Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of platelet aggregation and coagulo-fibrinolytic systems in thrombogenesis of lactic acid-induced pulmonary thrombosis in rat were studied using an anti-coagulant, platelet aggregation inhibitor, fibrinolytic or anti-fibrinolytic agents. In normal rat, heparin (2.5 mg/kg), acetylsalicylic acid (30 mg/kg) and tranexamic acid (100 mg/kg) suppressed specifically coagulation, platelet aggregation induced by collagen or thrombin and fibrinolysis respectively. Urokinase (10,000 units/kg) activated powerfully fibrinolytic system in addition to suppressing slightly platelet aggregation. The pretreatment with heparin, acetylsalicylic acid or urokinase markedly prevented the formation of thrombus initiated by the infusion of lactic acid at the doses used. Additive effect was also obtained by combined administration of these agents. On the other hand, it was interesting to note that tranexamic acid (100 mg/kg) did not affect the thrombus formation at all despite a potent anti-fibrinolytic effect of this agent. These results indicate that both platelet aggregation and enhancement of coagulation activity are important factors responsible for the formation of thrombi in DIC, while the fibrinolytic activity in blood seems not to be involved in it. On the basis of the findings, mechanism for triggering activation of coagulation and platelet aggregation is also discussed here.
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PMID:Patho-physiological studies on lactic acid-induced pulmonary thrombosis in rat. I. Effect of heparin, acetylsalicylic acid, urokinase and tranexamic acid. 118 8

The localization of tissue plasminogen activator (t-PA) on microthrombi in various organs of disseminated intravascular coagulation rats (DIC rats) was investigated by using microautoradiographic technique. After the injection of [125I]fibrinogen, experimental DIC rats induced by the infusion of thrombin for 1 h were submitted to microautoradiograms (MARGMs) of some major organs. The radioactivity of [125I]fibrin thrombi, which were observed as silver grains, was localized in the glomeruli and parts of small vessels in the kidney. In the liver, microthrombi were seen in sinusoid vessels and on Kupffer cells. In addition, many microthrombi were noted in small vessels in the lung and marginal zones in the spleen. Two min after the intravenous administration of [125I]t-PA to DIC rats, many silver grains were observed on each MARGM of the kidney, lung, liver and spleen showing the formation of microthrombi. From the identical results with the observations of MARGMs after the injection of [125I]fibrinogen, we confirmed that t-PA was highly accumulated to microthrombi formed in small vessels of the organs. The scattered silver grains were widely observed on the hepatocytes. This result suggested that t-PA bound to the parenchymal cell surface might be transported into the hepatocytes by receptor-mediated endocytosis. On the other hand, when [125I]urokinase plasminogen activator [( 125I]u-PA) was administered intravenously to DIC rats, many silver grains were observed on MARGM of the proximal tubules in the kidney but not seen on MARGMs of the glomeruli in the kidney, nor in the lung, liver, and spleen. This observation suggested that u-PA might not have a characteristic to accumulate to thrombi.
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PMID:Localization of tissue plasminogen activator on experimental microthrombi in rats. Microautoradiographic observations. 190 22

We should distinguish fibrin degradation products (FbDP) from fibrinogen degradation products (FgDP) in order to analyze fibrinolysis in vivo. We analyzed some disorders associated with hyperfibrinolytic states using ELISA for FbDP, FgDP and total fibrin (ogen) degradation products (TDP) (ORGANON TEKNIKA). Each ELISA was useful in terms of reproducibility and dilution linearity of plasma samples. There was no cross-reaction between FbDP and FgDP. The FgDP/FbDP ratio in normal individuals was 1.65. In patients with DIC, it was 0.43, with FgDP level being increased. These results suggest that fibrinolysis is enhanced in patients with DIC, but it is accompanied by fibrinogenolysis. On the other hand, the FgDP/FbDP ratio in patients given urokinase (UK) was 2.88. This suggests that fibrinogenolysis is enhanced in them. In our study, the FgDP/FbDP ratio increased as DIC improved. Thus, we can regard this as an index of therapeutic effects in patients with DIC. We conclude that these three ELISA are useful in analyzing disorders associated with hyperfibrinolytic states.
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PMID:[Differentiation between fibrin degradation products and fibrinogen degradation products by using newly developed ELISAs]. 192 Aug 69

The localization of tissue plasminogen activator (t-PA) or urokinase plasminogen activator (u-PA) on thrombi was investigated in disseminated intravascular coagulation rats (DIC rats) induced by thrombin. One hour after the intravenous infusion of thrombin to rats, the plasma fibrinogen level decreased, while the plasminogen activator activity in the plasma euglobulin fraction increased. The whole body autoradiography was studied after an injection of [125I]fibrinogen in DIC rats. The high radioactivity which indicated the presence of microthrombi was observed in the renal cortex, liver, spleen and lung. Furthermore, a large venous thrombus with higher radioactivity was observed in the abdominal vena cava. These results show that the thrombin-treated animal is one of the best DIC models. After the intravenous administration of [125I]t-PA, the autoradiograms of DIC rats showed a radioactivity in the blood and much higher radioactivities in the renal cortex, spleen and lung in comparison with the normal rat. However, there was no difference in the distribution of [125I]u-PA between normal and DIC rats at all. The strong radioactivity of [125I]t-PA but not [125I]u-PA was observed on the surface of large thrombus in the vena cava. These results suggest that t-PA localizes more preferentially on microthrombi than u-PA. The ratio of the radioactivity in the tissue to that in the blood was calculated to compare quantitatively the localization of [125I]t-PA and [125I]u-PA on microthrombi formed in organs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Localization of tissue plasminogen activator on experimental thrombi in rats. 212 28

A model was experimentally made with 2 hours serial infusion of thromboplastin (Tp) into rabbits to examine the drug's effect on a hemorrhagic tendency and to elucidate the coagulation and fibrinolytic system in acute DIC encountered in obstetrics, and the system was periodically observed. Groups given the drug, given it during pregnancy, those which bled massively, and those with accelerated fibrinolysis were prepared. The results are as follows. 1) Fibrinogen, PT, APTT, TEG, ELT, AT-III, antiplasmin activity, and platelet count varied markedly from the initiation of Tp injection, and returned to normal following termination. 2) Blood from the heparin dose group showed non-coagulation but decreases in the platelet count and fibrinogen were inhibited. 3) In the aprotinin dose group, serial 2 hour administration induced inhibition of fibrinolysis despite the relatively delayed appearance of anti-fibrinolytic activity. 4) No fibrinolytic effects were seen in anti-plasmin activity or ELT in the tranexamic acid dose group. 5) Lowering of parameters examined was marked in the Tp dose group during pregnancy. 6) The mortality rate up to 6 hours after Tp infusion was 54.5% with solely given, and 10% with group given drug. 7) Death within one hour of Tp infusion in the mass bleeding group, being rated for 50%, was improved to 16.7% by the pre-administration of urokinase.
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PMID:[Treatment of obstetrical disseminated intravascular coagulation--sequential changes of coagulation and fibrinolytic system in DIC rabbits]. 618 25

Presence of chronic DIC (disseminated intravascular coagulation) eliciting an impeded blood coagulation has been postulated of late as one of the etiology causing toxemia of pregnancy, for which studies have been immunologically made. These theories remain unestablished. In this regard, the role of complement in blood coagulation has been noted, and their correlation is being elucidated. The author introduced a concept of complement to etiological theory of an impeded blood coagulation origin, by which toxemia of pregnancy was studied with emphasis placed on their correlation. The results obtained are as follow: 1) Thrombin and thromboplastin allowed in vitro to decreases the potency of complement, and the lowering also was seen even in the case of simultaneous supplement of urokinase and plasminogen. 2) The decrease also was periodically seen in rabbit's DIC experimentally made. 3) An increase in CH50, C3, C4, and factor B of normal pregnancy were of significance when compared with those of the control (p less than 0.001), while C1 inactivator decreased significantly (p less than 0.001). 4) CH50 was 52.2 +/- 2.4U/ml in severe toxemia, a decrease being of significance (p less than 0.01) as compared with that in third trimester of normal pregnancy. Those other parameters which tended to decrease included hemolytic activity of alternative pathway (AP-CH50), C4, and factor B except C1 inactivator with a trend being high.
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PMID:[Studies on relationship between complement and blood coagulation system in toxemia of pregnancy (author's transl)]. 706 48

We found 5 cases of prostatic carcinoma with metastasis with alpha 2 macroglobulin (alpha 2 M) concentration below approximately 40 mg/dl in serum. All these patients had bone metastasis, and none of them had DIC. We found no other cases with such a low concentration of alpha 2 M. Their alpha 2 M level increased to normal level after treatment with transurethral resection of prostate or hormone agents, and the level was correlated with the clinical symptom. During the clinical course, their alpha 2 M level was negatively correlated with prostate-specific antigen (PSA) and prostatic acid phosphate (PAP). All these results suggest that alpha 2 M concentration in serum reflects the severity of prostatic carcinoma with metastasis and that alpha 2 M deficiency is an indicator of metastasis. The acute phase proteins of CRP and serum amyloid A did not increase in spite of the presence of metastasis in these patients with extremely low alpha 2 M level (< 20 mg/dl), suggesting that alpha 2 M is involved in the metabolism of these acute phase proteins. On immunohistochemical studies, their specimens of prostatic carcinoma gave positive stain for PSA and urokinase-type plasminogen activator (u-PA). Both PSA and u-PA formed a complex with alpha 2 M in vitro. The alpha 2 M deficiency in these patients might be due to the complex formation between alpha 2 M and these prostate-originated proteases and to the rapid disappearance of the complex.
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PMID:[Studies on alpha 2 macroglobulin deficiency in association with cancer metastasis]. 910 63

During activation of the fibrinolytic system plasminogen is converted to plasmin by tissue plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). t-PA is predominantly released from endothelial cells, u-PA primarily by renal parenchymal cells. The activation of plasminogen is regulated by plasminogen activator inhibitor-1 (PAI-1), plasmin is controlled by alpha 2-plasmin inhibitor. The fibrinolytic system is not only involved in the intravascular dissolution of fibrin (thrombi), it also plays a vital role in normal physiologic reproduction, wound repair, angiogenesis, and tissue remodeling. Fibrinolysis is also a vital component in the pathogenesis of neoplastic disease. It is essential in releasing cells from their primary site of origin, providing nutrition for neoplastic cell growth and promoting cell mobility and motility. In neoplastic cells the degradation of the extracellular matrix proteins is facilitated by excessive expression of u-PA, t-PA, and u-PAR. In many forms of carcinoma increased expression of u-PAR and u-PA is associated with significantly shorter survival. Greater expression of u-PA in breast cancer cells, for example, is associated with shorter survival and increased relapse rate. Progressively aggressive neoplastic cells evidence high expression of u-PA and u-PAR activities, variable expression of t-PA, and enhanced PAI-1 and PAI-2 activities. In acute nonlymphocytic leukemias, poor outcome correlates with high t-PA levels. In acute progranulocytic leukemia there is a high incidence of DIC. Neoplastic prostatic tissue also expresses high u-PA activity and the more aggressive the cell line, the greater the number of u-PAR and the higher the u-PA activity. In gynecologic malignancies, a greater expression of u-PA in combination with cathepsin D is associated with widespread disease and poor prognosis. High u-PA values were also seen in patients with brain, gastric, and hepatic malignancies. It is evident that the plasminogen-plasmin system is a vital component in the biology of neoplastic disease and that it is, in theses conditions, in no way beneficial to the host.
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PMID:The fibrinolytic system in neoplasia. 912 11

Treatment of mouse Lewis lung carcinoma with razoxane or dacarbazine was protracted for 10 transplant generations. While the capacity of the treated tumors to grow locally in immuno-competent or in immuno-depressed hosts was retained and not significantly modified, the metastatic phenotype was eliminated when the treated tumor cells were transplanted into immuno-competent hosts. The reduction in metastatic potential was slightly less pronounced, in terms of both number and volume of metastases, when the treated tumor cells were transplanted into immuno-depressed hosts. These properties were retained after 3 transplant generations without treatment. Northern blotting and zymography of primary-tumor crude extracts revealed that treatment with either razoxane or dacarbazine for one generation approximately doubled the expression of MMP-2 and MMP-9, while lacking any effect on that of 1.0 and of 3.5 kb TIMP-2. When the treatment was maintained for 10 generations, the expression of MMP-2 and MMP-9 for both drugs showed up-regulation of approximately 10- and 2-fold respectively. TIMP-2 mRNA of 1.0 kb doubled its expression, while that of 3.5 kb registered just above the control. Dacarbazine doubled the expression of uPA after 10 generations, while razoxane boosted it approximately 3-fold after either 1 or 10 generations. The permanent loss of metastatic phenotype induced in Lewis lung carcinoma by dacarbazine and razoxane is thus attributable to biological mechanisms independent of down-regulation of expression and/or activation of the 2 gelatinases.
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PMID:Suppression of metastatic potential and up-regulation of gelatinases and uPA in LLC by protracted in vivo treatment with dacarbazine or razoxane. 937 40

Measurement of plasminogen, the key component of fibrinolysis system, is one of the basic methods for estimation of fibrinolysis. Methods based on the use of chromogenic substrates are often used in diagnosis. Plasminogen measurements are important for laboratory diagnosis of thrombophilia caused by deficiency or abnormalities of this fiber, for detection and evaluation of the DIC syndrome, and for monitoring the treatment by fibrinolytic preparations (streptokinase, t-PA, urokinase, etc.). An original chromogenic substrate having no foreign analogs has been created at Institute of Genetics and Selection of Industrial Microorganisms and Research Center of Hematology (Moscow). Unlike previously described plasmin substrates, pNa has been obtained by microbiological methods with Russian commercial enzymes subtilisine 72 and megaterine. This paper presents the results of plasminogen measurements in patients with DIC with the use of the original chromogenic substrate. The results were compared with those of tests with Berihrom-Plasminogen diagnostic kit (Behringwerke AG).
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PMID:[A method for determining plasminogen with a Russian chromogenic substrate and its diagnostic significance]. 1087 27


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