediately after RES. At 5 min after RES, the leakage of FITC-labeled albumin and thrombus formation in the mucosal microvasculature were visually demonstrated by using an intravital microscopic system. At 30 min, hemorrhagic erosions and linear ulcers were observed in the gastric mucosa. Pretreatment with human antithrombin-III (AT-III) in the range of 0.1-10 U/kg dose-dependently attenuated both the fibrinolytic activation and microvascular alteration promoted by RES. Human AT-III also prevented RES-induced gastric mucosal injury. Thrombin inhibitory activity in the gastric vein decreased (69.0 +/- 2.1%) just after RES, and further reduced at 30 min (47.7 +/- 5.3%). The present study suggests a hypothesis that human AT-III has a preventive effect on the gastric mucosal hemorrhagic changes via attenuating the fibrinolytic activation and subsequent microcirculatory disturbances.
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PMID:Attenuating effect of antithrombin III on the fibrinolytic activation and microvascular derangement in rat gastric mucosa. 816 29

The presence of procoagulants and fibrin deposition have been demonstrated in malignant tumors. Although thrombin, a key enzyme in coagulation, has other various biological functions, the significance of its presence in tumors is not known. We studied the effects of thrombin on the expression of urokinase-type plasminogen activator (uPA) which is known to play a role in tumor invasion, using a human prostate cancer cell line PC-3. Human alpha-thrombin added to cultures of PC-3 produced a dose-dependent and time-dependent increased secretion of uPA that was greatest at 3-6 h after exposure to thrombin. Increase in uPA antigen paralleled the increase in mRNA level, which reached a maximum at 4 h. Thrombin showed the maximum effect on uPA expression at a concentration 1-2 units/ml. Zymography showed that transient exposure to thrombin induced an increase in fibrinolytic activity which could be quenched by anti-uPA antibody. The thrombin receptor-activating peptide also caused an increase in uPA protein and mRNA level, indicating the presence of the same thrombin specific receptor on PC-3 cells as on platelets and endothelial cells. Thrombin did not affect the expression of other components of the plasminogen activation system, tissue-type plasminogen activator and type-1 plasminogen activator inhibitor, and uPA receptor. These results indicate that thrombin increases uPA expression selectively by the stimulation of a functional thrombin receptor on PC-3 cells. Since uPA is known to play a role in pericellular proteolysis of extracellular matrix, thrombin may be involved in the regulation of tumor invasion and metastasis.
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PMID:Enhancement of the expression of urokinase-type plasminogen activator from PC-3 human prostate cancer cells by thrombin. 820 53

The effect of thrombin on the fibrinolytic potential of human vascular smooth muscle cells (SMC) in culture was studied. SMC of different origin responded to thrombin treatment with a dose and time dependent increase in tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) levels in both cell lysates and conditioned media with maximum effects achieved at 10-20 IU/ml thrombin. PAI-1 antigen levels also increased in the extracellular matrix of thrombin treated SMC. PAI-2 levels in cell lysates of such SMC were not affected by thrombin. The effect was restricted to active thrombin, since DFP-thrombin and thrombin treated with hirudin showed no increasing effect on t-PA and PAI-1 levels in SMC. Enzymatically active thrombin also caused a four-fold increase in specific PAI-1 mRNA and a three-fold increase in t-PA mRNA. Furthermore we demonstrated the presence of high and low affinity binding sites for thrombin on the surface of SMC with a KD = 4.3 x 10(-10)M and 9.0 x 10(4) sites per cell and a KD = 0.6 x 10(-8) M and 5.8 x 10(5) sites per cell respectively. Thrombin could come in contact with SMC in case of vascular injury or following gap formation between endothelial cells. Our data support the idea that besides its known proliferative effect for SMC, thrombin could also modulate their fibrinolytic system.
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PMID:Thrombin stimulates expression of tissue-type plasminogen activator and plasminogen activator inhibitor type 1 in cultured human vascular smooth muscle cells. 825 51

In Vienna, Austria, health workers took blood samples from 16 healthy, nonsmoking 19-35 year old women before and after they began using a combined oral contraceptive (OC) (Gynovin) (30 mcg ethinyl estradiol and 75 mcg gestodene) to assess the OC's effects on blood coagulation and fibrinolysis and the effect of the estrogen component on endothelial cells. Fibrinogen levels increased significantly after OC use (283 mg/dl vs. 342 mg/dl after the 1st treatment cycle; p .005). These levels remained significantly higher (326 mg/dl and 339 mg/dl after the 2nd and 3rd treatment cycles; p .005 and .05, respectively). Thrombin antithrombin III complex (TAT) and prothrombin fragment F1+2 levels increased just minimally during OC treatment. Levels of fibrin split-product D-dimer, plasma tissue plasminogen activator (t-PA) activity, and plasmin-antiplasmin (PAP) complexes were significantly higher during all OC treatment cycles than they were before treatment. Active plasminogen activator inhibitor (PAI-1) antigen, t-PA, and urokinase plasminogen activator antigen levels fell significantly after OC treatment and remained low during OC treatment. Experiments with the culture of human umbilical vein endothelial cells showed that ethinyl estradiol did not significantly affect the tissue factor content or surface thrombomodulin activity of these endothelial cells (i.e., hemostatic regulatory activities). It also did not change the secretion of the fibrinolytic components t-PA and PAI-1. None of the women developed thrombosis. Even though these findings did not clearly show OC-induced hemostatic activation in this relatively small group of women, clinical researchers should still determine activation markers to monitor the activation state of blood coagulation in certain OC users, such as obese women and those who smoke cigarettes.
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PMID:Studies on oral contraceptive-induced changes in blood coagulation and fibrinolysis and the estrogen effect on endothelial cells. 839 73

To characterize potential mechanisms for enhanced thrombolysis in the presence of thrombin inhibitors, we measured lysis of 125I-fibrin-(ogen)- labelled clots after incubation in rotating tubes with whole blood containing tissue-type plasminogen activator (t-PA, 1500 ng/ml) and either saline or increasing concentrations of recombinant desulphatohirudin (hirudin), or heparin. Thrombin activity in washed clots was negligible, but incubation of clots with t-PA in non-anticoagulated blood resulted in marked thrombin activity within 5 min as measured by fibrinopeptide A generation. Incubation with hirudin over a range of concentrations increased clot lysis compared with t-PA alone (control) from 132 +/- 18% of control with 0.5 microgram/ml (n = 4) to 216 +/- 48% of control with 10 micrograms/ml (n = 4). Incubation with less than 0.5 U/ml of heparin attenuated clot lysis (35 +/- 22% of control with 0.08 U/ml, n = 3) while concentrations > or = 0.5 U/ml increased lysis (178 +/- 13% of control with 1.7 U/ml, n = 4). Similar results were obtained for incubations in recalcified platelet-poor plasma indicating that platelets are not required for the enhancement of clot lysis induced by thrombin inhibitors. However, incubations in recalcified plasma from a patient with afibrinogenaemia abolished the increased lysis observed with 10 micrograms/ml of hirudin and addition of physiological concentrations of fibrin monomer (400-800 nM) or fibrinogen degradation products (500 nM) to the mixture of whole blood, t-PA and hirudin blunted the extent of clot lysis. Thus, inhibition of thrombin activity induced by exposure of clots to t-PA prevents concomitant formation of fibrin that attenuates fibrinolysis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of concomitant thrombin-mediated fibrin formation enhances clot lysis in whole blood. 845 55

Over the last few years methods have been developed to assess appearance of thrombin during blood clotting in a clinical setting. This can be achieved either by measurement of the specific thrombin markers or by analysis of the thrombin generation kinetics. Thrombin markers rise following coronary occlusion and, surprisingly, their plasma levels become further increased during and after thrombolytic treatment with streptokinase or tissue-plasminogen activator. In myocardial infarction enhanced thrombin generation extends over the weeks, well beyond the acute phase of the disease. It indicates increased risk to a patient and might call for more anticoagulation or angioplasty. The benefit of aspirin as conjunctive treatment for thrombolysis has been clearly demonstrated. The well-founded concept is that aspirin exerts its anti-thrombotic action through inhibition of platelet cyclooxygenase. Recent evidence indicates that antithrombotic effects of aspirin might be explained, partly at least, by its inhibition of thrombin formation. Indeed, in both healthy subjects and survivors of myocardial infarction, aspirin, either at a single dose of 500 mg or at a dose of 300 mg per day administered over two weeks, effectively inhibits thrombinogenesis. Such response to aspirin is blunted in hypercholesterolemia. Subjects with high serum cholesterol levels might profit less than others from the anti-thrombotic action of aspirin.
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PMID:Thrombin generation in myocardial infarction and hypercholesterolemia: effects of aspirin. 857 30

The mechanism of thrombin induction of tissue- and urokinase-type plasminogen activator (t-PA and u-PA) biosynthesis was investigated in cultured human fetal lung fibroblast cells, IMR-90. Northern blot analysis of total RNA from thrombin-treated cells showed marked accumulations of both t-PA and u-PA mRNA during 24 h. Nuclear run-on experiments showed that the transcription rates of both genes were increased in the thrombin-treated cells. These thrombin effects were inhibited by cycloheximide (CHX), an inhibitor of protein biosynthesis. Treatment of IMR-90 cells with CHX alone caused an increase in u-PA mRNA but not in t-PA mRNA. CHX, however, did not affect the transcription rates of both genes in the cells. Thus, on-going protein synthesis is required for increased accumulations of both t-PA and u-PA mRNA by thrombin but not for the constitutive expression of u-PA gene in IMR-90 cells. Therefore, we conclude that the accumulations of t-PA and u-PA mRNA due to thrombin result mainly from increased rates of their gene transcriptions, and that this influence is exerted in part by proteins synthesized by thrombin stimulation. Thrombin also increased plasminogen activator inhibitor type-1 (PAI-1) in the levels of both antigen and mRNA more rapidly than it increased t-PA in IMR-90 cells. In conditioned medium, most of the secreted PAI-1 seemed to form a complex with t-PA. Northern blot analysis using a PAI-2 cDNA probe showed that the levels of PAI-2 mRNA were markedly increased in response to thrombin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transcriptional regulation of tissue- and urokinase-type plasminogen activator genes by thrombin in human fetal lung fibroblasts. 858 10

To examine whether exercise-induced thrombin formation is accompanied by increased in vivo plasmin formation, we measured molecular markers and neoantigens of the hemostatic system in 10 male subjects (mean 29 yr. range 19-38) before, immediately after, and 2, 8, and 21 h after a triathlon lasting 128-163 min. Thrombin-antithrombin (TAT) complexes, fibrinopeptide A (FPA), and tissue plasminogen activator (t-PA) antigen were maximally increased immediately after exercise and decreased thereafter rapidly. Prothrombin fragment 1 + 2 (PTF1 + 2), fibrin degradation products (FbDP) and plasmin-antiplasmin (PAP) complexes rose to a similar extent 0 and 2 h after exercise decreased thereafter. The maximal levels of PTF1 + 2, TAT, FPA, and FbDP were 1.5-, 2.1-, 1.8-, and 1.9-fold above baseline, respectively. This investigation shows that strenuous prolonged exercise leads to a moderate activation of blood coagulation resulting in thrombin and fibrin formation which is accompanied by a greatly enhanced plasmin generation. It is concluded that the hemostatic of healthy individuals is well kept in balance when stimulated by prolonged strenuous exercise.
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PMID:Balanced activation of coagulation and fibrinolysis after a 2-h triathlon. 858 81


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