Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Medroxyprogesterone acetate (MPA), which is widely used clinically as an anticancer steroid preparation, is a very useful drug that seldom causes severe side effects such as bone marrow suppression, and can be dispensed at the outpatient clinic for an oral administration at home to the advantage of QOL. Recently however, there have been several reports suggesting its relationship with thrombosis. We measured t-PA, protein C, factor X, AT III, TAT, plasminogen, PIC, fibrinogen, and D-dimer in 11 patients with gynecologic malignancies who are treated with MPA (600 mg/day) and 11 controls. Then we examined the effects of the drug on blood coagulation and fibrinolytic activities. No changes in these parameters clearly suggested thrombogenesis in either group at this measurement or during the observation period (17 months at the maximum). The present study found no remarkable abnormalities in the blood coagulation and fibrinolytic activities. Thus, to avoid the use of MPA to patients at risk is considered to be the most important precaution for prevention of thrombosis.
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PMID:[Effect of high-dose medroxyprogesterone acetate on coagulative and fibrinolytic factors in patients with gynecological cancers]. 153 83

Epidermal growth factor (EGF) domains are found in many proteins, particularly those of the coagulation/fibrinolytic system. We and others have demonstrated that tissue plasminogen activator (t-PA) and prourokinase are modified by the attachment of fucose to equivalent threonine residues within their EGF domains. Factor XII and protein C each contain two EGF domains; in both proteins, the EGF domain nearest the N terminus has a threonine residue in a position homologous to that which is fucosylated in t-PA. In protein C, this site is 3 residues from the position of another post-translational modification, beta-hydroxylation of Asp-71. We isolated peptides containing these sites to determine, primarily by mass spectrometric analysis, the presence of O-linked fucose and/or beta-hydroxyaspartate. We found that factor XII is fully fucosylated at Thr-90. Protein C is unmodified at the equivalent site (Thr-68) and is completely beta-hydroxylated at Asp-71. It has been recently reported that the first EGF domain of human factor VII has O-linked fucose at the equivalent position (Ser-60) (Bjoern, S., Foster, D. C., Thim, L., Wiberg, F. C., Christensen, M., Komiyama, Y., Pedersen, A. H., and Kisiel, W. (1991) J. Biol. Chem. 266, 11051-11057), while it is unmodified at Asp-63 despite having the consensus sequence for beta-hydroxylation at the latter site. These observations raise the possibility that O-linked fucosylation and beta-hydroxylation of EGF domains are mutually exclusive post-translational modifications.
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PMID:O-linked fucose is present in the first epidermal growth factor domain of factor XII but not protein C. 154 94

This study examines the assumption that both the anticoagulant and fibrinolytic activity that follow the generation of thrombin induced by infusion of factor Xa/PCPS are due to generation of activated protein C. Untreated controls or animals given unrelated antibody were compared with animals pretreated with a specific monoclonal antibody to protein C (HPC4). Compared with untreated controls excess HPC4 substantially reduced the level of protein C activation as observed by protein C immunoblotting and enzyme-linked immunosorbent assay for antitrypsin/activated protein C complexes. Despite this, the anticoagulant activity as reflected by the decline of factors Va and VIIIa levels (as observed by coagulation assays and by factor V immunoblotting) was significantly greater than controls. The fibrinolytic activity (as observed by assays of tissue plasminogen activator, D-Dimer, alpha 2-antiplasmin) also was significantly greater than controls. We conclude that neutralization of the protein C anticoagulant system while resulting in a significantly more intense coagulant response to Xa/PCPS does not preclude inactivation of factors Va and VIIIa and the full expression of the fibrinolytic response. We conclude further that after thrombin generation in vivo, protein C activation is not a prerequisite for the promotion of the fibrinolytic response previously observed, and that the inactivation of factors Va/VIIIa may be mediated by enzymes other than activated protein C. The reduction in alpha 2-antiplasmin levels in association with increased tissue plasminogen activator activity suggests that plasmin is a likely candidate.
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PMID:Anticoagulant and fibrinolytic activities are promoted, not retarded, in vivo after thrombin generation in the presence of a monoclonal antibody that inhibits activation of protein C. 155 68

In a study of biological risk factors for sudden death in patients with coronary artery disease, 320 patients were, prospectively, recruited and followed-up over two years. None of the patients had heart failure or recent myocardial infarction. The following variables were recorded: previous acute myocardial infarction, hypertension, smoking habits, ventricular arrhythmia; the angiographic variables included: left ventricular ejection fraction, Jenkins' and mean atherosclerotic scores; lipid profile: cholesterol, triglycerides, high density lipoprotein cholesterol, low density lipoprotein cholesterol, apolipoproteins Al and B; hemostatic profile: fibrinogen, fibrinopeptide A, antithrombin III, factor VIII antigen, factor VIII coagulant, protein C, plasminogen, alpha 2-antiplasmin, euglobulin clot lysis time and tissue plasminogen activator before and after venous occlusion, tissue plasminogen activator inhibitor, platelet factor 4, beta-thromboglobulin. During the follow-up period, 12 of the patients died suddenly. In these patients, ejection fraction was lower: 49 +/- 16% versus 61 +/- 14% for the other patients (P less than 0.02), fibrinogen higher: 3.9 +/- 0.8 g/l versus 3.5 +/- 0.8 for the living patients (P less than 0.05) and protein C lower: 89 +/- 39% versus 111 +/- 39% (P = 0.06) for the other patients. In multivariate analysis: lower ejection fraction (P less than 0.008), older age (P less than 0.03) and lower protein C (P less than 0.01) were correlated with sudden death. Among the patients with coronary artery disease, the raised fibrinogen and the decreased protein C appeared to be risk factors for sudden cardiac death. These alterations reflected a prothrombotic state which might increase the ischemic risk, due to an acute thrombosis, leading to the fatal ventricular arrhythmia. Determination of these hemostatic variables might be a useful adjunct for assessment of the vital prognosis of patients with coronary artery disease, especially the risk of sudden death in addition to other known clinical, electrocardiographic, hemodynamic risk factors. This would also guide both the instigation of complementary investigations and appropriate therapy in such high risk group of patients.
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PMID:Biological risk factors for sudden death in patients with coronary artery disease and without heart failure. 156 56

We retrospectively evaluated the hemostatic system of 13 patients during implantation (2 to 35 days) of the Jarvik 7-70 total artificial heart (TAH). Although all patients were clinically manageable while on the TAH, 5 had excessive generalized bleeding. After the heart transplant procedure, 2 patients had neurological events and 1 patient, thrombosis of the leg. While the patients were supported by the TAH, the routine coagulation assays (prothrombin time, activated partial thromboplastin time, fibrinogen, factor assays, and platelet count) showed slight abnormalities but no correlation to hemorrhagic or thrombotic events. In contrast, plasma and cellular activation markers, which are highly sensitive and specific for hypercoagulability, fibrinolysis, or platelet activation, revealed activation in all patients. Most striking was the marked activation of the fibrinolytic system (p less than 0.05 to 0.001). Correlations of individual patient data compared with the average TAH group response could be made between excessive enhancement of fibrinolysis (increased D-dimer and tissue plasminogen activator and decreased plasminogen activator inhibitor) and bleeding. A hypercoagulable state (increased fibrinogen and thrombin-antithrombin complex and decreased antithrombin III and protein C), decreased fibrinolysis (decreased tissue plasminogen activator and D-dimer), activated platelets (increased thromboxane B2), or combinations of these were associated with thrombosis. The hemostatic activation returned to normal 1 day after removal of the TAH. These data suggest that the patient with a TAH requires more sophisticated laboratory monitoring and individualized treatment for excessive fibrinolysis, hypercoagulable state, or platelet activation to avoid thrombotic and hemorrhagic complications.
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PMID:Hemostatic abnormalities in total artificial heart patients as detected by specific blood markers. 157 Sep 81

Thrombin, the final enzyme of the coagulation system, also influences profibrinolytic activity by several mechanisms. These include cellular release of tissue plasminogen activator, activated protein C-induced fibrinolysis, and inactivation of plasminogen activator inhibitor, type 1 (PAI-1). In this report, the role of thrombin in the regulation of PAI-1 is investigated. Our studies demonstrate that thrombin inactivation of PAI-1 occurs via an enzymatic mechanism rather than an enzyme-inhibitor complex mechanism. Evidence to support this conclusion is: (1) concomitant analysis of PAI-1 and thrombin activities demonstrate decreased PAI-1 activity but no loss of thrombin activity; (2) no visible thrombin--PAI-1 complexes by SDS-PAGE analysis; and (3) lack of formation of 125I-thrombin-PAI-1 complexes. Thrombomodulin, a thrombin binding cofactor that modifies thrombin's functions, did not influence the inactivation of PAI-1 by thrombin. We propose that thrombin enzymatically inactivates PAI-1 without forming a stable enzyme-inhibitor complex. The reaction is not affected by thrombomodulin. Overall this reaction occurs so slowly that it is not physiologically relevant without some modifying factor(s).
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PMID:Thrombin and the thrombin-thrombomodulin complex interaction with plasminogen activator inhibitor type-1. 165 27

Monoclonal antibodies against thrombomodulin have become a useful means to study the structure and function of thrombomodulin. In this study, we used a monoclonal antibody against human thrombomodulin, named SZ-53, to investigate the function of thrombomodulin on the surface of cultured human umbilical vein endothelial cells. Preincubation of endothelial cells with SZ-53 before addition of thrombin not only inhibited thrombomodulin mediated activation of protein C, but also inhibited thrombin mediated release of t-PA and PGI2 from endothelial cells. The inhibitory effects depended on the concentration of SZ-53 IgG. According to our experimental results, we suggest that thrombomodulin on the surface of endothelial cells could participate in the regulation of thrombin mediated release of t-PA and PGI2 from these cells.
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PMID:A monoclonal antibody (SZ-53) against thrombomodulin inhibits thrombin-mediated release of t-PA and PGI2 from endothelial cells. 166 94

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

Fetomodulin is a surface marker protein of differentiated F9 embryonal carcinoma cells. Gene cloning has recently identified it as thrombomodulin which binds thrombin and proteolytically activates protein C. Activity assays and RNA blotting were adopted to analyze F9 cell differentiation with specific reference to another well-characterized marker, tissue plasminogen activator. Retinoic acid induced primitive endoderm differentiation of F9 cells and simultaneously activated tissue plasminogen activator synthesis. This differentiation, however, did not result in fetomodulin expression. When primitive endoderm cells were exposed to 1 mM dibutyryl cyclic AMP, the tissue plasminogen activator level rose further within 6 hr. In contrast, the cofactor activity of fetomodulin stayed below a detectable level for as long as 15 hr and then increased with time. Expression of the two marker proteins appeared to be regulated differently.
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PMID:Differential expression of fetomodulin and tissue plasminogen activator to characterize parietal endoderm differentiation of F9 embryonal carcinoma cells. 169 71

To explore mechanisms of coagulation activation in adenocarcinoma of the prostate, the occurrence and distribution of components of coagulation and fibrinolysis pathways in situ were studied by means of immunohistochemical techniques applied to frozen sections of fresh malignant and benign hyperplastic prostatic tissue obtained at transurethral resection. Fibrinogen was distributed throughout the perivascular and tumor connective tissue in both malignant and benign disease but was not present in adjacent areas of normal prostate. Antibodies specific for fibrin and D-dimer crosslink sites stained vascular endothelium focally in both malignant and benign tissues. Both neoplastic cells and benign hyperplastic glandular epithelial cells stained weakly and in a patchy distribution for tissue factor and focally for low-molecular-weight urokinase-type plasminogen activator. Focal staining of vascular endothelium was also observed for tissue plasminogen activator and plasmin-antiplasmin complex neoantigen. By contrast, no tissue staining was observed for factor VII, factor X, factor XIII "a" subunit, high-molecular-weight urokinase-type plasminogen activator, plasminogen activator inhibitors 1 to 3, protein C, and protein S. Thus, the similarity in findings between benign hyperplastic and neoplastic prostate tissue, the lack of either an intact tumor cell-associated coagulation pathway or fibrin formation, and the presence of fibrin on vascular endothelium are consistent with the concept that coagulation activation in prostatic cancer may not be due to a direct effect of the tumor cells on the clotting mechanism. Rather, such activation may be induced by a soluble tumor product that activates procoagulant activity on certain host (for example, vascular endothelial) cells. These findings, together with the lack of effect of warfarin anticoagulation on the clinical course of patients with prostatic cancer, contrast with findings in certain other tumor types and suggest that coagulation activation may not contribute to progression of adenocarcinoma of the prostate.
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PMID:Fibrin formation on vessel walls in hyperplastic and malignant prostate tissue. 170 19


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