Tissue-type plasminogen activator (t-PA) : physiological and clinical aspects
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The fibrinolytic properties of two molecular forms of extrinsic (tissue-type) plasminogen activator, purified from human melanoma cells in culture, were compared.One form, obtained under protection of aprotinin, consisted of a single polypeptide chain with M, = 72,000 while the other form, obtained without aprotinin, consisted of two polypeptide chains with M, = 30,000-40,000 each.The two forms had the same fibrinolytic activity (clot lysis time) in a purified system composed of fibrin and plasminogen, and both forms dissolved '261-fibrinogenlabeled plasma clots immersed in whole plasma at very similar rates.However, sodium dodecyl sulfate-gel electrophoresis revealed that '"I-labeled one-chain plasminogen activator was converted into a two-chain form during the lysis of a purified fibrin clot.Therefore, the kinetic parameters of the activation of native (NH2 terminus Glu) plasminogen were determined in a system containing aprotinin (1,000 kallikrein inhibitor units/ml), which prevented the conversion of the onechain form into the two-chain form.The rate of plasmin formation was measured by using '2SI-labeled plasminogen and by quantitation of the plasmin B-chain by sodium dodecyl sulfate-gel electrophoresis.In the presence of fibrin (1 mg/ml) one-chain plasminogen activator had an apparent Michaelis constant of 2.42 PM and a catalytic rate constant of 0.22 s-' corresponding to a second-order rate constant of 89 n"'s-'.These kinetic parameters for the two-chain form were 1.07 PM, 0.10 s" and 94 11"'s-l.In the absence of fibrin the apparent Michaelis constants were larger than 100 PM and the second-order rate constants 0.32 and 0.36 plasminogen activating properties of both molecular forms of plasminogen activator are similar.The two molecular forms adsorbed to a similar extent to purified fibrin clots: 50% binding occurred at a concentration of about 0.14 mg fibrin/ml.Plasma clots immersed in mixtures of whole human plasma and '261-labeled one-chain plasminogen activator (150 ng/ml) dissolved slowly (approximately 50% lysis in 5 h).Sodium dodecyl sulfate-gel electrophoresis revealed that during the fibrinolytic process the plasminogen activator bound to the fibrin clot consisted almost exclusively of a two-chain form, in contrast to the plasminogen activator in the surrounding plasma.This suggested that one-chain plasminogen activator is quickly converted to a two-chain form on the fibrin surface and therefore that physiological fibrinolysis induced by native one-chain plasminogen activator nevertheless occurs mainly via a two-chain derivative.However, at present this conversion does not seem to play a role in the regulation of fibrinolysis. *-ls-', respectively.These findings suggest that the Ondenoeksacties (project 80-85/3).The costs of
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BACKGROUND The fibrinolytic system is part of the defense against thrombotic and cardiovascular events, but so far no study has shown that clinical measurements of fibrinolytic key components such as tissue plasminogen activator (t-PA) or plasminogen activator inhibitor type 1 (PAI-1) have any predictive value beyond 3 years. METHODS AND RESULTS In 1983 through 1985, 213 consecutive patients with angina pectoris and angiographically verified coronary artery disease were sampled, and the mass concentration of t-PA and the activity of PAI-1 were measured in citrated plasma samples. At a mean follow-up time of 7 years, the all-cause mortality was checked. No patient was lost to follow-up. The data were analyzed by Cox regression, and t-PA mass concentration was found to be the only laboratory risk factor significantly related to mortality in all patients (P < .022) and also in the major subgroup (78% of all patients) subjected to coronary bypass surgery (P < .027). In the latter subgroup, body mass index was also related to mortality. CONCLUSIONS An increased mass concentration of t-PA is a new risk factor of long-term mortality in patients with angina pectoris and coronary artery stenosis. This paradoxical effect probably reflects increased t-PA levels attributable to enzyme inhibitor complex formation in subjects with increased plasma levels of t-PA inhibitors.
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Owing to various human activities, arsenic (As) concentrations have increased in lakes and other aquatic ecosystems around the world. This increase of As concentrations has become a concern because of the known toxic, carcinogenic, mutagenic, and teratogenic effects of As on ecosystem organisms and humans. Understanding the biogeochemistry of As in the aquatic environment is therefore a topic of fundamental interest. This study presents a review of the major biogeochemical processes controlling the concentration of solid and dissolved As in freshwater lakes. These processes are dynamic and vary both temporally and spatially because of a complex relationship between microbial activity and various geochemical processes. Particularly the oxidation of As sulphides and the reduction of Fe and Mn oxyhydroxides at the sediment–water interface play an important role in the mobilization of As. These and other interactions among the various biogeochemical processes are synthesized in a conceptual model of As mobility in lakes.Key words: arsenic cycling, biogeochemistry, freshwater lakes.
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