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)

Intravenous infusion of desmopressin (DDAVP, 0.4 micrograms/kg b.w. in 12') causes an increase in the level of extrinsic plasminogen activator, measured in plasma euglobulin fractions with added C1-inactivator on fibrin plates. A poor response or no response at all was elicited in two out of 21 patients with spontaneous thrombosis, 18/38 with hyperlipoproteinaemia and 10/14 with terminal renal insufficiency requiring haemodialysis. Haemodilution during the first 30' after starting the DDAVP-infusion occurred both in responders and in non-responders; so did haemodynamic reactions: increase in heart rate, drop in diastolic blood pressure, facial flushing. The rise of fibrinolytic activity was shown not to be associated with decreased hepatic blood flow. Normal factor VIII-rises in "non-responders" indicate the responsiveness of the receptive organs, including the hypothalamus, to DDAVP. Despite a normal baseline level of fibrinolytic activity in the blood, as occurs for instance in terminal renal insufficiency, the vascular endothelium may be refractory to stimulation. In some patients especially in type IV hyperlipoproteinaemia, a selective defect of the release of plasminogen activator is postulated. In subjects with low fibrinolytic activity at rest, as observed in spontaneous thromboembolism and in hypertriglyceridaemia, the failure to release plasminogen activator upon stimulation with DDAVP might be a consequence of an impairment of synthesis as well.
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PMID:The use of desmopressin acetate (DDAVP) as a test of the fibrinolytic capacity of patients--analysis of responders and non-responders. 681 44

The role of the microvascular endothelium in the integration of inhibitory and catabolic pathways of hemostasis is discussed in light of recent findings of direct biochemical links between endothelium and regulatory plasma proteins. These findings include the following: (1) On the vascular endothelium, a cofactor for antithrombin III (with an activity comparable to stationary phase heparin) catalyzes thrombin inhibition in vivo. (2) A second cofactor on endothelium binds thrombin in a manner that enhances by several orders of magnitude the ability of thrombin to activate protein C. (3) Activated protein C has both anticoagulant and catabolic activities; anticoagulant activity results from the susceptibility of factors Va and VIIIa to inactivation by activated protein C, whereas catabolic activity arises from the stimulation by activated protein C of the release from endothelium of fibrin-dependent plasminogen activator. (4) Because it requires fibrin as a cofactor, the plasminogen activator lyses clots without provoking fibrinogenolysis. Location of these activities on endothelium separates coagulation in time and space from catabolic pathways, and provides for their expression after the initiation of hemostasis.
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PMID:The control of hemostasis. Role of endothelium in the regulation of inhibitory and catabolic pathways. 689 31

Recent work has implicated plasminogen activator released from macrophages as a possible mediator of the demyelinating process in experimental allergic encephalomyelitis and multiple sclerosis (MS). We have studied the capacity of white matter and plaques from MS patients to break down fibrin clots, using a histochemical technique. Fibrinolytic activity was localized exclusively to areas around blood vessels and capillaries in both patients and controls. While there was marked variation between individuals, the unaffected white matter from MS patients was, on the average, not more active than that of controls, but plaques tended to show more numerous foci of lysis, often also more intense, than adjacent white matter; there was no correlation with disease activity or age of the plaques as determined by histological criteria. The localization and degree of fibrinolysis observed were not related to the presence of lymphocytic infiltrates, gliosis, or macrophages. However, the findings do not exclude an involvement of fibrinolytic enzymes (although originating from vascular endothelium rather than macrophages) in the genesis of the MS plaque, which commonly starts around a small vein.
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PMID:Fibrinolytic activity of plaques and white matter in multiple sclerosis. 721 4

To determine the effects of interferon (IFN) treatment for chronic hepatitis C on vascular endothelium, we measured the concentrations of tissue plasminogen activator (t-PA) and its inhibitor (PAI-1) in the plasma from patients before and after IFN treatment for 14 consecutive days. The plasma t-PA and PAI-1 levels were measured before and after treatment. The plasma t-PA level was significantly increased after IFN treatment (p < 0.01) but no significant difference in plasma PAI-1 level was observed before and after treatment. The ratio of t-PA/PAI-1 was significantly increased after IFN treatment (p < 0.05). These changes may be caused by the effect of IFN on endothelium, leading to an activation of the endothelium derived fibrinolysis factors. Increase in plasma t-PA concentration may induce hyperfibrinolysis which may be one of the causes of suborbital hemorrhage. Further study on the fibrinolysis pathway in the blood is necessary to elucidate the mechanisms of the many side effects observed during IFN treatment.
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PMID:[Changes in plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) by the interferon treatment for chronic hepatitis C]. 747 59

The aim of the present study was to find out whether plasminogen activator inhibitor type-1 (PAI-1) controls the formation of plasmin in patients with ischaemic heart disease. We examined PAI activity, PAI-1 antigen, tissue type plasminogen activator (t-PA) activity, t-PA antigen, plasmin-alpha2-antiplasmin complex (PAP-complex) and fibrin degradation products D-dimer in 62 patients before (unstimulated) and after infusion of 1-desamino-8-D-arginine vasopressin (DDAVP; stimulated). DDAVP was used in a standardized dose to trigger the release of t-PA from the vascular endothelium. We observed that under basal conditions (unstimulated) median plasma t-PA activity for the whole group of patients was 86.5 mIU/ml (0-900), and after stimulation 2550 mIU/ml (0-6800), P < 0.0001; median plasma concentration of t-PA antigen was 14.7 ng/ml (7.0-115.5) under basal conditions, and after stimulation 34.1 ng/ml (15.8-58.6), P < 0.0001; median plasma PAI activity was 16.9 IU/ml (1.5-144.8) under basal conditions, and after stimulation 3.1 IU/ml (0-118.5), P < 0.0001; median plasma concentration of PAI-1 antigen was 21.5 ng/ml (8.1-132.2) under basal conditions, and after stimulation 14.9 ng/ml (4.8-149.0), P < 0.0001; the median plasma concentration of PAP-complex was 469.5 ng/ml (185.0-1802.0) under basal conditions, and after stimulation 695.5 (243.0-2292.0), P < 0.0001; median plasma concentration of D-dimer was 298.0 ng/ml (103.0-948.0) under basal conditions, and after stimulation 296.5 ng/ml (97.0-917.0), P < 0.0008.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasminogen activator inhibitor type-1 determines plasmin formation in patients with ischaemic heart disease. 748 12

Adrenergic stimulation induces an acute fibrinolytic response in the vascular wall and can play an important role in limiting thrombus growth. The incidence of thrombotic disease increases with age. As many adrenergic functions are affected by aging, the vascular response to adrenergic stimulation was studied in young (3 +/- 1 months) and aged (18 +/- 3 months) rats, using an experimental model of vascular perfusion. Five min epinephrine (EPI) infusion (0.15-25 microM) induced a dose-dependent increase in tissue-type plasminogen activator (t-PA) release and in perfusion pressure, in both young and aged rats. In the latter, however, the basal activity of t-PA was significantly higher than in young animals (0.22 +/- 0.02 vs 0.13 +/- 0.01 U/ml; means +/- SE; p < 0.01, n = 40) and EPI infusion induced a significantly higher increase in t-PA activity (0.78 +/- 0.06 vs 0.47 +/- 0.08 U/ml, p < 0.01, for 6.25 microM EPI). The response was characterized by a delayed onset. In contrast, the increase in the perfusion pressure by EPI was significantly lower in aged that in young rats, its basal levels being normal. To evaluate whether the increased vascular response of t-PA was peculiar for adrenergic stimulation, we infused platelet activating factor (PAF), an inducer of t-PA release, not related to catecholamines. PAF, during five-minute infusion induced a rapid and dose-dependent (100-1250 pM) increase in t-PA release, to the same extent in both young and aged rats. In conclusion, basal t-PA secretion was increased in aged rats probably as a response of vascular endothelium to chronic stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enhanced vascular plasminogen activator (t-PA) release by epinephrine in aged rats. 748 13

The very low density lipoprotein (VLDL) receptor binds apolipoprotein E-rich lipoproteins as well as the 39-kDa receptor-associated protein (RAP). Ligand blotting experiments using RAP and immunoblotting experiments using an anti-VLDL receptor IgG detected the VLDL receptor in detergent extracts of human aortic endothelial cells, human umbilical vein endothelial cells, and human aortic smooth muscle cells. To gain insight into the role of the VLDL receptor in the vascular endothelium, its ligand binding properties were further characterized. In vitro binding experiments documented that lipoprotein lipase (LpL), a key enzyme in lipoprotein catabolism, binds with high affinity to purified VLDL receptor. In addition, urokinase complexed with plasminogen activator-inhibitor type I (uPA.PAI-1) also bound to the purified VLDL receptor with high affinity. To assess the capacity of the VLDL receptor to mediate the cellular internalization of ligands, an adenoviral vector was used to introduce the VLDL receptor gene into a murine embryonic fibroblast cell line deficient in the VLDL receptor and the LDL receptor-related protein, another endocytic receptor known to bind LpL and uPA.PAI-1 complexes. Infected fibroblasts that express the VLDL receptor mediate the cellular internalization of 125I-labeled LpL and uPA.PAI-1 complexes, leading to their degradation. Non-infected fibroblasts or fibroblasts infected with the lacZ gene did not internalize these ligands. These studies confirm that the VLDL receptor binds to and mediates the catabolism of LpL and uPA.PAI-1 complexes. Thus, the VLDL receptor may play a unique role on the vascular endothelium in lipoprotein catabolism by regulating levels of LpL and in the regulation of fibrinolysis by facilitating the removal of urokinase complexed with its inhibitor.
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PMID:The very low density lipoprotein receptor mediates the cellular catabolism of lipoprotein lipase and urokinase-plasminogen activator inhibitor type I complexes. 759 75

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

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


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