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)

In order to find out which hemostasis parameters would have the predictive value for the development of preeclampsia, modified antithrombin III (ATM, representative of the antithrombin III-serine esterase complex), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), beta-thromboglobulin (BTG), antithrombin III (AT III), fibrinogen, fibrin(ogen) degradation product (FDP), FDP D-dimer and euglobulin lysis time (ELT) were measured in 20 normal non-pregnant women, 21 normal pregnant women, 6 high-risk pregnant women, 14 preeclampsia pregnant women, and 5 patients with disseminated intravascular coagulation (DIC). Only tPA and AT III were found significantly different between the preeclampsia and the normal or high-risk pregnant women: tPA was found progressively and significantly increased from the normal pregnant, to the high-risk pregnant, then to the preeclampsia women (p less than 0.05). AT III was significantly lower in the preeclampsia than in the normal pregnant (p = 0.0001) or in the high-risk pregnant women (p = 0.002). In the 2nd trimester, tPA, PAI, fibrinogen and FDP were significantly higher, and AT III was significantly lower in the preeclampsia than in the normal pregnant women, whereas in the 3rd trimester, tPA and AT III were significantly higher or lower, respectively, in the preeclampsia than in the normal pregnant women. No significant difference of ATM could be found between the preeclampsia and the normal or high-risk pregnant women. From the present study, we suggest that tPA and AT III would be used as the main predictors, and FDP and D-dimer as the complementary predictors for the development of preeclampsia and should be detected in the normal or high-risk pregnant women.
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PMID:The predictive value of the hemostasis parameters in the development of preeclampsia. 162 Dec 41

The effects of physical training on hemostatic parameters were evaluated in 56 postmyocardial infarction (MI) patients before and after one month of systematic physical training and in 30 control post-MI patients, who did not undergo such training. There were no significant changes in prothrombin time (PT) and alpha 1-antitrypsin (alpha 1AT) at the beginning and end of the study in either group. Levels of fibrinogen, Factor VIII: C (VIII:C) and von Wildebrand antigen (vWf:Ag), and activities of ATIII and plasminogen (Plg) were significantly decreased in the group with physical training (p less than 0.05), while values were unchanged in the control group. Hematocrit, platelet counts, and alpha 2-plasmin inhibitor (alpha 2PI) activities also decreased in the physical training group (p less than 0.05). In contrast, these variables increased in the control group (p less than 0.05). Activated partial thromboplastin time (aPTT) tended to be prolonged in the group with physical training, while it was shortened in the control group. In a subset of 20 patients with physical training, resting levels of plasmin-alpha 2PI complex (PIC), thrombin-antithrombin III complex (TAT), protein-C (P-C:Ag), plasminogen activator inhibitor-1 (PAI-1), VII:C, and P-C activities had significantly decreased after one month of physical training (p less than 0.05), although tissue plasminogen activator activities remained unchanged. Physical training appeared to suppress coagulability as indicated by the decrease in fibrinogen, VIII:C, vWf:Ag, VII:C, and TAT, and prolongation of aPTT. The decrease in plasminogen, t-PA:Ag, alpha 2PI, PAI-1, and PIC after physical training may result from the decreased coagulability. In conclusion, physical training appears to induce a suppression of the coagulation system in patients in the recovery phase of MI.
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PMID:Blood coagulability and fibrinolytic activity before and after physical training during the recovery phase of acute myocardial infarction. 162 56

Twenty-five patients with different stages of liver cirrhosis were evaluated with regard to the degree of liver synthesis reduction, the extent of the decrease of blood coagulation factors and/or alterations of the fibrinolytic system. For the assessment of the residual level of liver synthesis we used pseudo-cholinesterase and serum albumin as references. We did not find a correlation between these quantities and antithrombin III or fibrinogen, but highly significant inverse correlations with tissue plasminogen activator activity and D-dimer concentration. We found considerable alterations in the concentrations of the coagulation and fibrinolysis factors, with the exception of fibrinogen and plasminogen activator inhibitor. Significant increases were seen for thrombin-antithrombin III complex, tissue plasminogen activator activity and D-dimer, while significant decreases were seen for antithrombin III and alpha 2-antiplasmin, compared with a group of healthy volunteers. In the group of patients with liver cirrhosis and reduced liver synthesis, as documented by lowered pseudo-cholinesterase and serum albumin, the reduction of both antithrombin III and alpha 2-antiplasmin was most prominent. Intravascular coagulation was negligibly small. For the fibrinolytic system, the increase of tissue plasminogen activator, the decrease of the fibrinolysis inhibitor (alpha 2-antiplasmin) and the elevated D-dimer concentration seem to be important. These results suggest an acceleration of fibrinolysis and the prolonged presence of cross-linked fibrin degradation products.
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PMID:The extent of diffuse intravascular coagulation and fibrinolysis in patients with liver cirrhosis. 162 24

Release of tissue plasminogen activator (t-PA) and its interaction with plasma protease inhibitors were studied in two patients with massive defibrination, one after electroshock and soft tissue injury and the other after complicated labor; both had very severe hemorrhage. Large quantities of free t-PA were present in the circulation for several hours. Complexes of t-PA with plasminogen activator inhibitor 1 (PAI-1), alpha 2-macroglobulin and C1-inhibitor were also observed. PAI-1 antigen rose dramatically in both patients, and complexes of t-PA with PAI-1 rose rapidly during the period of observation. In contrast, the complexes of t-PA with alpha 2-macroglobulin and C1-inhibitor, present initially, persisted for short periods only and disappeared when free t-PA disappeared from the circulation. Plasmin was generated initially, as indicated by the presence of plasmin-alpha 2-antiplasmin complexes. Plasma concentrations of alpha 2-macroglobulin, C1-inhibitor, antithrombin III, and alpha 2-antiplasmin were severely depleted initially, but rapidly returned to normal. The observations demonstrate that there is a major release of t-PA in such defibrinating patients, that there is a role for protease inhibitors other than PAI-1 in the regulation of endogenous t-PA, and indicate the great rapidity with which such free t-PA is complexed and cleared.
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PMID:Complexing of tissue plasminogen activator with PAI-1, alpha 2-macroglobulin, and C1-inhibitor: studies in patients with defibrination and a fibrinolytic state after electroshock or complicated labor. 168 22

Twenty-nine patients with acute myocardial infarction were given recombinant tissue plasminogen activator (tPA) within 6 hr after onset of chest pain (mean: 3.2 hr) with a total dose of 100mg iv drip given within 3hr for thrombolytic therapy. Serial determinations of total FDP, FDP D-Dimer (specific for FbDP), fibrinogen (Fg), PT, APTT, reptilase time (RT), plasminogen, alpha 2-antiplasmin (AAP), euglobulin lysis time (ELT) and antithrombin III (ATIII) were performed before and 1, 2, 4, 6, 12, 24, 48 hr after initiation of tPA injection in the 29 patients in order to evaluate the hemostatic changes after thrombolytic therapy. Decreases of plasminogen, Fg, AAP & ELT were found from 1 hr after therapy and persisted to 24, 12, 24 & 12 hr, respectively, with the maximum decrease usually between 1-4 hr. Increases of FDP, FDP D-dimer, PT, APTT & RT were found from 1, 1, 2, 1 & 1 hr after therapy, respectively, and sustained to 24, 12, 12, 24 & 12 hr, respectively, with maximum increases between 1-4 hr. No significant changes of ATIII were noted during the 48-hr study-period. 4 of these 29 patients (13.79%) had the complication of localized bleeding, 1 of them needed 1 unit of packed red blood cell transfusion. All thrombolysis-related changes recovered within 24 hr after tPA therapy. No parameter we have studied so far could be used for the prediction of the possibility of coronary patency after tPA therapy. But markedly elevated FDP was found to be associated with high risk of bleeding complication. As the coagulation changes persist for 24 hr or longer, careful monitoring of the coagulation tests and close observation of clinical bleeding signs up to 48 hr are necessary in patients treated with tPA.
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PMID:Serial thrombolysis-related changes after thrombolytic therapy with TPA in patients with acute myocardial infarction. 169 93

Disseminated thrombotic processes in the microcirculation are considered to be an important cause of multiple organ failure in septic patients. Fibrinolysis is one endogenous mechanism protecting the circulation from overwhelming thrombosis. Therefore, we looked for alterations of fibrinolytic parameters (tissue plasminogen activator (t-PA), tissue plasminogen activator inhibitor (PAI), D-dimer, euglobulin-clot-lysis-time (ECLT), plasminogen, alpha 2-antiplasmin) and of some coagulation parameters (prothrombin time, fibrinogen, platelets, antithrombin III, protein C, factor XII) in clearly defined septic patients and for the relations of these values to the severity of the disease (APACHE II-score). An increase in D-dimer and t-PA-antigen was registered in all patients, while factor XII and plasminogen were decreased, indicating an activated fibrinolysis. In contrast the systemic fibrinolytic capacity of the blood was strongly inhibited: t-PA-activity was not detectable, PAI-function was elevated, the ECLT was prolonged and alpha 2-antiplasmin was normal. Coagulation was moderately activated: the platelets, antithrombin III and protein C were decreased, the prothrombin time was prolonged and fibrinogen was normal. The changes in t-PA-antigen, PAI-function, factor XII, prothrombin time and antithrombin III were significantly related to the APACHE II-score of the patients. We conclude that the activation of coagulation is accompanied by an activation of fibrinolysis in the microcirculation, but that systemically the increased inhibitors of fibrinolysis (PAI, alpha 2-antiplasmin) induce a decrease of the fibrinolytic capacity of the blood. The severity of the disease determines the extent of the alterations.
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PMID:Activation and inhibition of fibrinolysis in septic patients in an internal intensive care unit. 169 55

Serine protease inhibitors ("serpins") are highly homologous proteins which inhibit selected "target" serine proteases by acting as a pseudo-substrate. Their specificity is primarily determined by the amino acid sequence around the carboxyl-terminally located reactive center (P1-P1'). In addition, the association rate constant between a serpin and a serine protease can be dramatically increased by non-protein cofactors, such as heparin in the case of thrombin inhibition by antithrombin III. In an attempt to alter the specificity of PAI-1 from an inhibitor of the fibrinolytic system to an inhibitor of coagulation, we replaced P1-P1' or P3 through P3' of the reactive center of PAI-1 by the corresponding residues of antithrombin III and assessed whether the mutant proteins, purified from lysates of transformed Escherichia coli cells, had acquired thrombin inhibitory properties. The experiments were performed in the presence and absence of vitronectin, a multifunctional protein which has been shown to bind PAI-1 in plasma and in the matrix of endothelial cells. The second-order rate constants for t-PA inhibition of "wild-type" PAI-1 and PAI P1-P1'ATIII, irrespective of the presence of vitronectin, were similar, whereas replacing P3-P3' resulted in a 40-fold decrease of the second-order rate constant towards t-PA, again independent of vitronectin. In the absence of vitronectin, reactivity of PAI-1 and its "antithrombin III-like" variants towards thrombin was slow; however, PAI-1 P3-P3' ATIII had a 10-fold higher k1 than wild-type PAI-1 (1.3 x 10(4) M-1 s-1 versus 1.1 x 10(3) M-1 s-1). In contrast, in the presence of vitronectin, PAI-1 and even more rapidly PAI-1 P3-P3'ATIII were found to be effective thrombin inhibitors, with k1 values of 2.2 x 10(5) M-1s-1 and 1.8 x 10(6) M-1 s-1, respectively. Thus, in the presence of vitronectin, PAI-1 P3-P3'ATIII displays a 3-fold higher k1 with thrombin than with t-PA. It is shown that vitronectin enhances, in a dose-dependent manner, the formation of sodium dodecyl sulfate-resistant complexes between PAI-1 or mutants thereof and thrombin. Therefore, vitronectin is the first protein described to function as a cofactor for serpin specificity. PAI-1 is proposed to be a versatile inhibitor which, in the presence of vitronectin, can modulate both coagulation and fibrinolysis.
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PMID:Alteration of serpin specificity by a protein cofactor. Vitronectin endows plasminogen activator inhibitor 1 with thrombin inhibitory properties. 169

Plasminogen activator inhibitor type 1 (PAI-1), the fast-acting inhibitor of tissue-type plasminogen activator (t-PA) and urokinase (u-PA), is a member of the serpin superfamily of proteins. Both in plasma and in the growth substratum of cultured endothelial cells, PAI-1 is associated with its binding protein vitronectin, resulting in a stabilization of active PAI-1. Recently, it has been demonstrated that the PAI-1-binding site on vitronectin is adjacent to a heparin-binding site (Preissner et al., 1990). Furthermore, it can be deduced that the amino acid residues, proposed to mediate heparin binding in the serpins antithrombin III and heparin cofactor II, are conserved in PAI-1. Consequently, here we have investigated whether PAI-1 also interacts with heparin. At pH 7.4, PAI-1 quantitatively binds to heparin-Sepharose and can be eluted with increasing [NaCl]. Binding of PAI-1 to heparin-Sepharose can be efficiently competed with heparin in solution (IC50, 7 microM). In the presence of heparin, the protease specificity of PAI-1 toward thrombin is substantially increased. This is shown by (i) quenching of thrombin activity of PAI-1 in the presence of heparin and (ii) induction of the formation of SDS-stable complexes between thrombin and PAI-1 by heparin. In a dose response curve, both effects reached a maximum at approximately 1 unit/mL and then diminished again upon further increasing the heparin concentration, strongly suggesting a template mechanism as an explanation for the observed effect. In contrast to vitronectin, heparin does not stabilize the active conformation of PAI-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Functional interaction of plasminogen activator inhibitor type 1 (PAI-1) and heparin. 170 36

Patients with systemic lupus erythematosus (SLE) have an increased risk of thrombosis and this is increased in the presence of antiphospholipid antibodies (APA). These APA are also associated with thrombosis in patients who do not have SLE. We compared haemostatic parameters in SLE patients with and without APA, and also compared patients who had APA but not SLE with healthy normal controls. No relationships between the natural anticoagulants, antithrombin III, heparin cofactor II, protein C and protein S, and the presence of APA were found. In the patients with SLE both tissue plasminogen activator antigen and plasminogen activator inhibitor (PAI) were increased, but these changes were not due to APA which had no effect on fibrinolysis in these patients. In the patients with APA who did not have SLE the fibrinolytic response to venous occlusion was reduced due to raised levels of PAI; similar changes have, however, been reported in some patients with idiopathic thrombosis.
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PMID:The fibrinolytic response to venous occlusion and the natural anticoagulants in patients with antiphospholipid antibodies both with and without systemic lupus erythematosus. 170 91

In disseminated intravascular coagulation (DIC) with acute promyelocytic leukemia (APL) in the absence of severe infection, marked fibrinolysis was noted in comparison with normal levels of antithrombin III, which is a major inhibitor of the coagulation system. Increased plasminogen activator inhibitor-1 (PAI-1) antigen levels in plasma from patients with septicemia decreased the ratio of the plasma clot lysis rate induced by an anti-alpha 2-plasmin inhibitor monoclonal antibody to the tissue-type plasminogen activator (t-PA) concentration. This decrease was not as prominent in plasma from patients with DIC, especially those with APL. To explore the character of PAI-1 in these plasmas, we measured the specific activity of PAI-1 by determining the ratio of active PAI-1 antigen to t-PA-unbound PAI-1 antigen. To calculate the amount of active PAI-1 antigen, the amount of t-PA/PAI-1 complex before and after the addition of a fixed amount of t-PA to the sample was measured by a sandwich solid-phase enzyme-linked immunosorbent assay using anti-PAI-1 and anti-t-PA monoclonal antibodies. The assay to measure total PAI-1 antigen used three monoclonal anti-PAI-1 antibodies and had similar sensitivities to free active, latent, vitronectin-bound and t-PA-bound PAI-1. The specific activity of PAI-1 decreased in patients with DIC (43.7% +/- 30.6%) and in DIC cases with APL (10.3% +/- 6.0%) in comparison to patients with septicemia (83.7% +/- 20.2%) or normal controls (85.8% +/- 27.3%). In DIC associated with APL, degraded forms of PAI-1 were detected in plasma by immunoblotting. These results suggest that a decrease in the specific activity of PAI-1 and an increase in secondary fibrinolysis result in a hyperfibrinolytic state in DIC patients with APL.
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PMID:The specific activity of plasminogen activator inhibitor-1 in disseminated intravascular coagulation with acute promyelocytic leukemia. 170 94


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