-
Blood Coagulation & Fibrinolysis : An... Jul 2000There has been a recent decline in interest in fibrinolysis, suggesting that its physiological basis is sufficiently understood and that therapeutic thrombolysis has... (Review)
Review
There has been a recent decline in interest in fibrinolysis, suggesting that its physiological basis is sufficiently understood and that therapeutic thrombolysis has reached its limit. The importance of the subject has not diminished since cardiovascular disease is now a leading health problem even in developing countries. Certain highlights and inconsistencies are reviewed. The clinical trials of tissue plasminogen activator (t-PA) revealed a major discrepancy between its fibrinolytic efficacy and its clinical benefit (the 't-PA paradox') that is unexplained. Dose-finding studies also showed that the fibrinolytic efficacy of t-PA required significant nonspecific plasminogen activation. Furthermore, the longstanding belief that t-PA is responsible for physiological fibrinolysis and urokinase-type PA (u-PA) for pericellular plasminogen activation is belied by extensive experimental animal data, but these findings have had little impact on traditional thinking. As a result, the mechanisms responsible for the u-PA paradigm of fibrinolysis have received little attention. Clinical experience with pro-u-PA remains limited and most clinical trials have used infusion rates at which pro-u-PA is largely converted systemically to urokinase. This is due to the unanticipated instability of pro-u-PA in plasma at pharmacological concentrations. Insufficient understanding of basic mechanisms of fibrinolysis has handicapped the design of chimeric or mutant activators. It is submitted that physiological fibrinolysis remains to be better defined, and that it is premature to conclude that therapeutic thrombolysis will be inevitably accompanied by side effects that undermine this method of inducing reperfusion.
Topics: Fibrinolysis; Humans; Mutagenesis; Plasminogen Activators; Streptokinase; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator
PubMed: 10937799
DOI: 10.1097/00001721-200007000-00001 -
Kidney International Apr 1988An assay was developed to measure plasminogen activator activity from isolated human glomeruli. Activator was extracted from individual glomeruli with 0.2 M...
An assay was developed to measure plasminogen activator activity from isolated human glomeruli. Activator was extracted from individual glomeruli with 0.2 M phosphate-buffered saline, pH 7.4 (PBS), containing 0.01% Triton X-100 and quantitated in 125I-fibrin films. Quenching studies using antibodies to tissue plasminogen activator and urokinase revealed that the extracted glomerular plasminogen activator activity contained both tissue plasminogen activator of urokinase. Monoclonal and polyclonal antibodies raised to tissue plasminogen activator demonstrated low-level inhibition of urokinase activity and monoclonal and polyclonal antibodies to urokinase demonstrated low-level inhibition of tissue plasminogen activator activity. The assay should be applicable to the study of glomerular plasminogen activator activity in experimental and human kidney diseases. The detection of antibody cross-reactivity to tissue plasminogen activator and urokinase may be related to the sensitivity of the 125I-fibrin assay and to the structural similarities of these activators.
Topics: Humans; Kidney Glomerulus; Plasminogen Activators
PubMed: 3386139
DOI: 10.1038/ki.1988.78 -
Immunology Today May 1991
Topics: Amino Acid Sequence; Animals; Antigens, Ly; Molecular Sequence Data; Plasminogen Activators; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Sequence Alignment; Sequence Homology, Nucleic Acid; Urokinase-Type Plasminogen Activator
PubMed: 1652256
DOI: 10.1016/S0167-5699(05)80051-9 -
Journal of Animal Physiology and Animal... Jun 2012There is growing evidence that plasminogen activator inhibitor type 1 (PAI-1) is expressed in adipose tissue and its expression is implicated in inflammation that...
There is growing evidence that plasminogen activator inhibitor type 1 (PAI-1) is expressed in adipose tissue and its expression is implicated in inflammation that accompanies obesity-associated diseases. The physiological role of other genes implicated in the plasminogen-activating cascade such as urokinase-type plasminogen activator (u-PA), u-PA receptor (u-PAR) and plasminogen activator inhibitor type 2 (PAI-2) in ovine adipose tissue remains unknown. The objective of this study was to examine the changes in the expression of four plasminogen activator (PA)-related genes during the early post-weaning period in dairy ewes. A total of 21 subcutaneous adipose tissue samples were obtained from seven lactating dairy ewes of the Chios breed at weeks 1, 2 and 4 after weaning. Results indicated that expression of all PA-related genes was detected in most of the samples examined. Greatest expression of u-PAR corresponded to highest (week 1), while greatest expression of PAI-2 corresponded to lowest (week 4) rate of lipolysis, as indicated by the expression of hormone-sensitive lipase, in the ovine adipose tissue. There were no significant differences in the expression of the other two PA-related genes (u-PA, PAI-1) throughout the experimental period. Plasminogen activator-related genes are not expressed in a coordinated manner in the adipose tissue of lactating dairy sheep in the early post-weaning period. In conclusion, adipose tissue mobilization is correlated with highest expression of u-PAR and lowest expression of PAI-2.
Topics: Adipose Tissue; Animals; Dairying; Female; Gene Expression Regulation; Lactation; Plasminogen Activators; Sheep; Weaning
PubMed: 21561489
DOI: 10.1111/j.1439-0396.2011.01154.x -
Coronary Artery Disease Jun 2001Optimal induction of coronary thrombolysis depends in part upon the nature of the specific plasminogen activator used. The two general classes of plasminogen activators... (Review)
Review
Optimal induction of coronary thrombolysis depends in part upon the nature of the specific plasminogen activator used. The two general classes of plasminogen activators available clinically differ in a fundamental respect delineated by the term, clot selectivity. Clot selective agents are less prone to induce plasminemia and consequent occult activation of the coagulation cascade than are non-selective agents. However, under clinical conditions, all plasminogen activators result in some activation of the cascade with consequent generation of thrombin. Accordingly, optimal therapy requires the use of conjunctive anticoagulation to preclude the deleterious effects of rebound generation of thrombin, which has been well documented biochemically. The potential value of antiplatelet agents that can attenuate the positive feedback loop between activation of platelets and markedly amplified generation of thrombin in the setting of coronary thrombolysis is under active exploration. With appropriate monitoring of the efficacy of such agents in vivo it should be possible to enhance even further the benefits that can be conferred by pharmacologically induced coronary thrombolysis.
Topics: Animals; Anticoagulants; Aspirin; Blood Coagulation; Dogs; Fibrin; Fibrinolysis; Fibrinolytic Agents; Humans; Myocardial Infarction; Plasminogen Activators; Rabbits; Terminology as Topic; Thrombin; Tissue Plasminogen Activator
PubMed: 11428542
DOI: 10.1097/00019501-200106000-00009 -
Thrombosis Research Mar 1993Plasminogen activator activity (PAA), t-PA antigen level, plasminogen activator inhibition (PAI) and plasmin inhibition (PI) showed a circadian variation in rat aorta,... (Comparative Study)
Comparative Study
Circadian variation of plasminogen activator activity, plasminogen activator inhibition and plasmin inhibition in aorta, heart, brain and lungs of the rat. Sex-related differences.
Plasminogen activator activity (PAA), t-PA antigen level, plasminogen activator inhibition (PAI) and plasmin inhibition (PI) showed a circadian variation in rat aorta, heart, brain, and lungs of both sexes, but in a different way depending on the organ and the fibrinolytic parameter studied and the sex as well. In general, the lowest values of PAA and t-PA antigen were found in the early morning and the highest values in late afternoon, while PAI or PI showed the opposite pattern (with the exception of lungs). In kidneys and liver the fibrinolytic parameters studied showed no circadian variation. Sex-related differences, mostly quantitative, were noted in aorta, heart, brain and kidneys, with lower PAA and t-PA antigen and higher PAI or PI in the male than in the female.
Topics: Animals; Aorta; Brain Chemistry; Circadian Rhythm; Female; Fibrinolysin; Fibrinolysis; Lung; Male; Myocardium; Organ Specificity; Plasminogen Activators; Rats; Rats, Wistar; Sex Characteristics
PubMed: 8497858
DOI: 10.1016/0049-3848(93)90231-c -
Current Drug Targets Nov 2011
Topics: Animals; Humans; Molecular Targeted Therapy; Plasminogen; Plasminogen Activators; Plasminogen Inactivators; Receptors, Urokinase Plasminogen Activator; Translational Research, Biomedical
PubMed: 21707480
DOI: 10.2174/138945011797635894 -
Thrombosis Research Mar 1986A plasminogen activator has been partially purified from benign serous cystadenomas by a combination of Sephadex G-200 gel filtration, CM-Sephadex ion exchange,...
A plasminogen activator has been partially purified from benign serous cystadenomas by a combination of Sephadex G-200 gel filtration, CM-Sephadex ion exchange, Concanavalin A-Sepharose and arginine-Sepharose affinity chromatographies. Its apparent size was very large and could not penetrate Sepharose 6B or 5% SDS polyacrylamide gel. It hydrolyzed plasminogen in a manner similar to that of urokinase in terms of their apparent Michaelis constants, although a one-minute lag period had to be allowed for this activation before the hydrolysis of plasminogen. It was very sensitive to reducing agent such that 5 mM dithiothreitol could completely destroy its activity. The activator crossreacted with anti-uterine plasminogen activator IgG, but did not react with anti-urokinase at all. It also bound fibrin well. In the absence of plasminogen, the activator was devoid of amidolytic activity towards S-2251, S-2302 and S-2288 but had a small but measurable activity against S-2444.
Topics: Chromatography, Affinity; Chromatography, Gel; Chromatography, Ion Exchange; Cystadenoma; Dithiothreitol; Female; Humans; Kinetics; Ovarian Neoplasms; Plasminogen; Plasminogen Activators
PubMed: 3961743
DOI: 10.1016/0049-3848(86)90369-5 -
American Journal of Health-system... Apr 2001
Topics: Catheters, Indwelling; Humans; Plasminogen Activators; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator
PubMed: 11296614
DOI: 10.1093/ajhp/58.7.617 -
The Journal of Thoracic and... Feb 1997
Topics: Fibrinolysis; Humans; Pericarditis; Plasminogen Activators; Therapeutic Irrigation; Urokinase-Type Plasminogen Activator
PubMed: 9040647
DOI: 10.1016/S0022-5223(97)70353-2