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)

Defibrotide, a deoxypolyribonuclide, has been found to modulate endothelial cell function causing increase in t-PA and decrease in PAI levels and also increase in PGI2 production. In addition, it increases platelet c-AMP levels and decreases MDA and TXB2 formation in human. Defibrotide inhibits platelet aggregate formation in vitro experiments as well as end-to-end anostomosis in rats. So, defibrotide inhibits the activation of platelets. Besides an increase of protein C and S levels a synergic action of heparin was observed in animal experiments. A strong antithrombotic effect has been observed in animal models. The drug has a beneficial effect in the cases of DVT, POVD, stroke and thromboembolism. Through its action we may say that the drug acts in a novel fashion in contrast to the other drugs used in this area. Defibrotide is a single-stranded polydeoxyribonucleotide obtained from deoxyribonucleic acid of mammalian lungs by controlled depolimerization. Since 1981 in our laboratory and in the clinical department we have been investigating a newly developed agent defibrotide in vitro experiments, animal experiments, and also its clinical pharmacology and clinical application. Some of our findings are already published and compared with literature (40, 43, 46). Because of the limited space we are not going to review the literature in detail but we are going to summarize our observations on this compound in the following order. I--in vitro experiments, II--Animal experiments, III--clinical pharmacology in human.
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PMID:The pharmacology and clinical pharmacology of defibrotide: a new profibrinolytic, antithrombotic and anti-platelet substance. 210 24

In this review, an attempt has been made to present new data on the mechanisms that can be involved in DVT and to emphasize the role of the cell in these processes. It has been demonstrated that cells can mediate the relevant expression of tissue factor without cell disruption and that the fibrinolytic responses can also be modulated by the cells. It has also been demonstrated that the fibrinolytic system seems to be designed to work on the cell surface based upon (1) the existence of specific receptors, (2) the modulation of the expression of these receptors and (3) the comprehensive increase in plasmin generation by up-regulating, for example, the plasminogen receptors. It could also be worthwhile to attempt to explain some beneficial effects of drugs such as heparins by studying their action on these compartments. It is important to note that recently Rosenfeld et al. have described an increase in t-PA and u-PA binding to endothelium by pre-incubation of endothelial cells with unfractionated heparin. This work would be a first step in a very exciting and interesting new era in the prevention of venous thromboembolism.
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PMID:Biochemical aspects of the pathogenesis of venous thrombosis. 228 80

Nine patients with, and 11 without, venous thromboses (DVT) from two families were studied. In family 1, four members with, and one without, DVT had t-PA activity below the lower limit of the controls (21.3 IU/ml, n = 19) after 20 min venous occlusion (VO). After VO t-PA antigen (t-PA:Ag) was below the lowest value of the controls (22.8 ng/ml) in all five cases with low t-PA activity. All the family members, both with and without thrombosis, had normal t-PA inhibitor activities (PAI). In family 2 t-PA activity after VO was low in three symptomatic and four asymptomatic family members. t-PA:Ag was also low in four of these. PAI level was normal in all but one family member. Mild type I von Willebrand's disease was discovered in four members of family 2. Deficient t-PA:Ag response was found in two of these. Antithrombin III, protein C and protein S were normal in both families. It is concluded that low fibrinolytic capacity, independent of PAI, is associated with familial DVT. Our data suggests autosomal dominant inheritance.
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PMID:Familial hypofibrinolysis and venous thrombosis. 249 18

Using affinity chromatography on lysine Sepharose 4B, a fast-acting tissue plasminogen activator inhibitor (t-PAI) was partially purified from t-PAI-rich plasma from patients with recurrent DVT. Its inhibition of tissue plasminogen activator (t-PA) was demonstrated in functional assays and its reaction with 125I-t-PA was analyzed by autoradiography following SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis). When the t-PAI was mixed with an equimolar concentration of t-PA at 37 degrees C, the half-life of free one-chain and two-chain 125I-t-PA was 1.8 and 0.8 min, respectively. The rate of complex formation between 125I-t-PA and t-PAI was similar both in patient plasma, pregnancy plasma and platelet lysates made from platelet-rich normal, patient and pregnancy plasma. The molecular weights of the complexes between t-PA and the inhibitors in patient plasma and in the different platelet lysates were identical, while that of the inhibitor complex formed in pregnancy plasma was found slightly higher by SDS-PAGE indicating that the pregnancy plasma t-PAI differs from the fast-acting t-PAI found in plasma from thrombotic patients and in platelet lysates.
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PMID:Plasminogen activator inhibitors in plasma and platelets from patients with recurrent venous thrombosis and pregnant women. 308 15

Fibrinolysis of 19 patients who developed CVI after deep vein thrombosis was examined. Mean age of patients at the first thrombosis was 31.8 years. For testing fibrinolysis fibrinogen, plasminogen, AP, ECLT, with venous occlusion were determined. In 10 patients t-PA and PAI-1 activities were also measured and plethysmography was carried out. For screening blood coagulation abnormalities of TCT count, PT, APTT, TT, AT III, protein C were tested. The common abnormality was the decreased fibrinolysis. Patients had been on coumarin for 6.14 years before entering the study. Under coumarin treatment 6 patients had relapsed DVT, 4 had crural ulcer and CVI deteriorated in 8 patients. Therefore we added fibrinolysis increasing PPS to coumarin. PPS dose was individually determined by PPS loading test (150-500 mg). Mean observation time with the combined treatment was 2.92 years. Clinical check up and fibrinolysis test were carried out every 6 months. Clinical improvement occurred in 13 patients, (decrease of swelling, pain etc). Two out of 4 patients with stasis ulcer experienced complete healing; in 1 the ulcer territory diminished in size. Maximum venous outflow improved in 7 patients, 3 patients were non-responders. We observed an increase of fibrinolysis in 10 patients. Venous occlusion enhanced the fibrinolysis increasing effect of PPS. The activity reached its maximum by the first control. The fibrinolysis increase and the clinical improvement do not always run parallel, therefore other effects of PPS as the reason for being beneficial in CVI must be considered (antiinflammatory, ect.). Combination of coumarin and PPS seems to be an effective therapy in CVI with decreased fibrinolysis.
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PMID:[Management of chronic venous insufficiency with the combination of coumarin (Syncoumar) and oral pentosan polysulfate (PPS, SP 54) (preliminary report)]. 767 12

A deletion/insertion polymorphism (4G or 5G) in the promoter of the plasminogen activator inhibitor type 1 gene has been suggested to be involved in regulation of the synthesis of the inhibitor, the 4G allele being associated with enhanced gene expression. A relationship between 4G/5G polymorphism and PAI-1 levels was found in patients with cardiovascular and metabolic diseases, but not in healthy subjects. In the present work we studied the distribution of PAI-1 4G/5G genotype and its relation to fibrinolytic capacity in 70 unrelated patients with deep vein thrombosis. Each patient was assayed before and after 20 min. Venous occlusion for euglobulin lysis time, t-PA antigen and activity, and PAI-1 antigen and activity. The prevalence of 5G homozygous carriers was significantly lower in patients than in controls (10% vs. 26%, p=0.009). The 5G allele frequency was reduced, even though not significantly, in DVT patients compared to healthy subjects (0.40 vs. 0.51, respectively). In the patient group, the mean PAI-1 antigen and activity levels were significantly higher than among controls and related to the 4G/5G polymorphism. In patients with 4G/5G and 4G/4G genotype a significant correlation was found between PAI-1 levels and the global fibrinolytic activity as evaluated by euglobulin lysis time. The prevalence of a reduced fibrinolytic potential due to PAI-1 excess was 45.7% among DVT patients. Moreover, the prevalence of PAI-1 induced hypofibrinolysis was strongly related to PAI-1 polymorphism, since it was significantly lower in 5G homozygous patients (28.6%) than in both 4G/5G carriers (55.3%, p <0.001) and 4G homozygous patients (57.9%, p <0.001). In conclusion, in patients with deep vein thrombosis the 4G polymorphism of PAI-1 gene promoter may influence the expression of PAI-1 and it should be taken into consideration as a facilitating condition for pathological fibrinolysis together with other environmental and genetic factors. Whether this has any significance in regard to the pathogenesis of venous thrombosis remains to be proven.
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PMID:4G/5G polymorphism of PAI-1 gene promoter and fibrinolytic capacity in patients with deep vein thrombosis. 986 67

The goals of treatment of acute iliofemoral DVT should be prevention of fatal PE, reduction of pain and swelling of the involved leg, trying to stop the development of phlegmasia cerulea dolens and venous gangrene, prevention of disabling PTS by early removal of the blood clot, avoiding proximal venous obstruction, preserving normal, functioning valves in the leg veins, and preventing reflux. The authors recommend an aggressive approach with rapid removal of the occluding thrombus in the leg veins extending up into the iliac veins in active patients with a short history of symptomatic DVT, usually less than 7 days. This approach is not justified in chronically ill, bedridden, high-risk, or aged patients, or those with serious intercurrent disease or limited life expectancy. In these patients, such interventions can only be indicated for limb salvage in phlegmasia cerulea dolens when conservative treatment does not prevent the development of an acute compartment syndrome with venous gangrene. The preferred means of accomplishing early and quick removal of the thrombus is CDITT. Most of the authors' positive experience with thrombolysis is based on the use of urokinase. The Food and Drug Administration (FDA) has put this drug on temporary hold for almost 1 year. The alternative drugs (e.g., tissue plasminogen activator [tPA]) have not been tested for CDITT of DVT, and tPA is not FDA-approved for this indication. When there are contraindications or failure of thrombolysis, TE with a temporary AVF is a valid alternative.
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PMID:Indications for surgical treatment of iliofemoral vein thrombosis. 1080 68

Although the incidence of pediatric thrombosis has increased over the last decade, noncatheter-related deep venous thrombosis (nCDVT) is rare in children. Congenital and acquired hypercoagulable states may play an important role in the pathogenesis of nCDVT. In this study, we evaluated fibrinolytic parameters by measuring individual concentrations of fibrinolytic proteins and by tissue factor initiated whole blood thromboelastography (TEG), in which a fibrin clot was lyzed by exogenously added tissue plasminogen activator (tPA). Children with nCDVT were compared with age and sex-matched controls. TAFI concentrations were significantly higher in the patient group but there was no difference in the PAI-1, tPA and lipoprotein (a) concentrations. Significantly decreased fibrinolysis was found on TEG in the patient group suggesting that hypofibrinolysis may play an important role in the pathogenesis of nCDVT in children. To our knowledge, this is the first pediatric study that has systematically evaluated the role of fibrinolysis in the pathogenesis of DVT. Given our results, the role of fibrinolysis in the pathogenesis of nCDVT in children should be further evaluated in larger studies.
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PMID:Fibrinolytic parameters in children with noncatheter thrombosis: a pilot study. 2030 41

The use of thrombolytic agents has greatly improved patient outcomes, but the prothrombotic response to these drugs in vivo is unknown. Approximately 24 h after we induced thrombosis in male Sprague-Dawley rats, we placed an infusion line in the inferior vena cava and administered either saline or a thrombolytic agent (tissue plasminogen activator [tPA] or plasmin) for 30 min. Blood was drawn immediately after infusion; rats were euthanized 24 h after infusion for collection of blood and tissue (inferior vena cava and thrombus). Thrombus size was decreased in the tPA-treated rats but not in those that received saline or plasmin; this change correlated with the significant rise in D-dimer levels noted immediately after infusion in the tPA-treated rats. Plasma soluble P-selectin, a prothrombotic marker, was elevated at 24 h in the plasmin group compared with the other treatment groups. There were no significant differences in plasma C3a, C5a, or C5b9 levels or in thrombus C3 levels between groups. According to ultrastructural analysis, thrombus structure and vein wall effects did not differ between groups. Local tPA did not induce a prothrombotic state during acute DVT or after thrombolytic therapy in a rodent model of venous thrombolysis. Conversely, levels of the prothrombotic marker plasma soluble P-selectin increased when plasmin was administered.
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PMID:Prothrombotic effects of thrombolytic therapy in a rat (Rattus norvegicus) model of venous thrombolysis. 2375 27