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)

Acute and subacute deep venous thrombosis can be followed by two serious complications: pulmonary embolism feared in the early stadium and the postthrombotic syndrome (PTS) as a late complication. After a lapse of months and years there might appear a complete or incomplete recanalization, but the valves of the veins will be destroyed. Therefore it is understandable to strive first an active therapy as thrombectomy or thrombolysis to remove thrombosis. There will be released a physiological tissue plasminogen activator from the endothelium of the vein increasing a local fibrinolytic activity. But it is not strong enough to reopen the occlusion within a few days. This is only possible adding exogenous activators as streptokinase, urokinase and recently rt-PA. Heparin is well known at low-dose subcutaneously for thrombosis prophylaxis. The high doses of heparin infusion intravenously with 30-40,000 units daily are used "therapeutically" inhibiting growth-promotion of the thrombus and reducing the incidence of pulmonary embolism markedly. In respect of a postthrombotic syndrome (oedema, leg ulcers) it needs the evaluation of the early and follow up late results and the analysis of efficiency and risk of the two models of treatment. It was necessary comparing the success rate of reopening of the occluded veins after some days and follow up 5 or 6 years in clinical studies. The reopening rate in thrombolysis was about 3 times higher than in heparin therapy. But in contrast bleeding was 3 times lower in heparin therapy. For the long term follow up, physical examination, doppler-sonography phlebodynamometry and vein occlusion plethysmography were assessed. The acute intervention, regarding treatment, turned out to be the crucial prognostic parameter. Syndromes and clinical findings did indeed correlate quite well with the outcome of fibrinolytic treatment. Postthrombotic syndrome was rare in cases with complete patency. In cases where patency was only partially or not at all achieved, postthrombotic syndrome was present to a higher degree the more central and the more extensive the remaining thrombus was. In deep venous thrombosis of the lower extremity thrombolytic therapy is recommended mostly to younger patients with acute, the popliteal and the femoral vein including thrombosis, except of contraindications. More over in each of an individual case it has to be decided whether the aggressive or conservative therapy is to prefer.
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PMID:[The treatment of deep venous thrombosis. Thrombolysis vs heparin]. 209 22

The effect of purified human activated protein C (APC) on fibrinolysis was studied by using in vitro clot lysis techniques. Clots were formed from citrated blood or plasma (supplemented with 125I-labeled fibrinogen) by adding thrombin and Ca(2+)-ions; lysis of the clots was achieved by the addition of tissue-type plasminogen activator before clot formation. The gradual release of labeled fibrin degradation products from the clot into the supernatant was taken as a measure for the lysis rate. It was demonstrated that the acceleration of clot lysis by APC added before clot formation depends on the presence of Protein S, Ca(2+)-ions and phospholipids. These observations suggest a role of APC as anticoagulant in clot lysis, since the cofactors for the expression of its anticoagulant and profibrinolytic effect are very similar. Indeed, we could demonstrate that the profibrinolytic effect of APC in vitro is associated with reduction of thrombin generation through the coagulation cascade by inactivation of factor VIIIa and factor Va. For instance, APC did not accelerate the lysis of factor X deficient blood clots. More generally, thrombin generation was associated with retarded fibrinolysis in vitro. Consequently anticoagulants such as APC or Heparin are profibrinolytic, whereas pro-coagulants such as phospholipids (in cell-free plasma) inhibit fibrinolysis through the generation of thrombin. Thrombin thus plays a crucial role as a link between coagulation and fibrinolysis. As thrombin is able to inhibit the lysis of blood and plasma clots, and not of purified fibrin clots, we hypothesize that thrombin inhibits lysis through an as yet unidentified mediator in plasma.
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PMID:Protein C and fibrinolysis: a link between coagulation and fibrinolysis. 210 14

Two in vitro models of coronary thrombolysis in man, i.e. dislodgement of thrombi formed from non-anticoagulated human blood, either by (i) shear-stress or (ii) interaction of platelets with type I collagen fibre, were studied. Heparinization (1 U/ml) of blood prior to thrombus formation by (i) strongly inhibited spontaneous dislodgement (P less than 0.0001). Heparin (1 U/ml), when added with streptokinase (SK) or tissue-type plasminogen activator (rt-PA) prior to thrombus formation, considerably delayed thrombolysis. Furthermore, thrombolysis occurred much earlier when thrombi were perfused with SK or rt-PA in native than in heparinized blood. Heparin inhibited binding of 125I-rt-PA (17%, P less than 0.02) and plasminogen (88%, P less than 0.0005) to platelets activated by ADP in citrated platelet-rich plasma. We conclude that heparin interferes with the fibrinolytic system at the surface of activated platelets. Our findings suggest that heparin administration prior to thrombolytic therapy for acute myocardial infarction should be questioned.
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PMID:Heparin inhibits spontaneous thrombolysis and the thrombolytic effect of both streptokinase and tissue-type plasminogen activator. An in vitro study of the dislodgement of platelet-rich thrombi formed from native blood. 210 72

Heparin stimulates the activity of tissue plasminogen activator (t-PA) and binds to t-PA. To study this interaction, a complex between t-PA and N-acetylated heparin was formed and then linked to Sepharose. This procedure selectively links the t-PA to the column because the acetylated heparin has no free amino groups. The procedure also protects the heparin-binding site(s) on the enzyme during coupling to the matrix. The t-PA column separates heparin into two fractions, one with low affinity for t-PA and one with high affinity. Both fractions of heparin effectively accelerate inactivation of thrombin by antithrombin III. However, the fractions differ in their ability to stimulate t-PA: the low-affinity heparin has no effect on the activity of t-PA, whereas the high-affinity heparin enhances this activity. These heparin fractions will be useful in characterizing the biochemical basis and physiological consequences of the heparin--t-PA interaction.
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PMID:Fractionation of heparin by chromatography on a tissue plasminogen activator-Sepharose column. 210 84

The severity of the infarct-related residual coronary stenosis after spontaneous or therapeutic thrombolysis was quantitatively assessed in 91 patients with an acute myocardial infarction who were allocated to treatment in the acute stage with either a thrombolytic agent (100 mg of recombinant tissue-type plasminogen activator given over 3 h, 49 patients) or a placebo (42 patients). Heparin and aspirin were given to both groups until angiography was performed. Digital subtracted images of the infarct-related coronary vessel were obtained 10 to 14 days after hospital admission and were subsequently analyzed with the use of a computer-assisted coronary stenosis measurement system. Neither treatment group differed significantly in age, gender or location of the culprit coronary lesion. Median values (90% range) in the thrombolysis and control groups were, respectively, 1.95 (0.9 to 5.3) mm versus 1.7 (0.9 to 3.4) mm for stenosis length; 1.4 (0.8 to 2.7) mm versus 1.4 (0.9 to 1.8) mm for minimal luminal diameter; 57% (36% to 75%) versus 58% (44% to 71%) for diameter obstruction; 82% (59% to 95%) versus 82% (68% to 92%) for geometric area obstruction; and 78% (58% to 91%) versus 79% (66% to 90%) for densitometric area obstruction. The difference between the two groups was not statistically significant for any of these measurements. Thus, in this study no significant differences in anatomy or severity of residual coronary stenosis could be demonstrated at 10 to 14 days after an acute myocardial infarction in patients with a recanalized infarct-related vessel, whether or not thrombolytic therapy was given on admission. These results indicate that with effective antithrombotic treatment, gradual endogenous fibrinolysis or more rapid lysis induced by the infusion of a thrombolytic agent results in a similar infarct-related coronary lesion at the time of hospital discharge.
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PMID:Angiographic assessment of the infarct-related residual coronary stenosis after spontaneous or therapeutic thrombolysis. 212 5

Thrombolytic therapy has become an established procedure in patients with acute myocardial infarction (AMI). However, the aftercare of such patients is still uncertain. A meta-analysis of twenty trials of intravenous or subcutaneous heparin in AMI performed during the prethrombolysis period indicated a significant reduction in mortality, reinfarction, and stroke in treated patients. More recently, a study (SCATI) aimed at investigating the clinical effects of subcutaneous heparin (12.500 U two times daily) in the setting of thrombolytic therapeutical strategy in AMI, showed a lower in-hospital mortality, a trend towards lesser transient ischemic episodes in patients given streptokinase, and no difference in recurrent infarction rate. Ventricular thrombi were markedly reduced by heparin. Anti-platelet drugs were not permitted in the SCATI. In both GISSI 2 (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico) and International tissue plasminogen activator/streptokinase trials, aspirin was a recommended treatment, and subcutaneous heparin was randomized. No difference in mortality was noted in patients given heparin. In GISSI 2 recurrent ischemic episodes were also similar in treated and control groups, whereas embolic events were reduced by heparin. Major bleedings were rare in all trials. In conclusion, subcutaneous heparin is beneficial in AMI: however, the association with aspirin does not add consistent benefits. Heparin is effective in preventing thrombus formation and embolic complications - such effects are not shared by aspirin.
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PMID:Heparin in acute myocardial infarction. 215 Jun 62

Coronary thrombolysis revolutionized the treatment of acute myocardial infarction. Most of the experience was obtained with intravenous use of streptokinase and tissue-type plasminogen activator, the latter being superior to streptokinase in regard to coronary recanalization. Numerous other promising thrombolytic agents are being investigated. Both streptokinase and tissue-type plasminogen activator decreased mortality in large trials; comparison studies in terms of efficacy are presently being performed (GISSI 2). Aspirin is an important adjunct to thrombolytic therapy; it decreased mortality by itself (ISIS 2). Heparin is conventionally used together with thrombolysis. Its efficacy is under study (GISSI 2). Intracranial hemorrhage is the most devastating complication of thrombolysis. With the present dosage regimens, the incidence is approximately 0.5%. Percutaneous transluminal coronary angioplasty in conjunction with thrombolysis accomplished frequent and persistent recanalization of the infarct artery with low mortality, including high risk patients. The TIMI IIB study demonstrated that the results of a "conservative strategy" with aggressive management of recurrent ischemic events were comparable to those of an "invasive strategy." Subgroup analysis should, however, be awaited. High risk patients with low ejection fraction or with shock benefit by early mechanical coronary recanalization. The role of thrombolysis in the "late" stage of transmural myocardial infarction or in the acute ischemic syndrome (unstable angina/non-Q-wave myocardial infarction) is unclear and presently under investigation.
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PMID:Reperfusion therapy in acute myocardial infarction: present status and controversy. 219 Jul 22

We studied blood coagulation and fibrinolysis in 19 patients during surgery with cardiopulmonary bypass (CPB). CPB was performed with a rotating pump and a membrane oxygenator. Heparinization was achieved with heparin 3 mg.kg-1 and the ACT value was kept above 400 seconds throughout the CPB. Heparin was neutralized by protamine at a ratio of 1:1-1.5 of the total amount of heparin. Blood was collected four times from an indwelling arterial line. We obtained the first sample immediately after induction of anesthesia, the second sample before heparinization, the third sample before protamine administration, and the fourth sample at the end of the operation. FPA, FPB beta 15-42, alpha 2PI-Pl-C, D-dimer, and the t-PA activity were measured. A statistically significant elevation of FPA was observed during the operation. FPB beta 15-42, alpha 2PI-Pl-C, and the D-dimer rose significantly immediately after the beginning of the CPB and these elevations continued until the end of the operation. The t-PA activity was elevated significantly only during the CPB. In conclusion, the t-PA is released from the endothelial cells during CPB by some undetermined mechanism (primary fibrinolysis). Then, plasmin is generated by the t-PA and this dissolves the fibrin clots formed by thrombin before the beginning of the CPB (secondary fibrinolysis). Enhanced fibrinolytic activity before and after the CPB is physiological secondary fibrinolysis.
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PMID:[Increased fibrinolytic activity during surgery with cardiopulmonary bypass]. 238 94

The requirement of heparin in experimental coronary thrombolysis induced by tissue-type plasminogen activator (t-PA) was studied in closed-chest dogs with one hour old coronary thrombi and compared with that in urokinase (UK)-induced coronary thrombolysis. Animals were divided into 5 treatment groups as follows: group 1 received intracoronary t-PA alone (1,000 IU/kg/min; n = 5), and if thrombolysis was not induced within 40 to 50 min, dogs then received an intravenous injection of heparin (300 U/kg) plus intracoronary t-PA; group 2 received intravenous heparin at first, and if thrombolysis was not induced within 10 min, dogs subsequently received intracoronary t-PA (n = 5); group 3 also received intravenous heparin at first, and if thrombolysis was not induced within 10 min, dogs subsequently received t-PA but intravenously, as compared with the groups administered by the intracoronary route (n = 6); group 4 received intracoronary UK alone (1,000 IU/kg/min; n = 6); group 5 received intravenous heparin at first, and if thrombolysis was not induced within 10 min, dogs subsequently received intracoronary UK (n = 5). Thrombolysis was confirmed angiographically. In group I, coronary thrombolysis could not be induced within 44 +/- 4 min by intracoronary t-PA alone, but it occurred in 8 +/- 4 min when administered in combination with heparin in all dogs. Heparin alone failed to elicit reperfusion within 10 min in group 2, 3 and 5. t-PA, however, induced successful reperfusion in 16 +/- 5 min (group 2) and in 23 +/- 6 min (group 3), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Heparin requirement in tissue-type plasminogen activator-induced experimental coronary thrombolysis: comparison with urokinase-induced coronary thrombolysis. 244 Oct 82

The activity of tissue plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) is stimulated by heparin. Heparin binds tightly to t-PA, u-PA, and plasminogen and decreases the usual stimulatory effect of fibrin on t-PA activity. In the present study we have found that low molecular weight heparin (LMW-heparin) preparations obtained by nitrous acid depolymerization or heparinase treatment of standard heparin have different properties with respect to their interaction with the fibrinolytic system. LMW-heparin prepared by either method does not stimulate plasmin formation by t-PA. However, these preparations of heparin still efficiently accelerate the inhibition of thrombin by antithrombin III. Binding data show that LMW-heparin does not bind t-PA and Glu-plasminogen and only binds very weakly to Lys-plasminogen. These results illustrate that it is possible to selectively destroy the fibrinolytic stimulating properties of heparin while leaving the classical anticoagulant characteristics intact.
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PMID:Anticoagulant low molecular weight heparin does not enhance the activation of plasminogen by tissue plasminogen activator. 250 19


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