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

Both cigarette smoking and oral contraceptives (OCs) have been shown to exacerbate Crohn's disease. The pathogenic mechanism for Crohn's disease proposed by the authors--multifocal gastrointestinal infarction, mediated by a chronic mesenteric vasculitis--provides a framework for understanding these effects. Smoking induces morphologic injury to endothelial cells, inhibits aortic endothelial prostacyclin synthesis, and leads to elevated levels of plasma fibrinogen and decreased levels of plasminogen and tissue plasminogen activator activity. OCs that contain more than 50 mcg of ethinyl estradiol increase levels of procoagulant substrates and produce decreases in both anticoagulant and fibrinolytic activity. Enhanced expression of both monocyte and vascular endothelial cell procoagulant activity is the initiating event in the fibrin formation that initially characterizes Crohn's disease. Although microvascular changes have been observed in Crohn's disease patients who neither smoke nor use OCs, it appears likely that when further prothrombic stimuli such as OCs and nicotine are superimposed on Crohn's disease, the result is an exacerbation of disease activity.
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PMID:Smoking, the oral contraceptive pill, and Crohn's disease. 186 7

Oral contraceptives influence plasma proteins, causing changes in plasma procoagulants and fibrinolytic effectors. Estrogen is thought to be responsible for these changes, whereas progestogens, in particular those with an androgenic effect, may influence the magnitude of the changes. This concept is consistent with epidemiologic studies, suggesting a correlation between estrogen dose and cardiovascular episodes in oral contraceptive users. A delayed resolution of fibrin might contribute to an increased risk caused by decreased coagulation inhibition or fibrinolytic efficacy. Estrogen (30 micrograms or more) has a dose-dependent effect on clotting factors, including antithrombin III and proteins C and S. The effect of high- and low-dose oral contraceptives containing various progestogens on the fibrinolytic system is less clear. We have found that low-dose oral contraceptives containing levonorgestrel or lynestrenol enhance fibrinolysis, as revealed by an increase in plasminogen (30% to 40%), a decrease in histidine-rich glycoprotein (15% to 26%), an increase in tissue plasminogen activator activity (greater than 150%), and a decrease in tissue plasminogen activator inhibition (30% to 40%), concomitant with a slight decrease in tissue plasminogen activator antigen level (15% to 20%). New oral contraceptives contain less androgenic progestogens. Preliminary results of an ongoing study of women receiving either 20 micrograms of ethinyl estradiol with 150 micrograms of desogestrel or 30 micrograms of ethinyl estradiol plus 75 micrograms of gestodene revealed no change or changes similar to the older low-dose preparations after 6 months of treatment. Of particular importance was the finding that coagulation activation, expressed by the levels of thrombin-antithrombin III-complexes, fibrin formation, and the efficacy of fibrinolysis, expressed by the levels of fibrin degradation products, was identical in the two groups.
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PMID:Effects of newer oral contraceptives on the inhibition of coagulation and fibrinolysis in relation to dosage and type of steroid. 219 12

Epidemiologic studies have suggested a relationship between the use of oral contraceptives and mortality from cardiovascular diseases in older women. Therefore we studied generation and resolution of fibrin in 28 healthy women above age 30 years, using oral contraceptives containing 30 to 50 micrograms of ethinyl estradiol. Thirty healthy nonusers served as control subjects. The oral contraceptive group had increased plasma concentration of thrombin-antithrombin III complexes (p less than 0.01), which indicated an enhanced generation of thrombin, increased plasma activity of tissue-type plasminogen activator (p less than 0.01), decreased plasma activity of plasminogen activator inhibition (p less than 0.01), and increased plasma concentration of fibrin degradation products (p less than 0.04). Interestingly, the ratio of thrombin-antithrombin III complexes/fibrin degradation products did not deviate significantly between groups. Twelve of the 28 women using oral contraceptives were light smokers, that is, less than 15 cigarettes per day. There were no differences in the determined variables between smokers and nonsmokers. Our study suggests that healthy women older than 30 years who use oral contraceptives containing 30 to 50 micrograms of ethinyl estradiol have an enhanced generation and resolution of fibrin, while the hemostatic balance is unaltered. These findings are unaffected by moderate cigarette smoking.
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PMID:Enhanced generation and resolution of fibrin in women above the age of 30 years using oral contraceptives low in estrogen. 237 37

2 groups of healthy, informed volunteers were studied to assess tissue-type plasminogen activator (t-PA) inhibition in plasma of women using oral contraception (OC) and in normal women. The women in the 1st group (n=10, age range 21-30 years) had used a combined OC with 30 mcg ethinyl estradiol and 150 mcg levonorgestrel daily for 21 days per cycle for 4 months. They began using pills on the 7th day of their cycle. The 2nd group was made up of 15 women, age 20-28 years, with a regular menstrual cycle (range of 28-31 days) and with hormone levels within the normal range. None of the women had evidence of liver disease or active thrombotic disease, and none was taking other drugs. Blood samples were obtained in the morning with a minimum of stasis from an antecubital vein from fasting subjects in the supine position after a brief rest. The t-PA inhibition in plasma was determined by amidolytic titration with purified melanoma 2-chain t-PA. The measured inhibition was arbitrarily expressed in percentages relative to a pool of normal plasma. The t-PA activity was determined on fibrin plates as the activity measured in the presence of excess of C1-inactivator as described elsewhere. The mean levels of inhibition during the cycle were lower in the OC than in the normal group. The difference were statistically significant. When the separate sampling periods were compared, a statistically significant difference between the 2 groups were obtained for periods 2-5. There were only minor and insignificant fluctuations during the normal menstrual cycle. In the OC group the inhibition decreased from periods 1-5 with a statistical significance. Within both groups the fluctuations in t-PA inhibition were almost inversely related to the t-PA activities.
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PMID:Inhibition of tissue-type plasminogen activator in plasma of women using oral contraceptives and in normal women during a menstrual cycle. 309 96

This study demonstrated that the normal increase in euglobulin fibrinolytic activity (NEF) that occurs in the morning was not affected by taking oral contraceptives. 11 women taking a combined pill of 30 mcg ethinyl estradiol and 150 mcg 1-norgestrel for 21 days were compared with 15 menstruating controls. The assay for NEF involved precipitating euglobulins and assaying on bovine fibrin plates. Extrinsic tissue plasminogen activator (t-PA) was that fibrinolysis obtained after adding pure C1-inactivator. NEF was higher in women taking pills, especially during the middle of the cycle. In controls, NEF fluctuated less, but was higher during menses and in late luteal phase. t-PA variations were much less remarkable, but generally reflected the pattern seen with NEF. The only significant difference was the relatively greater increase in morning values in the pill group during beginning and end of the cycle. When the assay was repeated with the addition of flufenamate, to inactivate the C-1 inactivator, results did not differ between the 2 groups. These data do not point to any element in this fibrinolytic system that might be associated with the increased incidence of thromboembolic episodes in women taking oral contraceptives.
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PMID:The diurnal increase in euglobulin fibrinolytic activity in women using oral contraceptives and in normal women, and the generation of intrinsic fibrinolytic activity. 310 Dec 21

This study investigated the influence of ethinyl-estradiol and d-norgestrel on the release of tissue-type plasminogen activator (t-PA) from incubated specimens from human veins. The concentrations of PA released into the media were determined by immunoradiometric assay. The initial release of t-PA was positively correlated to the weight of the vein specimens. Only traces of t-PA were liberated after the 3rd day of incubation. No significant differences in total release were noted between the steroid exposed groups and the control group. However, a significantly higer initial t-PA release (82%) was found in the d-norgestrel exposed group compared to the control group (exposed to ethanol only). The initial t-PA release was also stimulated in the group exposed to both contraceptive steroids (73%), but exposure to ethinyl estradiol alone had no significant effect (62%). The stimulation of t-PA release associated with artificial steroids may reflect their androgenic effect.
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PMID:Regulatory effect of contraceptive steroids on the release of tissue-type plasminogen activator in vitro. 654 83

Clinicians followed 30 women, 18-37 years old, attending the family planning clinic of Falu Hospital in Sweden to compare the effect of a long interval of an oral contraceptive (OC) (30 mcg ethinyl estradiol + 150 mcg desogestrel) on the hemostasis system, lipid metabolism, and hormone binding proteins with that of a traditional 3-week regimen. They randomly allocated 20 women to the long-interval group (group I) and 10 to the 3-week group (group II). The long-interval consisted of 9 weeks taking the OC and 1 week not taking the OC. Between baseline and 12 months, sex hormone binding globulin (SHBG) levels increased 409% in group I (p .001) and 341% in group II (p .01). Corticosteroid binding globulin (CBG) levels increased 294% (p .001) for group I and 173% for group II. SHBG and CBG levels (markers of estrogenicity) were not significantly different between the 2 groups, however. Limited, insignificant changes took place with lipoprotein cholesterol fractions. VLDL-triglycerides and LDL-triglycerides increased significantly in group I (0.31-0.57 mmol/l) and group II (0.21-0.27 mmol/l) (p .05). Fibrinogen, factor VII, and thrombin/antithrombin III complex increased significantly in group I at 3 and 12 months. They had also increased in group II but not significantly. The coagulation inhibitors (i.e., antithrombin III, protein C, and protein S) remained virtually the same. Levels of tissue plasminogen activator antigen and tissue plasminogen activator inhibitor activity, both of the fibrinolytic system, fell (significant decrease only in group I). These findings show that the desogestrel-containing low-dose OC has limited effects on lipid metabolism, particularly the cholesterol subfractions, regardless of the regimen. It does increase minimally coagulation parameters, but the fibrinolytic system offsets this increase. In conclusion, the long-interval regimen is as safe as the 3-week regimen.
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PMID:Hemostasis profile and lipid metabolism with long-interval use of a desogestrel-containing oral contraceptive. 795 14

The effects of contraceptive steroids on the expression of endothelial homeostasis were examined by direct and indirect measures in women with insulin-dependent diabetes mellitus (IDDM) in a prospective nonrandomized controlled study. Study subjects were 13 women with uncomplicated IDDM treated with a monophasic combination of 30 micrograms ethinyl estradiol and 75 micrograms gestodene for 12 consecutive cycles and 13 women of comparable diabetic status as control. During the study period, none of the participants developed increased renal albumin excretion, which was used as a direct measure of endothelial function. In the indirect assessment of endothelial function, we found a proportionate increase in plasma levels of thrombin-antithrombin III (TAT) complexes and D-dimer during treatment. Hormonal intake was followed by decreased antigen concentrations of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (type 1 [PAI-1]), whereas the activities of t-PA and PAI-1 were unchanged. Plasma levels of plasminogen and histidine-rich glycoprotein (HRG) increased and decreased, respectively, whereas an increase in von Willebrand factor was observed in the treatment group. No significant changes in direct or indirect measures were observed in the control group during the observation period of 12 months. In conclusion, no adverse effect on endothelial function was demonstrated by direct measures, but our findings suggest that a procoagulant state, compensated by enhanced activity of the fibrinolytic system, is induced by hormonal treatment. Clinical and metabolic monitoring is recommended if the use of oral contraceptives in women with IDDM is extended.
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PMID:Assessment of endothelial function during oral contraception in women with insulin-dependent diabetes mellitus. 796 93

34 healthy women aged 21-30 years were assigned to 12 consecutive menstrual cycles of treatment with monophasic combinations. 15 women with a median age of 24 years received 20 mcg ethinyl estradiol (EE) and 150 mcg desogestrel (DSG) and 19 women with a median age of 23 years were treated with 30 mcg EE and 75 mcg gestodene (GST). Three women from the EE+DSG group and four women from the EE+GST group quit after six months because of personal reasons. Two more women from the EE+GST group quit after six months because of mammary tension and weight gain. Two women in each group smoked between one and ten cigarettes daily, the rest were nonsmokers. The evaluation of the hemostatic system was carried out in the luteal phase before the treatment began and within the last ten days in the third, sixth, and twelfth treatment cycle. In both groups plasma levels of fibrinogen (7.2 mcmol/l pretreatment to 8.7 mcmol/l posttreatment) and factor VIIc (80% pretreatment to 126% posttreatment) increased significantly under treatment, while the capacity of coagulation inhibition was affected after three months by increased protein C concentrations (15% in the EE+DSG group and 14% in the EE+GST group) and significantly decreased levels of protein C's cofactor, protein S levels by 11% and 15%, respectively. Increased fibrinolytic capacity was indicated by elevated activity and reduced antigen levels of tissue plasminogen activator and reduced activity and concentration of tissue plasminogen activator inhibitor. The ratio between thrombin antithrombin-III-complexes (TAT) and fibrin degradation products were unchanged, signifying no effect of hormonal intake on the balance between thrombin formation and fibrinolysis. The dynamic balance between coagulation and fibrinolysis was undisturbed during treatment with both hormonal compounds, and findings do not provide evidence for increased risk of thrombosis in normal women.
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PMID:[Hemostatic balance during treatment with the newest contraceptives]. 829 9

In Vienna, Austria, health workers took blood samples from 16 healthy, nonsmoking 19-35 year old women before and after they began using a combined oral contraceptive (OC) (Gynovin) (30 mcg ethinyl estradiol and 75 mcg gestodene) to assess the OC's effects on blood coagulation and fibrinolysis and the effect of the estrogen component on endothelial cells. Fibrinogen levels increased significantly after OC use (283 mg/dl vs. 342 mg/dl after the 1st treatment cycle; p .005). These levels remained significantly higher (326 mg/dl and 339 mg/dl after the 2nd and 3rd treatment cycles; p .005 and .05, respectively). Thrombin antithrombin III complex (TAT) and prothrombin fragment F1+2 levels increased just minimally during OC treatment. Levels of fibrin split-product D-dimer, plasma tissue plasminogen activator (t-PA) activity, and plasmin-antiplasmin (PAP) complexes were significantly higher during all OC treatment cycles than they were before treatment. Active plasminogen activator inhibitor (PAI-1) antigen, t-PA, and urokinase plasminogen activator antigen levels fell significantly after OC treatment and remained low during OC treatment. Experiments with the culture of human umbilical vein endothelial cells showed that ethinyl estradiol did not significantly affect the tissue factor content or surface thrombomodulin activity of these endothelial cells (i.e., hemostatic regulatory activities). It also did not change the secretion of the fibrinolytic components t-PA and PAI-1. None of the women developed thrombosis. Even though these findings did not clearly show OC-induced hemostatic activation in this relatively small group of women, clinical researchers should still determine activation markers to monitor the activation state of blood coagulation in certain OC users, such as obese women and those who smoke cigarettes.
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PMID:Studies on oral contraceptive-induced changes in blood coagulation and fibrinolysis and the estrogen effect on endothelial cells. 839 73


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