Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ELISA was used to measure tissue plasminogen activator antigen in blood plasma and urine of 42 patients with active lupus nephritis (16 with isolated urinary syndrome, 13 with nephrotic syndrome, 13 with rapidly progressive LN). Control groups consisted of 17 patients with inactive LN and 15 healthy subjects. Inhibition of fibrinolysis in vascular system correlating with the disease severity was found in patients with active LN. This may result from both defective synthesis of tissue plasminogen activator and neutralizing action of antiactivator. Urinary fibrinolytic activity was inhibited only in patients with rapidly progressive LN because of hyperactive synthesis of antiactivator. The above changes occur as endothelial cell dysfunction due to activating and damaging action of immune complexes, antibodies, cytokines on vascular endothelium. Zero activator activity of plasma and urine in patients with active LN reflects severe dysfunction of endothelial cell caused by its structural disorganization.
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PMID:[Tissue-type plasminogen activator in patients with lupus nephritis]. 763 68

Hyperhomocysteinaemia, defined as an abnormally high plasma homocysteine concentration after an oral methionine load, is common in young (< or = 50 years) patients with peripheral arterial occlusive disease. It is thought to predispose to atherosclerosis by injuring the vascular endothelium. Treatment with pyridoxine and/or folic acid may lower plasma homocysteine levels. In mildly hyperhomocysteinaemic patients with peripheral arterial occlusive disease, we studied the effect of daily treatment with pyridoxine (250 mg) plus folic acid (5 mg) on homocysteine metabolism (i.e. plasma concentrations in the fasting state and after methionine loading, in 48 patients) and on endothelial function (in 18 patients). Endothelial function was estimated as the plasma concentrations of the endothelium-derived proteins, von Willebrand factor (vWF), thrombomodulin (TM), and tissue-type plasminogen activator (tPA). At baseline, fasting homocysteine levels were above normal in 24 of the 48 patients (50%); post-load levels, by definition, were above normal in 100% of patients. After 12 weeks of treatment, fasting and post-load levels were normal in 98 and 100% of patients, respectively. Endothelial function was assessed in 18 patients who completed 1 year of treatment. At baseline, median vWF (235%) and TM (57.1 ng mL-1) levels were above normal. At follow-up, vWF levels had decreased to 170% (P = 0.01) and TM levels had decreased to 49 ng mL-1 (P = 0.04). tPA levels were normal at baseline and did not change. Endothelial dysfunction is present in young patients with peripheral arterial occlusive disease and hyperhomocysteinaemia. Pyridoxine plus folic acid treatment normalizes homocysteine metabolism in virtually all patients, and appears to ameliorate endothelial dysfunction.
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PMID:Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease. 778 64

Plasma thrombomodulin (TM), a specific marker of vascular endothelial injury was measured pre-, per-, and postoperatively in 16 consecutive patients undergoing orthotopic liver transplantation (OLT). The TM level, which was already elevated preoperatively, remained unchanged during OLT, except for an acute and transitory spike at the time of graft reperfusion. This TM peak is probably attributable to an acute release from the patient's endothelium because the TM level in the last saline rinse of the graft before implantation was low. This TM spike was not correlated with the progressive tissue-type plasminogen activator (t-PA) increase, plasminogen activator inhibitor 1 (PAI-1), or von Willebrand factor (vWF) values. The absence of accumulation of TM in plasma, unlike that of t-PA, suggests that the liver does not play a major role in TM clearance in humans. At the end of surgery, individual TM values returned to preoperative levels and remained unchanged during the 7 days following surgery. This observation suggests that the high (or very high) TM levels measured in these patients might be due to an indirect rather than a direct effect of liver dysfunction on the vascular endothelium which remained damaged during the postoperative period. The possibility that TM might be a predictive marker for thrombotic OLT complications remains to be investigated in a postoperative follow-up study.
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PMID:Plasma thrombomodulin in orthotopic liver transplantation. 780 28

The baboon model of E. coli sepsis illustrates three concepts with respect to the host response and vascular endothelium. First, the endothelium is the primary target. E. coli sepsis is an acute inflammatory disease of the vascular endothelium. Second, the endothelium is not a passive target. Initially it regulates both the inflammatory and coagulopathic aspects of E. coli sepsis through membrane associated regulatory receptor/plasma protein assemblies including protein C/thrombomodulin, activated protein C/protein S, C4bBP/protein S, tissue factor pathway inhibitor/Xa, antithrombin III/glycosaminoglycans. Third, when overridden by inflammatory events, the endothelium can change its anticoagulant phenotype and mount a massive procoagulant fibrinolytic counter-attack on its luminal side through the expression of tissue factor and release of tissue plasminogen activator. Fourth, again when overridden by inflammatory events, the endothelium can change its antioxidant phenotype and produce a "distal" tissue hypoxia on its abluminal side through induction of free radical generation and peroxidation of mitochondrial lipid membranes of those tissues with high metabolic rates. It has become increasingly clear that the so-called anticoagulant systems which act on the proximal factors of the clotting cascade (protein C, TFPI, AT-III, PGI2) also attenuate the amplification of the inflammatory response. Aspects of the mechanism by which this occurs are coming to light. This includes the attenuation of Il-6 response by TFPI and the attenuation of the complement effects by C4bBP/PS. The specifics of these observations in the E. coli sepsis model will be reviewed.
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PMID:Studies on the inflammatory-coagulant axis in the baboon response to E. coli: regulatory roles of proteins C, S, C4bBP and of inhibitors of tissue factor. 783 58

In the past decade, thrombolytic therapy has become standard treatment of acute myocardial infarction. When the importance of thrombosis in the pathogenesis of acute infarction was fully recognised, several plasminogen activators were developed, streptokinase, urokinase, recombinant tissue-type plasminogen activator (t-PA, alteplase), anistreplase and saruplase (prourokinase). Thrombolytic agents are plasminogen activators which possess as a common characteristic the ability to activate plasminogen to plasmin, and result in fibrinolysis and varying degrees of depletion of circulating fibrinogen, factor V and factor VIII. A lot of animal experiments provided the basis for the rationale that recanalisation and reperfusion early in the course of myocardial infarction would limit myocardial necrosis, improve left ventricular function, and improve patient outcome. Native tissue plasminogen activator is normally secreted by vascular endothelium and the most important property of the drug is its relative fibrin specificity. Fibrin strikingly increases the rate of conversion of plasminogen to plasmin by t-PA. The isolation of the complementary DNA coding for t-PA, its insertion into the genome of Chinese hamster ovary cells, and its expression in suspension cultures of these cells have facilitated the large-scale production of t-PA, making it available as a drug for the treatment of acute myocardial infarction. A variety of dosage schemes have been used for alteplase, the standard schedule has been 100 mg given over 3 hours. Higher doses and faster administration (accelerated, front-loaded) are associated with higher patency rates. Alteplase has generally but not always been shown to have higher reocclusion rates than the non-fibrin-specific plasminogen activators. Reocclusion has been shown to be associated with adverse clinical outcome. Therefore, the rate of reocclusion is considered an important measure in evaluating thrombolytic regimens. The combination of alteplase with either urokinase or streptokinase has resulted in early patency rates comparable to alteplase alone, and low rates of reocclusion. Large, randomised clinical trials have demonstrated that thrombolytic therapy reduces mortality significantly in patients with ST elevation treated within the first 6 to 12 hours of acute myocardial infarction. As compared to an overall reduction of mortality with thrombolytic treatment, neither the GISSI-2/international trial nor the Third International Study of Infarct Survival (ISIS-3) trial of more than 60,000 patients found a difference in associated mortality between the use of streptokinase and the use of t-PA, or between the use of these agents and that of anistreplase. The addition of subcutaneous heparin to the regimens did not significantly reduce mortality as compared with no use of heparin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[t-PA in thrombolytic therapy of acute myocardial infarct]. 784 90

The vascular endothelium plays a pivotal role in regulating the hemostatic system. Various cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) are known to perturb endothelial cells to reduce antithrombogenicity. On the other hand, blood flow has been shown to affect the endothelium to maintain its antithrombogenicity under some levels of shear stress in the laminar flow system. We examined the role of hemodynamic forces on the vascular system under cytokine stimulation using a cone-plate type viscometer. Treatment of endothelial cells with either IL-1 beta or TNF-alpha under static conditions increased PAI-1, vWF and prostacyclin release, while t-PA secretion was unchanged. When cells were exposed to steady shear stress of 0, 6, 12, 18 and 24 dyne/cm2, the release of t-PA, t-PA-PAI complex and prostacyclin elevated with the increase of shear stress intensity, while a gradual decrease of total PAI-1 secretion was observed and vWF secretion was unchanged. On the contrary, active PAI-1 secretion was significantly decreased under the shear stress of over 18 dyne/cm2. Interestingly, cytokines, which did not affect t-PA secretion of resting cells, increased the t-PA secretion and had an additive effect on prostacyclin secretion with shear stress under the shear stress of over 18 dyne/cm2. PAI-1 elevation induced by cytokines was markedly abolished under the same shear forces. No additive effect was observed in the secretion of vWF. Thus, shear stress attenuates the alteration of the balance in the fibrinolytic and coagulation system induced by cytokines. These findings clearly indicate that hemodynamic forces play a crucial role in regulating the hemostatic activity in vivo.
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PMID:[Effect of shear stress on hemostatic regulation in endothelium]. 784 84

The acute release of tissue-type plasminogen activator t-PA from the vascular endothelium is of decisive importance for the prevention of intravascular fibrin deposits. A dose-dependent t-PA release from the isolated perfused vascular preparations may be induced by mediators (platelet-activating factor, bradykinin, histamine) adrenergic and cholinergic transmitters (isoprenaline, acetylcholine), thrombin, heparin and analogues, and 1-desamino-8-D-arginine-vasopression (DDAVP). Most of the compounds were shown to enhance the t-PA activity also in animal experiments (rats, rabbits, mini pigs). The pharmacologic stimulation of the t-PA release may be convenient for short-term thrombosis, prophylaxis and partial thrombolysis. Presently, this could only be achieved by unfractionated and low molecular weight heparins which have been shown to release t-PA.
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PMID:Pharmacological stimulation of t-PA release. 791 Sep 71

Circulating plasma immunoreactive thrombomodulin (i-TM) reflects the injury of vascular endothelium, and desmopressin stimulates tissue plasminogen activator (tPA) release from endothelium. Therefore, in order to estimate the damage of vascular endothelium in patients on regular dialysis treatment (RDT), we studied 1) basal plasma levels of i-TM and 2) a capability to release tPA by desmopressin. The basal plasma i-TM levels of the patients (n = 23) were significantly higher than those of the normal controls (p < 0.001). The basal plasma tPA levels of the patients (n = 8) were significantly lower than those of the controls (p < 0.05). The maximum increments of tPA from the basal levels by desmopressin in the patients were significantly reduced compared to those of the controls (p < 0.001). There was a significant inverse correlation in those cases between the maximum increments of tPA and the basal plasma levels of i-TM (p < 0.05, r = -0.75). The results actually suggested that there is a vascular endothelial damage in patients on RDT.
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PMID:Vascular endothelial dysfunction in patients on regular dialysis treatment. 795 73

The acute release of tissue-type plasminogen activator (t-PA) activity and of von Willebrand Factor (vWF) antigen from vascular endothelium was studied ex vivo using the rat hindquarter isolated perfusion model. The release of these proteins has been reported to occur simultaneously in response to a variety of endothelial cell agonists including bradykinin, thrombin and platelet activating factor. It has therefore been suggested that similar endothelial cell pathways and mechanisms are involved in the release of t-PA and vWF in vivo. This paper shows that the releases of t-PA and of vWF are not always closely linked and may depend on the agonist utilized to effect release. In our hands, the bradykinin-induced release of these proteins appears to be essentially identical, but this is not true for adenosine diphosphate (ADP). Rather, ADP is capable of causing the acute release of t-PA without the simultaneous release of vWF in the ex vivo rat hindquarter model. This indicates that the bradykinin- and ADP-induced pathways for t-PA release are probably distinct and that the releases of t-PA and vWF are not as closely linked as previously believed.
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PMID:Adenosine diphosphate stimulates the endothelial release of tissue-type plasminogen activator but not von Willebrand factor from isolated-perfused rat hind limbs. 816 98

Since basic fibroblast growth factor (bFGF) modulates the functions of vascular endothelial cells, we hypothesized that this factor may be involved in the regulation of the blood coagulation-fibrinolytic system mediated by the cells. Confluent cultures of vascular endothelial cells from human umbilical vein were treated with recombinant human bFGF (bFGF) in a serum-free medium and the content of tissue plasminogen activator antigen (t-PA:Ag) in the medium was determined by EIA. Treatment with bFGF resulted in a significant decrease in the release of t-PA:Ag from the cells accompanied with a less t-PA activity in the medium. In contrast, the t-PA:Ag release from human aortic endothelial cells was significantly increased by bFGF. The bFGF-induced decrease in the t-PA:Ag release from the venous endothelial cells was completely blocked by anti-bFGF antibody. The incorporation of [3H]leucine into the acid-insoluble fraction of the cells was significantly increased by bFGF; however, the activity of lactate dehydrogenase leaked into the medium was significantly decreased, suggesting that the suppression of the t-PA:Ag release caused by bFGF in the venous endothelial cells was not due to either a nonspecific inhibition of protein synthesis or a nonspecific cell damage. Since bFGF is postulated to be released from damaged endothelial cells, the present data suggest the regulation by bFGF of hemostasis mediated by endothelial cells when the vascular endothelium was damaged.
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PMID:Basic fibroblast growth factor suppresses tissue plasminogen activator release from cultured human umbilical vein endothelial cells but enhances that from cultured human aortic endothelial cells. 819 18


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