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)

Thrombolytic therapy mimics and enhances physiological fibrinolysis. The following substances are presently available for clinical use: the nonphysiological thrombolytics streptokinase, the APSAC (acylated plasminogen-streptokinase activator complex), the physiological plasminogen activators urokinase and tissue plasminogen activator (t-PA). Whereas the first three systematically activate the fibrinolytic system, t-PA possesses relative fibrin selectivity. The fibrin-selective active pro-urokinase has not yet been officially approved for the treatment of thromboembolic diseases, but it is being clinically tested. Fibrinolytic therapy has an established place in the management of acute myocardial infarction and of massive pulmonary embolism. When an acute deep venous thrombosis is diagnosed with a proximal extension into the popliteal vein, thrombolytic therapy is clearly superior to heparin. The lysis has proven to be an effective form of treatment of peripheral occlusive arterial disease. Local thrombolytic therapy is an option for acute and chronic femoro-popliteal occlusions involving the trifurcation into the calf arteries and for embolic occlusions of the same segment in patients with contraindications to surgical therapy. First study results of thrombolytic therapy of stroke are promising.
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PMID:[Fibrinolytic agents--who benefits when?]. 748 76

Venous stasis occurs when people are at bedrest, because of altered venous flow characteristics. This is commonly believed to be one etiology behind the development of deep venous thrombosis (DVT). The hemostatic effects of bedrest and their possible role in DVT development have not been fully examined. We hypothesized that bedrest would lead to increases in hemostatic function and that these increases could be important in the development of DVT. Twelve non-smoking volunteers were studied during supine positioning for 36 hours. Platelet reactivity and plasma concentrations of fibrinogen, alpha 2-antiplasmin, plasminogen, thromboxane beta 2, plasminogen activator inhibitor-1, tissue plasminogen activator and neuroendocrine hormones (cortisol, epinephrine and norepinephrine) were measured at 8:00 a.m., 10:00 a.m., 4:00 p.m. and 8:00 a.m. Cortisol demonstrated an early morning increase while catecholamines were unchanged throughout. Fibrinogen, alpha 2-antiplasmin, plasminogen and platelet reactivity were no different at any time point. Fibrinolytic proteins changed over time, manifested by decreased PAI-1 antigen and activity levels at 24 h. Based upon the parameters measured, bedrest causes no increase in hemostatic function. In fact, bedrest causes the potential for enhanced fibrinolysis, that differs from that previously reported for normal activity over 24 h. This may represent a protective mechanism to counter the effects of stasis from bedrest.
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PMID:The effects of bedrest on circadian changes in hemostasis. 753 Mar 85

Dextran is known to increase the plasminogen activation rate in vitro and to decrease the alpha2-antiplasmin activity. We decided to explore the effect of dextran on plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) during surgical trauma. Thirty-one patients undergoing elective surgery were given 500 ml of 6% dextran 70. Another nine patients serving as controls were given 500 ml of a glucose-electrolyte solution. The activities of t-PA and PAI-1 during surgery were determined, as was the concentration of t-PA antigen. PAI-1 activity was decreased by 19% after infusion of 250 ml of dextran. After 500 ml, the activity was reduced by 22% (both P < 0.05). The activity of t-PA was increased by 43% and 29% (both P < 0.05) and the antigenic amount of t-PA was increased by 18% and 15% (both P < 0.05) after infusion of 250 ml and 500 ml of dextran, respectively. No changes in these variables were observed in the control patients. It is concluded that infusion of dextran promotes fibrinolysis by enhancing plasminogen activation in patients subjected to trauma. Since elevated levels of PAI-1 prior to surgery are known to predispose to deep vein thrombosis, which may form already during the operation, the effect of dextran on PAI-1 described here may explain its clot preventing properties.
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PMID:Effect of dextran on plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) during surgery. 754 Jul 88

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

Defibrotide is a deoxyribonucleic acid derivative extracted from mammalian organs, which has been developed for the treatment of a number of vascular disorders. It appears to increase fibrinolysis and may possess antithrombotic, antiatherosclerotic and anti-ischaemic actions, probably due to its ability to selectively increase prostaglandin I2 and E2 levels and to increase tissue plasminogen activator and decrease plasminogen activator inhibitor function. Defibrotide is available as an intravenous and intramuscular preparation, and also as an oral formulation for long term use. Trials performed to date have provided initial evidence that defibrotide is effective in the treatment of peripheral obliterative arterial disease and acute thrombophlebitis, while preliminary data suggest possible use in preventing fibrin deposition in the circuitry of renal haemodialysis equipment. Efficacy in preventing deep vein thrombosis after surgery has been demonstrated but defibrotide does not appear to offer any therapeutic advantage over heparin. Further clinical experience is required in other disorders, including acute myocardial infarction, Raynaud's phenomenon, renal thrombotic microangiopathy and renal transplant rejection, before adequate assessment of efficacy in these areas can be made. Defibrotide is well tolerated, as assessed in trials of up to 6 months duration, with a low global incidence of adverse events (< 1 to 9%). Mild allergic reactions and gastrointestinal disturbances have occasionally been described, and a hypotensive effect has also infrequently been observed. Thus, available data suggest that defibrotide is a well tolerated agent with little or no anticoagulant activity, which is conveniently available in both parenteral and oral formulations. Initial data indicate that the drug may be a useful alternative in the treatment of peripheral obliterative arterial disease and thrombophlebitis, while its therapeutic potential in other vascular disorders and efficacy relative to established agents remains to be fully determined.
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PMID:Defibrotide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. 768 75

During the last 10 years anticoagulant (AC) therapy and thrombolytic treatment of venous thromboembolism (VT) have been evaluated in randomized studies. Adjusted subcutaneous (s.c.) heparin and low molecular weight heparin (LMWH) are found at least as effective as intravenous (i.v.) infusion of heparin in deep venous thrombosis (DVT) without an increased bleeding risk. In pulmonary embolism (PE) randomized trials assessing the efficacy of s.c. heparin and LMWH are missing. Oral AC-treatment can be initiated from the first or second day in VT. The recommended duration is three months for medical patients, and 4 weeks seem appropriate for surgical patients that are completely mobilized and without persisting predisposing factors. Long-term efficacy of thrombolytic treatment of DVT has only been assessed in small trials showing a trend towards reduced risk of developing chronic venous insufficiency. Short-term thrombolytic treatment of DVT is evaluated in ongoing trials. In the treatment of PE short-term thrombolysis with either t-PA or urokinase is found to be as effective as long-term thrombolytic treatment with a reduced bleeding risk. Thrombolytic therapy rapidly reduces embolic mass and stabilizes haemodynamics, but mortality and long-term efficacy of thrombolysis and AC-treatment versus AC-treatment alone in PE are being assessed in ongoing studies.
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PMID:[Anticoagulant and thrombolytic therapy in deep venous thrombosis and pulmonary embolism]. 778 97

Twenty-five patients with phlebographically confirmed deep vein thrombosis of the lower limb were treated with intravenous infusions of low molecular weight heparin for 7 to 29 days. The mean dosage was 15.2 +/- 3.0 Uanti-Xa (equivalent 7.6 +/- 1.5 U-aPTT). Phlebograms were taken before, during and after the treatment with low molecular weight heparin and evaluated using the score system of Marder. Nearly complete recanalization of the occluded veins was found in six (24%) patients, improvement of the Marder score of 60 to 90% was found in four patients and of 30 to 60% in seven patients, while eight patients remained unchanged. With an average dose of 15.2 I.U./kg/h the heptest was prolonged to 70 to 120 seconds while the aPTT-level did not significantly increase. tPA-antigen-levels increased significantly in most of the patients after the third day of treatment, while PAI-activity remained unchanged. A positive conclusion between the decrease of the Marder score and the duration of treatment was found. Thus the low molecular weight heparin used in this investigation proved to be effective and safe in treating deep vein thrombosis.
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PMID:Regression of deep vein thrombosis by i.v.-administration of a low molecular weight heparin--results of a pilot study. 801 18

Lysis block treatment (LBT) is a new form of fibrinolytic therapy for deep vein thrombosis and arterial occlusion in the distal parts of the limbs. Strictly local lysis was achieved by placing a cuff around the thigh or the upper arm, inflating the cuff to a pressure of 500 mmHg ("Bier's blockade"), and giving heparin and tissue plasminogen activator (rt-PA) by intravenous injection into the dorsal pedis or antecubital veins. Occlusion lasted for one hour. This new technique was demonstrated in 22 patients. Six patients presented with popliteal vein thromboses and 1 patient with a distal femoral vein thrombosis. In addition, 15 arterial occlusions were treated comprising 3 calf, 6 popliteal, 3 distal femoral, and 2 digital sites and 1 brachial site. Five of 7 venous and 9 of 15 arterial occlusions were partially or totally removed. The activated partial thromboplastin time remained nearly unchanged during LBT and only a limited and short-term lengthening was recorded after restoration of blood flow. This was of importance for patients with bleeding tendencies, which are normally a contraindication for systemic lysis. LBT may therefore be considered as a useful alternative to systemic fibrinolytic treatment.
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PMID:Lysis block treatment: a new form of local thrombolysis. 812 90

The first generation high-dose ( 80 mcg estrogen) oral contraceptives (OCs) were associated with an increased risk of deep venous thrombosis (DVT). So manufacturers removed the high-dose OCs and first replaced them with OCs with 50 mcg estrogen, resulting in a lower incidence of thromboembolic events (40 vs. 20/100,000 users). When they introduced an even lower dose OC (30 mcg estrogen), the incidence fell further (about 8/100,000 users). Yet, women using the lowest-dose OCs still have DVT more often than do control women. Life-style, age, and smoking may be confounding factors, however. It is not clear whether loss of endogenous ovarian steroid production or the effects of the orally administered contraceptive steroids cause significant changes in hemostatic factors (antithrombin III, protein S, protein C, plasminogen, tissue-type plasminogen activator, plasminogen activator inhibitor 1, histidine-rich glycoprotein, and VII, VIII, X, XII coagulation factors) during OC use. These changes tend to be within normal ranges. There is some doubt that these changes have any clinical significance. In nonsmokers, increased activity of anticoagulant factors and fibrinolytic factors counteract the effects on coagulation factors. Progestin-only OCs appear to affect hemostasis but have not increased the risk of thrombosis. There are considerable differences between people in pharmacokinetics and pharmacodynamics of contraceptive steroids. These differences may account for the increased risk of thromboembolic events in some people. Further research should identify methods of individualizing the dose of contraceptive steroids for a single patient. It should also explore the close interrelationship between hemostasis and lipid metabolism, carbohydrate metabolism, and hypertension in the development of cardiovascular disease in OC users. Providers should discourage women with a past history of DVT from using hormonal contraception.
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PMID:Coagulation and anticoagulation effects of contraceptive steroids. 817 1

Hip joint replacement surgery, using acrylic cement for prosthesis fixation, is associated with intraoperative cardiorespiratory dysfunction, and a high frequency of postoperative proximal deep vein thrombosis (DVT). Levels of prothrombin fragments 1+2 (F1+2), tissue plasminogen activator antigen (t-PA), plasminogen activator inhibitor 1 activity (PAI-1), D-dimer and interleukin 6 (IL-6) were measured in arterial (AB) and mixed venous blood (MVB) in five patients during and after total hip replacement operation with acrylic cement prosthesis fixation. Sequential peaks of F1+2, t-PA, PAI-1 and IL-6 appeared, starting with activation of coagulation during preparation of bone, closely followed by activation of fibrinolysis. Later, this was counteracted by an antifibrinolytic response and increase of IL-6. After a fibrinolytic shutdown on the third postoperative day as evidenced by a drop in t-PA and D-dimer concentrations, a second wave of coagulation was seen at the end of the first week. The present model, with frequent sampling of blood entering and leaving the lungs, confirms our earlier findings of the lung as a key organ in promoting coagulation following traumatic activation.
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PMID:Sequential intrapulmonary and systemic activation of coagulation and fibrinolysis during and after total hip replacement surgery. 836 70


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