Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although heparin is often given as an adjunct to tissue plasminogen activator (t-PA), the effect of heparin on t-PA induced fibrin(ogen)olysis is controversial. To address this controversy, we examined the effects of standard and low molecular weight heparin (enoxaparine) on both t-PA induced clot lysis and t-PA mediated fibrinogenolysis in a human plasma system. Accordingly, 125I-labeled fibrin clots were incubated in t-PA containing citrated plasma in the presence or absence of these glycosaminoglycans, and the extent of thrombolysis was determined by measuring residual radioactivity of the clots, while B beta 1-42 levels were used as a specific index of fibrinogenolysis. Over a wide range of t-PA concentrations (0.1 to 1.6 micrograms/ml), neither heparin nor enoxaparine influences either t-PA induced clot lysis or t-PA mediated B beta 1-42 generation. These findings suggest that either agent could be used as an adjunct to t-PA without compromising either the thrombolytic potential of t-PA or its clot-selectivity.
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PMID:Standard and low molecular weight heparin have no effect on tissue plasminogen activator induced plasma clot lysis or fibrinogenolysis. 165 68

We examined the effects of polysaccharides on t-PA mediated plasminogen activation using single-chain tissue plasminogen activator (sct-PA) and two-chain tissue plasminogen activator (tct-PA). Unfractionated heparin, low molecular weight heparin (LMW heparin) and dextran sulfates enhanced the activation rate of plasminogen by sct-PA about three-fold to six-fold. Chondroitin sulfate C did not enhance the activation. The activation of plasminogen by tct-PA was slightly enhanced by unfractionated heparin, but not by other polysaccharides. Conversion of sct-PA to tct-PA was not stimulated by polysaccharides. SDS-PAGE showed no enhancement of the conversion from sct-PA to tct-PA by plasmin in the presence of polysaccharides. However, the enhancement of sct-PA mediated activation of plasminogen by unfractionated heparin, LMW heparin and dextran sulfates in the presence of aprotinin was shown with SDS-PAGE. It was suggested that unfractionated heparin, LMW heparin and dextran sulfates form complex with sct-PA and plasminogen, and stimulate the conversion of sct-PA to tct-PA.
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PMID:The effects of polysaccharides on plasminogen activation by single chain-and two chain-tissue plasminogen activator. 165

Human endothelial cells (EC) assemble plasmin-generating proteins on their surface. We have previously identified an EC membrane protein (Mr approximately 40,000) which specifically binds tissue plasminogen activator (t-PA) but not urokinase (Hajjar, K.A., and Hamel, N. M. (1990) J. Biol. Chem. 265, 2908-2916). In the present study, t-PA receptor protein (t-PA-R) was purified to apparent homogeneity from a detergent extract of human placental tissue by diisopropyl fluorophosphate-t-PA affinity chromatography and preparative gel electrophoresis. In a solid phase binding assay wells coated with t-PA-R bound both 125I-t-PA and 125I-Lys-plasminogen (PLG), but not 125I-urokinase in a specific, reversible, and noncompetitive fashion. Binding of 125I-Lys-PLG, but not 125I-t-PA, to t-PA-R was 80% inhibited by a 20-100-fold molar excess of the PLG-like lipoprotein(a), or by the lysine analog, epsilon-aminocaproic acid (50 mM). A polyclonal anti-t-PA-R antibody inhibited 66 and 79% of the specific 125I-t-PA and 125I-Lys-PLG binding, respectively, to EC monolayers. Biosynthetically labeled 40-kDa protein coprecipitated with t-PA- or Lys-PLG-Sepharose beads, but not with unconjugated Sepharose. In a functional assay, t-PA associated with immobilized t-PA-R generated 6.4 times more plasmin than an equivalent amount of t-PA in the fluid phase. These results suggest that t-PA-R can bind both t-PA and Lys-PLG in a manner that mimics the EC surface. This protein may play a role in modulating plasmin generation on cell surfaces.
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PMID:The endothelial cell tissue plasminogen activator receptor. Specific interaction with plasminogen. 165 83

The effect of Escherichia coli strains isolated from blood and cerebrospinal fluid of septic infants on plasminogen activation was studied. These strains typically carry a filamentous surface protein, S fimbria, that has formerly been shown to bind to endothelial cells and interact with plasminogen. The bacteria effectively promoted plasminogen activation by tissue plasminogen activator (t-PA) which was inhibited by epsilon-aminocaproic acid. A recombinant strain expressing S fimbriae accelerated t-PA-catalyzed plasminogen activation to a similar extent as did the wild-type strains whereas the nonfimbriate recipient strain had no effect. After incubation with t-PA and plasminogen, the S-fimbriate strain displayed bacterium-bound plasmin activity whereas the nonfimbriate strain did not. Bacterium-associated plasmin generation was also observed with a strain expressing mutagenized S fimbriae that lack the cell-binding subunit SfaS but not with a strain lacking the major subunit SfaA. Both t-PA and plasminogen bound to purified S fimbriae in a lysine-dependent manner and purified S fimbriae accelerated t-PA-catalyzed plasminogen activation. The results indicate that E. coli S fimbriae form a complex with t-PA and plasminogen which enhances the rate of plasminogen activation and generates bacterium-bound plasmin. This may promote bacterial invasion and persistence in tissues and contribute to the systemic activation of fibrinolysis in septicaemia.
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PMID:Enhancement of tissue plasminogen activator-catalyzed plasminogen activation by Escherichia coli S fimbriae associated with neonatal septicaemia and meningitis. 167 56

Thrombolytic therapy is likely to be effective in some patients with stroke, but further improvements may require combination treatment with neuroprotective agents that can be given rapidly with relative safety. We tested the effects of tissue plasminogen activator (t-PA) with the glutamate antagonist MK-801 or the calcium channel blocker nimodipine in an embolic stroke model. We found that MK-801, followed by t-PA, was more effective than t-PA alone in reducing neurologic damage. Nimodipine plus t-PA was not better than t-PA alone. Combined glutamate antagonist and thrombolytic therapy may provide increased efficacy and safety for stroke treatment.
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PMID:Tissue plasminogen activator plus glutamate antagonist improves outcome after embolic stroke. 168 57

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

To improve the efficacy of plasminogen activators, we produced a monoclonal antibody (RWR) that inhibits human alpha 2-antiplasmin (alpha 2AP). In addition to inhibiting alpha 2AP in plasma, RWR binds to and inhibits fibrin cross-linked alpha 2AP and reproduces the "spontaneous" clot lysis that is the hallmark of human alpha 2AP deficiency. By inhibiting the inactivation of plasmin by alpha 2AP, RWR interacts synergistically with plasminogen activators to increase the potency (for 50% clot lysis) of urokinase by 80-fold, tissue plasminogen activator by 27-fold, and streptokinase by 20-fold. Yet, for a given amount of fibrinolysis, the combination of RWR and lower doses of plasminogen activator leads to less fibrinogen consumption than is obtained with higher, equipotent doses of plasminogen activator alone. These results suggest a strategy for increasing the efficacy of plasminogen activators. More generally, this approach to amplifying enzymatic activity by immunoneutralizing an inhibitor may be useful in other biologic processes that are rigidly governed by inhibitors.
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PMID:Synergistic fibrinolysis: combined effects of plasminogen activators and an antibody that inhibits alpha 2-antiplasmin. 168 60

Explants from a glioblastoma multiforme were maintained for 4 weeks in a three-dimensional Gelfoam matrix culture in order to study the synthesis of alpha 2-antiplasmin (alpha 2AP), alpha 2-macroglobulin (alpha 2M), plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator (t-PA). Since the organ culture system promotes cellular differentiation in gliomas with increasing time in vitro, secretion of the proteinase inhibitors and t-PA was examined at weekly intervals. Increased immunohistochemical staining for glial fibrillary acidic protein, a marker of astroglial differentiation, was observed in the explants with advancing time in culture. The proteinase inhibitors alpha 2AP and alpha 2M were secreted into the medium in all 4 weeks, while PAI-1 was detected at significant concentrations by an enzyme-linked immunosorbent assay (ELISA) in Weeks 3 and 4 only. The quantity of each inhibitor secreted into fresh medium during a 24-hour interval increased with the age of the tumor explants in the Gelfoam culture system. At no time was a sensitive ELISA able to detect t-PA in the culture medium. This study demonstrates that glioblastoma multiforme cells in primary organ culture can secrete three major fibrinolysis proteinase inhibitors. The appearance of PAI-1 only after extensive culturing of the explants suggests a possible correlation with neoplastic astroglial maturation.
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PMID:Secretion of alpha 2-macroglobulin, alpha 2-antiplasmin, and plasminogen activator inhibitor-1 by glioblastoma multiforme in primary organ culture. 169 91

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

Patients with unstable angina pectoris (UAP; n = 20) and acute myocardial infarction (AMI; n = 34) were studied in the acute phase of ischaemic heart disease. We found significantly higher levels of thrombin-antithrombin-III (TAT) complexes, lower levels of systemic tissue plasminogen activator (t-PA) activity, and higher levels of plasminogen activator inhibitor (PAI) activity in the AMI patients compared to the UAP patients. In contrast to these specific changes, general acute phase reactants such as C-reactive protein, fibrinogen and von Willebrand factor did not differ significantly between the two groups. Studies of the relationship between coagulation (TAT-complexes) and fibrinolysis data revealed a significant positive correlation between plasma antigen concentrations of TAT-complexes and t-PA (P less than 0.02), and between TAT-complexes and PAI-I (P less than 0.002). These observations indicate a common pathophysiological mechanism underlying the changes in coagulation and fibrinolysis, suggesting that coagulation activity and t-PA-related fibrinolysis are interrelated processes in vivo, and probably take place at the level of the endothelial cell.
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PMID:Interrelationship between coagulant activity and tissue-type plasminogen activator (t-PA) system in acute ischaemic heart disease. Possible role of the endothelium. 170 58


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