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 is rarely used in venous thromboembolism because of the fear of hemorrhagic complications. Preliminary clinical experiences with recombinant tissue-type plasminogen activator (rt-PA) in patients with deep vein thrombosis have shown that even this fibrin-specific plasminogen activator causes an unacceptable rate of hemorrhagic complications. Theoretical considerations and the available experimental and clinical data suggest that infusion of rt-PA over a short period of time would result in a more favorable risk-benefit ratio. Shortening the period of rt-PA infusion results in higher peak plasma levels, thus allowing a higher concentration of the plasminogen activator on the surface and inside the occluding thrombus. In addition, a bolus infusion can prevent or minimize the interaction between rt-PA and the hemostatic system, reducing the likelihood of a systemic lytic state, of a platelet function defect, and, possibly, of bleeding side effects. In venous thromboembolism animal models, the efficacy of bolus rt-PA can be further increased by the adjunctive administration of an effective antithrombotic treatment. This is because the accretion of new fibrin on the thrombi counteracts the lysis of preformed fibrin and influences negatively the final thrombus size. Effective adjunctive antithrombotic treatment includes either high doses of heparin, producing an unclottable activated partial thromboplastin time (aPTT), or doses of recombinant hirudin, doubling the aPTT. When used as an alternative to rt-PA, bolus doses of a hybrid plasminogen activator with prolonged half-life efficiently reduce thrombus size by lysing preformed and newly formed fibrin. Preliminary clinical experience in patients with pulmonary embolism seems to confirm that rt-PA infused as a bolus is at least as effective as, and probably more effective than, rt-PA infused over a longer period.
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PMID:Bolus thrombolysis in venous thromboembolism. 155 82

This study assessed the efficacy and safety of increasing durations of constant-dose intravenous recombinant tissue-type plasminogen activator (rt-PA) in the treatment of deep vein thrombosis. Patients with venogram-documented proximal lower limb (popliteal, iliofemoral) or upper limb (axillary, subclavian) thrombi were given an initial 2-hour rt-PA infusion at 4 micrograms/kg/min, followed by a maintenance infusion of 1 microgram/kg/min for an additional 4, 22, or 33 hours (mean total rt-PA dosages of 54, 127, and 185 mg). A new quantitative venogram scoring system was applied to the study, based on measurements of thrombus volume before and after completion of treatment. Whereas none of the seven patients given treatment for 6 hours and only one of four given treatment for 24 hours showed significant lysis, four of seven who received a prolonged infusion for 35 hours showed lysis of more than 40% of the original thrombus. Overall, the prolonged 35-hour infusion induced 51% lysis of original thrombus, representing a thrombus volume of 16.7 ml dissolved. Hemorrhagic complications were common in all three groups, with four of 18 patients having significant bleeding, including one massive gastrointestinal hemorrhage, two patients with a decrease in hematocrit of more than 10%, and one patient with an intracranial hemorrhage who recovered completely. Pharmacokinetics of the rt-PA showed a steady state antigen concentration of 240 ng/ml and activity of 200 IU/ml during the initial 2-hour infusion and a postinfusion half-life of 5 minutes. Plasma fibrinogen concentrations decreased to approximately 40% to 50% of initial values with all three treatment regimens, but the nadir fibrinogen concentrations did not correlate with either therapeutic efficacy or bleeding complications. One patient with systemic lupus erythematosus had an unusual allergic reaction that manifested primarily as angioedema. This study suggests that rt-PA infusion of 35 hours induces greater thrombolysis of deep vein thrombosis than does a shorter course of 6 or 24 hours, without an increase in hemorrhagic complications.
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PMID:Comparison of dosage schedules of rt-PA in the treatment of proximal deep vein thrombosis. 158 98

To determine whether the response to thrombolytic therapy for lower-extremity deep venous thrombosis (DVT) can be predicted from the venographic appearance, 139 thrombosed venous segments were analyzed. Initial and follow-up venograms were obtained in 62 patients randomized to 24-hour infusions of recombinant human-tissue-type plasminogen activator (rTPA) (n = 34), rTPA plus heparin (n = 16), or heparin alone (n = 12). Segmental response to therapy was evaluated by means of blinded review of the paired venograms. The response (50%-100% lysis) to rTPA alone was significantly greater in venous segments involved with nonobstructive thrombi than in those with obstructive thrombi (12 of 23 vs five of 51; P less than .005). Results were similar for the combination of rTPA and heparin (five of six vs six of 30, P less than .01). No significant difference was seen in the response of either obstructive or nonobstructive thrombus to heparin alone. Thrombotic tails responded substantially (greater than 50% decrease in size) to rTPA with or without heparin in 22 of 24 patients. The venographic appearance of DVT appears to help in predicting the therapeutic response to thrombolytic therapy.
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PMID:Short-term response to thrombolytic therapy in deep venous thrombosis: predictive value of venographic appearance. 162 Aug 26

An impaired fibrinolytic activity after a venous occlusion test is the most common abnormality associated with thomboembolic disease. To better characterize the causes of abnormal responses we have measured different fibrinolytic parameters, before and after 10 and 20 min of venous occlusion, in 77 patients with a history of idiopathic deep vein thrombosis and/or pulmonary embolism and in 38 healthy volunteers. The patients had a lower mean fibrinolytic response to venous occlusion than the controls and higher antigen levels of tissue-type plasminogen activator (t-PA:Ag) and plasminogen activator inhibitor type 1 (PAI-1:Ag). Before venous occlusion, PAI-1 levels were at a molar excess over those of t-PA in all patients and controls. After 20 min of venous occlusion, the release of t-PA from the vascular endothelium resulted in a molar excess of t-PA over PAI-1 in the majority of controls (72%) but only in a minority of patients (39%). To identify patients with fibrinolytic abnormalities, reference intervals (RI) for fibrinolytic activity, t-PA:Ag and PAI-1:Ag were established in healthy controls. None of the patients had low levels of t-PA:Ag, but 17 (22%) had elevated PAI-1:Ag levels before venous occlusion and 12 (16%) exhibited low fibrinolytic activity after 20 min of venous occlusion. Ten of these were among the 17 subjects with high PAI-1:Ag levels before venous occlusion. Thus, the measurement of PAI-1:Ag levels before venous occlusion (i.e. in samples taken without any stimulation) is a sensitive (83%) and specific (89%) assay for the detection of patients with an impaired fibrinolytic response to venous occlusion.
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PMID:Hypofibrinolysis in patients with a history of idiopathic deep vein thrombosis and/or pulmonary embolism. 163 86

In a prospective randomized study heptest, thrombin-antithrombin complexes (TAT), D-dimer, and t-PA:ag were analysed pre- and postoperatively in 206 consecutive patients undergoing hip arthroplasty during thromboprophylaxis with either a LMW heparin (Enoxaparin) or Dextran 70. Deep vein thrombosis (DVT) developed in 6 of 102 (6%) Enoxaparin and in 21 of 104 (20%) Dextran patients diagnosed by bilateral phelobography. In the Enoxaparin group heptest showed a significant increase from the pre- to the postoperative level opposed to a significant decrease in the Dextran group. Postoperative levels of TAT, D-dimer, and t-PA:ag were significantly increased in both groups, however, TAT was significantly higher in patients in the Dextran group than in the Enoxaparin patients. D-dimer was significantly higher in Dextran patients with DVT postoperatively compared with patients without DVT. No differences concerning TAT or t-PA:ag were observed between patients with and without DVT in any of the groups.
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PMID:Components of coagulation and fibrinolysis during thrombosis prophylaxis with a low molecular weight heparin (Enoxaparin) versus Dextran 70 in hip arthroplasty. 171 55

Five criteria for poor response to a 20 min venous occlusion test were applied to 58 patients 3 months or more after acute deep vein thrombosis (DVT). The criteria were arbitrarily defined as the last 5 percentiles of response distributions in an age- and sex-matched healthy control group of 51 subjects. The criteria were: 1. euglobulin clot lysis time after venous occlusion greater than or equal to 140 min; 2. t-PA activity after venous occlusion less than or equal to 0.04 IU/ml; 3. increase in t-PA antigen above resting value less than or equal to 2-fold; 4. ratio between t-PA antigen increase and resting PAI activity less than or equal to 0.5 ng/IU; 5. PAI activity after venous occlusion greater than or equal to 6 IU/ml. The last criterion of poor response was the only one that was significantly more frequently reached by patients than by controls: 28% (p less than 0.005) of all DVT patients and 35% (p less than 0.005) of the subgroup with idiopathic DVT (N = 34) were found to be poor responders. The percentage of poor responders according to the other four criteria was 7-11% in all patients and 9-15% in the subgroup with idiopathic DVT and thus was not significantly higher than in controls (5% by definition). It was concluded that residual PAI activity after venous occlusion might be a useful criterion for prospective studies on recurrence of DVT.
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PMID:Poor fibrinolytic response to venous occlusion by different criteria in patients with deep vein thrombosis. 178 30

In the present study 57 consecutive patients with a first episode of venographically proven deep vein thrombosis were investigated to evaluate the release of tissue-type plasminogen activator (t-PA) and of urokinase-type plasminogen activator (u-PA) in response to DDAVP stimulation as well as the resting plasminogen activator inhibitor (PAI) concentration, comparing this to the results obtained in 66 similar patients with a clinical suspicion of thrombosis but with a normal venogram. All assays were performed without knowledge of the patient's status. Four patients in the deep vein thrombosis-group (7%) had an absent u-PA antigen response upon DDAVP infusion, while a normal response was observed in all control subjects. Patients and controls showed similar increases in t-PA antigen level upon DDAVP. High resting PAI antigen levels were encountered in 5 patients in the deep vein thrombosis-group (9%) and in 6 subjects in the control group (9%). The results from this controlled study indicate that a defective release of u-PA may occur in patients with deep vein thrombosis and may have pathogenetic significance. Furthermore it is concluded that elevation of PAI levels cannot be considered as a specific risk factor for venous thrombosis.
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PMID:Deep vein thrombosis and fibrinolysis. Defective urokinase type plasminogen activator release. 179 91

The incidence of deep vein thrombosis (DVT) and pulmonary embolism was studied prospectively in patients undergoing elective total hip replacement. 96 patients were randomly allocated to receive either low molecular weight heparin (LMWH) or unfractionated heparin (UFH). All patients had bilateral phlebography and pulmonary perfusion/ventilation scintigraphy 10-12 days after surgery. The following fibrinolytic variables were analysed in plasma and related to thromboembolism: tissue plasminogen activator (t-PA) activity, t-PA antigen (t-PA Ag), plasminogen activator inhibitor (PAI-1) activity and PAI-1 antigen (PAI-1 Ag). No significant difference was found, regarding the fibrinolytic response to surgery, between patients treated with LMWH and UFH. The level of PAI-1 activity was significantly increased before operation in patients developing DVT as compared to non-DVT patients (p less than 0.03). Immediately after surgery and in the morning the first postoperative day the levels of PAI-1 activity, PAI-1 Ag and t-PA Ag were positively correlated to thromboembolism. PAI-1 activity was the only preoperative fibrinolytic variable correlated to thromboembolism.
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PMID:Impaired fibrinolysis and postoperative thromboembolism in orthopedic patients. 185 6

The administration of a radiolabelled monoclonal antibody against tissue plasminogen activator allows detection of areas with increased fibrinolytic activity, i.e. those with an active thrombotic lesion. Eight patients with phlebographically verified deep venous thrombosis were examined. At the time of immunoscintigraphy study they were examined receiving anticoagulant therapy. Some 75-85 MBq indium 111-labelled antibody were injected, and scintigrams were obtained after 30 min and after 24 h. The precise site of the thrombus could not be visualized after 30 min due to high background activity, whereas after 24 h it was detectable in all patients. The thrombus/background ratios achieved are twice as high as those observed in a human antifibrin antibody study. These preliminary data suggest a high sensitivity of our t-PA-specific antibody for the detection of active deep venous thrombosis in man, and our antibody seems to offer theoretical advantages over both platelet and fibrin-specific antibodies.
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PMID:Detection of deep venous thrombosis with indium 111-labelled monoclonal antibody against tissue plasminogen activator. 193 40

91 unrelated patients with idiopathic or familial deep vein thrombosis (DVT) and 72 (34 with DVT) relatives from 26 families were screened for hypofibrinolysis by measuring tissue plasminogen activator antigen (t-PA:Ag) after venous occlusion (VO) for 10 and 20 min and by measuring t-PA inhibitor activity (PAI) at rest. 21 healthy subjects served as controls. Defective release of t-PA:Ag was found in eight out of the 91 patients (9%). A partial family study of six of these eight patients was performed. This study included 10 family members with and 21 without DVT. A defective release of t-PA:Ag was found in 50% (5/10) of the family members with DVT, which is significantly more frequent than the 9% (8/91) prevalence in the unrelated patients (P less than 0.001). Furthermore, 24% (5/21) of asymptomatic members of these families also had defective release of t-PA:Ag. In the 18 families where the propositus had a normal level of t-PA:Ag, none of the 24 studied family members with DVT had defective release of t-PA:Ag. In contrast to the defective release of t-PA:Ag, increased basal level of PAI did not show familial clustering. In conclusion, low release of t-PA during VO shows familial clustering in a proportion of the cases.
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PMID:Familial clustering of defective release of t-PA. 195 88


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