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

Three new tripeptide arginal thrombin inhibitors were shown to have potent anticoagulant and antithrombotic activity: D-MePhg-Pro-Arg-H (LY287045), D-1-Tiq-Pro-Arg-H (LY294291), and D-MePhe-Pro-Arg-H (Efegatran). Efegatran and the related arginals differ mechanistically from old and from new anticoagulant agents. As illustrated with x-ray diffraction analysis of crystals of the LY294291 complex with human thrombin, the family of arginals binds thrombin with the P3, P2, and P1 residues interacting with the putative S3, S2, and S1 fibrinogen-binding sites. A hemi-acetal bond at Ser 195 was shown to contribute to the tight-binding reversible competitive thrombin inhibition properties observed with the arginal family. Tight-binding Kass values from thrombin inhibition studies correlated with thrombin clottin inhibition potency. The thrombin time (TT) assay was prolonged twofold with 33 nM Efegatran, which demonstrated an apparent Kass value of 0.8 x 10(8) L/mol (for comparison, 17 nM hirudin was required to prolong the TT assay two-fold). There are empirical anticoagulant selectivity differences between Efegatran and hirudin, manifested by large activated partial thromboplastin time (aPTT)/TT effect ratios (30 to 55) found with the arginals, as compared to the small aPTT/TT effect ratio (2 to 3) found with hirudin. The underlying anticoagulant mechanism differences between the arginals and hirudin appear to be confined to the aPTT pathway and, therefore, might involve different effects toward thrombin feedback activation of factor VIII. The arginals did not substantially inhibit other coagulation factor serine proteases. Antithrombotic effects of Efegatran and the arginal family occur at low infusion doses in dogs and appear to correlate with effects on TT without requiring perturbation of the aPTT. Selectivity properties regarding the fibrinolytic enzymes were shown to be important for successful use of the arginals in vivo as adjunctive agents during tissue plasminogen activator (t-PA) thrombolysis. The data suggest that LY287045, LY294291, and Efegatran should be expected to be useful as antithrombotic adjuncts to thrombolytic therapy with t-PA, urokinase, or streptokinase and should be expected to spare endogenous fibrinolysis. Efegatran has been evaluated in phase I clinical studies and is currently under clinical investigation in phase II protocols as a new cardiovascular anticoagulant.
 ...
PMID:A family of arginal thrombin inhibitors related to efegatran. 880 15

Twenty-five young subjects were divided into experimental (n = 13) and control (n = 12) groups in order to examine the acute and chronic effects of exercise on blood coagulation and fibrinolysis. Blood coagulation and fibrinolysis variables were ascertained in both groups before and after a physical conditioning programme both at rest and following maximal exercise. The experimental group exercised for 12 weeks [30 min, 3 x week at 70% (6 weeks) and 80% (6 weeks) of maximum heart rate]. The control group maintained normal activity patterns. Significant activation (P < 0.05) of blood coagulation was observed in response to maximal exercise before and after the conditioning programme in both groups in activated partial thromboplastin time (APTT), thrombin clotting time (TCT), factor VIII procoagulant activity (FVIII PA) and factor VIII antigen (FVIII A). Likewise, blood plasminogen activator showed a significant increase (P < 0.05) in response to maximal exercise before and after conditioning in both groups. Although VO2 max following the conditioning programme was significantly increased in the exercise group versus control, no significant changes (P > 0.05) were observed in either group in blood coagulation and fibrinolysis parameters at rest or in response to maximal exercise. It is concluded that maximal exercise transiently accelerates blood coagulation and activates blood fibrinolytic activity, however physical conditioning appears not to influence the haemostatic and fibrinolytic systems at rest or in response to maximal exercise.
 ...
PMID:Blood coagulation and fibrinolysis at rest and in response to maximal exercise before and after a physical conditioning programme. 882 26

In the jugular vein of rabbits thrombus formation was induced by vessel wall damage using a balloon catheter and following reduction of blood flow by 80-90% for 60 min (partial stasis). The blood flow in the vein was measured continuously and the incidence of primary thrombus formation, the time until lysis with recombinant tissue-type plasminogen activator (rt-PA) as well as the incidence of rethrombosis after lysis were determined. At the end of the experiment the wet weight of the thrombus formed inside the vessel was measured. For the determination of haemostaseological parameters blood was drawn from the cannulated femoral artery. Recombinant full-length tissue factor pathway inhibitor (TFPI) was studied with regard to its effect both on primary thrombus formation and on rethrombosis after lysis. In control animals damage of the vessel wall combined with partial stasis led to the formation of occlusive venous thrombi. In vitro bolus injection of TFPI (5, 10, 20 micrograms/kg) at the time of thrombus induction prevented the formation of venous thrombi during the 1 h period of partial stasis. In the subsequent observation period a dose-dependent inhibition of later occurring partial or complete thrombotic occlusion was found. At the dose of 20 micrograms/kg i.v. in all animals TFPI prevented a complete thrombotic occlusion of the vein up to 3 h after stasis. To study the effectiveness of TFPI on rethrombosis after lysis TFPI was injected i.v. after lysis of the thrombus with rt-PA (600 micrograms/kg i.v. bolus + 600 micrograms/kg i.v. infusion over 60 min). In saline treated control rabbits a reocclusion of the vessel was seen in 8 of 10 animals. TFPI (10, 20, 40 micrograms/kg i.v.) injected at the end of rt-PA administration caused a dose-dependent inhibition of thrombotic reocclusion after lysis. At 40 micrograms/kg i.v. the formation of occlusive thrombi was prevented up to 3 h after lysis. TFPI at the doses used caused modest anticoagulant effects in global clotting assays; activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) were only slightly prolonged. A clear and dose-dependent prolongation of clotting times was only seen in the Heptest assay. The results show that the physiologic coagulation inhibitor TFPI acts as a strong antithrombotic agent in an experimental model of venous thrombus formation and thrombotic reocclusion after lysis in rabbits.
 ...
PMID:Recombinant full-length tissue factor pathway inhibitor (TFPI) prevents thrombus formation and rethrombosis after lysis in a rabbit model of jugular vein thrombosis. 890 5

Disturbances of the haemostatic balance may result in thrombosis or bleeding tendency. There have been abundant reports on the effects of exercise on blood haemostasis, but the results reported have been conflicting and difficult to interpret. This review outlines and critically evaluates the relevant literature on the effects of short term exercise and physical training on the 3 systems of blood haemostasis i.e. blood coagulation, fibrinolysis and platelet aggregation. Short term exercise is usually associated with a significant shortening of activated partial thromboplastin time (APTT) and a marked increase in factor VIII (FVIII). The rise in FVIII is directly related to exercise intensity and the individuals' training status. Exercise also induces a significant increase in blood fibrinolysis which is dependent on exercise intensity, duration and training condition. The rise in blood fibrinolysis is mainly due to an increase in tissue-type plasminogen activator (t-PA) and a decrease in its main inhibitor plasminogen activator inhibitor (PAI-1) which are released from the endothelial cells of the vessel wall. Platelet count increases in exercise and this is probably due to a fresh release of platelets from the spleen, bone marrow and lungs. Studies on the effects of exercise on platelet aggregation and markers of platelet activation have produced conflicting results, and the exact effects of exercise remain as yet undetermined. It is suggested that short term exercise activates blood coagulation and enhances blood fibrinolysis and the delicate balance between clot formation and clot dissolution is maintained in normal populations. No valid conclusion could be reached regarding the actual effects of physical training on blood coagulation, fibrinolysis and platelet aggregation. This is undoubtedly due to variations in training programmes employed, populations studied, and the analytical methods used.
 ...
PMID:Effects of exercise on blood coagulation, fibrinolysis and platelet aggregation. 892 46

Human peritoneal mesothelial cells (HMC) play a critical role in maintaining the intraperitoneal balance between fibrinolysis and coagulation by expressing the fibrinolytic enzyme tissue-type plasminogen activator (t-PA) as well as a specific plasminogen activator inhibitor, PAI-1, and the procoagulant protein tissue factor (TF). Of three compounds known to stimulate t-PA synthesis in cultured human endothelial cells, i.e., retinoic acid, the protein kinase C activator 4 beta-phorbol 12-myristate 13-acetate (PMA), and sodium butyrate, only butyrate (1 mM) caused about a threefold increase in t-PA synthesis and mRNA expression in HMC after 24 h of incubation, without markedly affecting PAI-1 synthesis. PMA (10 nM) induced a threefold increase in urokinase-type plasminogen activator (u-PA) mRNA, but u-PA antigen levels in the HMC conditioned media remained below the detection level (0.5 ng/ml), possibly as a result of rapid uptake and degradation by the u-PA receptor. The u-PA receptor mRNA levels were about fivefold enhanced above control levels after PMA treatment of the cells. An increase in intracellular adenosine 3',5'-cyclic monophosphate levels by forskolin (10 microM) diminished t-PA and PAI-1 levels 43 and 17%, respectively. Among the inflammatory mediators tested [tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha, and bacterial lipopolysaccharide], TNF-alpha (10-1,000 U/ml) showed the strongest procoagulant effects. We found that the isoflavone compound genistein (25 micrograms/ml) prevented the TNF-alpha-induced expression of PAI-1 and TF while also slightly counteracting the decrease in t-PA synthesis. The protein kinase C inhibitor R0-318220 (3 microM) only moderately opposed the TNF-alpha-induced changes in t-PA and PAI-1 synthesis but completely prevented the induction of TF mRNA. In summary, our results demonstrate that t-PA synthesis in HMC is relatively insensitive to pharmacological stimulation. To restore the balance between fibrinolysis and coagulation under inflammatory conditions, attempts to interfere with the TNF-alpha-signaling pathway were more successful.
 ...
PMID:Modulation of procoagulant and fibrinolytic system components of mesothelial cells by inflammatory mediators. 894 61

The effect of 12 wk of submaximal training on hemostatic variables was studied in 20 young sedentary men (Tr) and 19 nontraining matched controls (Con). After training, a more pronounced increase in factor VIII coagulant activity (P < 0.01), reflected in a decrease in activated partial thromboplastin time (P < 0.01) during maximal exercise, was seen. Both basal plasminogen activator inhibitor 1 antigen (PAI-1 Ag) and activity (PAI-1 Act; P < 0.05), as well as basal and exercise-induced tissue-type plasminogen activator antigen (t-PA Ag; P < 0.05), were decreased after training. The overall effect on fibrinolysis was reflected in an increase in the t-PA Act/t-PA Ag ratio in the Tr group. In contrast, during the same period (February-June), the Con group demonstrated an increase in basal PAI-1 Ag and PAI-1 Act (P < 0.05), together with an increase in basal and exercise-induced t-PA Ag (P < 0.05). Both basal and exercise-induced t-PA Act were unchanged, but t-PA Act/t-PA Ag was decreased (P < 0.05) in the Con group. We conclude that physical training promotes both coagulation and fibrinolytic potential during exercise and may reverse unfavorable seasonal effects on fibrinolysis.
 ...
PMID:Effect of endurance training and seasonal fluctuation on coagulation and fibrinolysis in young sedentary men. 904 45

We examined various hemostatic abnormalities in 395 patients with disseminated intravascular coagulation (DIC), in 177 patients in a Pre-DIC stage, and in 99 patients who did not exhibit DIC. Pre-DIC was defined as the condition at least one week before the onset of DIC. The differences in activated partial thromboplastin time (APTT), FDP, prothrombin time (PT) ratio, fibrinogen, and platelet count between DIC and Non-DIC patients were significant, but there were no significant differences in these parameters between Pre-DIC and Non-DIC patients. Plasma levels of fibrin-D-dimer, thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), soluble fibrin monomer (sFM), prothrombin activated peptide F1 + 2 (F1 + 2), thrombomodulin (TM), tissue type plasminogen activator (t-PA), and PA inhibitor (PAI-I) in DIC patients were significantly higher than levels in Non-DIC patients. However, only TAT, sFM and PAI-I values in the Pre-DIC patients were significantly higher than the values in the Non-DIC patients. Almost all the hemostatic molecular markers examined had high sensitivity for DIC, but only TAT and PPIC had high sensitivity for Pre-DIC. Specificity for DIC was also high with TAT, sFM, and F1 + 2. Early diagnosis and early treatment are important in DIC; we believe that it is possible to predict Pre-DIC by assessing values for the combination of hemostatic molecular markers.
 ...
PMID:Diagnosis of pre-disseminated intravascular coagulation stage with hemostatic molecular markers. The Mie DIC Study Group. 911 56

Disseminated intravascular coagulation (DIC) may lead to severe thrombotic or hemorrhagic complications. The present work was undertaken to study the effect of interleukin 6 (IL-6) on variations of key coagulation and fibrinolytic parameters in plasma in a baboon model of experimental DIC induced by injection of factor Xa and phospholipids at dosages leading to partial (48%) or complete fibrinogen depletion. Transient increases of D-dimer, fibrinopeptide A, thrombin-antithrombin and the activated partial thromboplastin time were observed. Each parameter had a particular (time and Xa/phospholipid dose dependent) pattern of changes. The principal effect of IL-6 was a more rapid restoration of fibrinogen concentrations and of overall coagulation tests. Injection of factor Xa/phospholipids led also to a rapid increase of tissue-type plasminogen activator (t-PA) the extent of which was dependent on Xa/phospholipid dose. Pretreatment with IL-6 induced a threefold increase of basal t-PA and a corresponding increase of the t-PA response. Plasminogen activator inhibitor type 1 (PAI-1) concentrations did not change after low dose Xa/phospholipids, but increased eightfold after high dose Xa/phospholipids, IL-6 pretreatment induced within 8 h a twentyfold increase of PAI-1 but no further increase was observed after injection of factor Xa/phospholipids. Thus, in vivo thrombin generation leads to dynamic modifications of the coagulation and fibrinolytic systems. The principal effect of IL-6 is a more rapid normalization of overall coagulation tests, due to normalization of fibrinogen, and an increased t-PA release response which is partially counteracted by increased PAI-1 concentrations.
 ...
PMID:The coagulation and fibrinolytic responses of baboons after in vivo thrombin generation--effect of interleukin 6. 918 1

We examined the effect of a specific thrombin inhibitor, Ro 46-6240, alone and combined with an antagonist of the platelet GP IIb/IIIa, Ro44-9883, on the response to tissue-type plasminogen activator in a canine model of thrombolysis. Platelet activity was determined by measuring the excretion of 2,3-dinorthromboxane (TX)B2, an enzymatic metabolite of TXA2. Ro 46-6240 administered before tissue-type plasminogen activator induced a dose-dependent prolongation of the activated partial thromboplastin time and prothrombin time. The time to reperfusion decreased dose-dependently (P < .01) to 10 +/- 6 min vs. 52 +/- 5 min in controls. Ro 46-6240 also prevented reocclusion, which occurred in every case in control experiments. Urinary excretion of 2,3-dinor-TXB2 increased from 3 +/- 1 to 37 +/- 9 ng/mg creatinine in controls after reperfusion. This increase was reduced in a dose-dependent fashion by Ro 46-6240, such that at the highest dose, urinary 2,3-dinor-TXB2 after reperfusion was 5.6 +/- 1 ng/mg creatinine. Similar functional and biochemical effects were seen when a subthreshold dose of Ro 46-6240 was combined with Ro 44-9883. At the dose used, Ro 44-9883 alone abolished platelet aggregation ex vivo but failed to modify the response to tissue-type plasminogen activator or the excretion of 2,3-dinor-TXB2 after reperfusion (51 +/- 6 ng/mg creatinine, n = 3). However, the combination of Ro 44-9883 and Ro 46-6240 reduced the time to reperfusion (40 +/- 8 vs. 68 +/- 15 min; n = 7, P < .05), prevented reocclusion and abolished the rise in urinary 2,3-dinor-TXB2 (5 +/- 1 ng/mg creatinine, n = 4). These findings suggest that thrombin mediates platelet activation during coronary thrombolysis. The increased platelet activity results in platelet aggregation and a subsequent increase in TXA2 formation.
 ...
PMID:Interaction of a thrombin inhibitor and a platelet GP IIb/IIIa antagonist in vivo: evidence that thrombin mediates platelet aggregation and subsequent thromboxane A2 formation during coronary thrombolysis. 919 Aug 51

The aim of this study was to compare the effects on fibrinogenolysis and thrombin generation of two recombinant tissue-type plasminogen activator (rt-PA) regimens in patients with pulmonary embolism entering a randomised, controlled study with a 1:2 allocation ratio to rt-PA, 100 mg over 2 h (Group A) or rt-PA, 0.6 mg/kg, maximum dose 50 mg, over 15 min (Group B). In both groups the heparin infusion was stopped 2-4 h before starting thrombolytic treatment and resumed accordingly to the activated partial thromboplastin time (aPTT) or thrombin clotting time (TcT). Seventeen patients in Group A and 30 patients in Group B were evaluated before starting thrombolytic treatment and 2, 6 and 24 h after its end for the following parameters: aPTT, TcT, fibrinogen, fibrinogen degradation products (FDP), plasmin-alpha 2 antiplasmin (PAP) and thrombin-antithrombin III (TAT) complexes. The two groups had similar coagulation parameters at baseline. Two h after starting rt-PA, the aPTT was more prolonged in Group A than in Group B patients (P = 0.01). Patients in Group B showed less reduction in plasma fibrinogen levels at all study times after rt-PA treatment (P = 0.008). The increase in plasma FDP (P = 0.037) and PAP (P = 0.001) levels was lower at 2 and 6 h samples in Group B compared with Group A. TcT was prolonged (P = 0.003) and TAT increased (P = 0.001) during treatment without differences between the two groups. AUC0-24 of fibrinogen, FDP and PAP levels confirmed the statistically significant differences (P = 0.04) between the two groups over the entire 24 h period of the study. Three patients in Group A (17.6%) and three (10.0%) in Group B suffered major or other important bleeding. Our results indicate that the administration of weight-adjusted reduced-dose rt-PA bolus produces less impairment of blood coagulation than the FDA approved regimen.
 ...
PMID:Fibrinogenolysis and thrombin generation after reduced dose bolus or conventional rt-PA for pulmonary embolism. The Coagulation Project Investigators of the Bolus Alteplase Pulmonary Embolism Group. 919 18


<< Previous 1 2 3 4 5 6 7 8 9 10