Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heparinization of blood inhibited the generation of fibrinopeptide A (FPA) after addition of thromboplastin (TP). Heparinization was more effective when performed in vivo than in vitro; the amounts of FPA at 60 s incubation were 8% and 32%, respectively, of control values in nonheparinized blood. When monospecific, neutralizing IgG against extrinsic pathway inhibitor (anti-EPI) were added to heparinized blood prior to TP, the amount of FPA increased to 65%. When monospecific IgG blocking antithrombin (anti-AT) was used, the amount of FPA increased to values similar to those in nonheparinized blood. When anti-AT and anti-EPI were both added to heparinized blood, FPA was generated about 25% faster than in normal blood. These results show that EPI contributes significantly to the anticoagulant effect of heparin in human blood.
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PMID:Heparin requires both antithrombin and extrinsic pathway inhibitor for its anticoagulant effect in human blood. 179 51

EPI released to the blood after injection of heparin, as well as recombinant EPI (r-EPI) added to normal plasma prolonged both the dilute Tissue Thromboplastin (TTP) time and the Activated Partial Thromboplastin Time (APTT). It is known that EPI inhibits both factor Xa and the factor VIIa-TTP complex. The prolongation of the APTT by EPI reflects only its inhibition of factor Xa. Addition of anti-EPI immunoglobulins (IgG) to normal plasma shortened the dilute TTP time 7.3 seconds (p less than 0.001) and the APTT by 0.7 seconds (p less than 0.001). In postheparin plasma, with polybrene added to neutralize the direct effect of heparin, the TTP was about 26 seconds longer and the APTT about 9 seconds longer than baseline values. These effects were completely abolished by anti-EPI IgG, as were the effects of r-EPI. The EPI activity (chromogenic substrate-assay) of this postheparin plasma was 1.7 U/ml. The EPI activity of the plasma spiked with r-EPI to obtain comparable effects on clotting were much higher; about 22 U/ml for the TTP effect and about 5 U/ml for the APTT effect. The findings indicate that r-EPI is considerably less potent than postheparin EPI as inhibitor of plasma coagulation. This is most striking when coagulation is initiated through the extrinsic pathway. Possibly, the anticoagulant effect of r-EPI mainly depends on its Xa inhibitory effect.
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PMID:Extrinsic pathway inhibitor (EPI) released to the blood by heparin is a more powerful coagulation inhibitor than is recombinant EPI. 192 55

A sensitive assay is described for the measurement of rabbit plasma EPI activity in experimental studies of induced hypercoagulable states in this species. It is based upon the ability of a dilution of rabbit plasma to inhibit human factor VIIa/rabbit brain tissue factor (TF) catalyzed activation of human factor IX (tritiated activation peptide release assay). Addition of 3H-factor IX to the reaction mixture is delayed for 45 minutes to allow full inhibition by EPI/factor Xa complex before the residual catalytic activity of factor VIIa/TF is measured. Although the diluted rabbit plasma test sample contains both EPI and factor X, supplemental factor X is added to the reaction mixture to assure that only EPI content of the test sample affects the assay result. However, the final concentration of factor X in the reaction mixture is critical. Too high a concentration of factor X diminishes the sensitivity of the assay. The reason for this phenomenon, which was observed with both human and rabbit factor X preparations, is unknown.
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PMID:A sensitive, accurate assay for extrinsic pathway inhibitor (EPI) activity in rabbit plasma: paradoxical effect of excess exogenous factor X. 208 Apr 94

The risk of cardiovascular complications is reported to be several times higher in severe exercise than in daily activity. EPI-mediated inhibition of factor VIIa/thromboplastin enzymatic activity is believed to be an important modulator of blood coagulation during hemostasis. The plasma concentration of EPI, corrected for changes in plasma volume, was determined in healthy male subjects prior to, immediately after and at various time intervals after strenuous exercise of different duration. A slight, but significant decrease in EPI (7.5 +/- 2.8%, p less than 0.03) was found after a short term run (1.7 km), whereas no significant change was seen after a middle term run (4.8 km). In contrast, we observed a marked increase in EPI after a long term run (20.3 +/- 6.9%, p less than 0.03) and in a second group of athletes participating in the Norwegian championship of 30 km cross country skiing (39.9 +/- 10.3%, p less than 0.02). A peak value was reached 2 h after the run, and after that the curve started to approach baseline values. The rise in EPI might reflect a significant release of EPI from the endothelium that is greater than eventually any consumption. Another explanation for this enhancement in EPI might be that the increase in lipoprotein lipase activity after physical exercise causes a rise in the availability of EPI since EPI is known to be associated with lipoproteins in the circulation. It is hypothesized that mobilization of EPI during extensive physical exercise may suppress activation of the clotting system.
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PMID:Physical exercise enhances plasma levels of extrinsic pathway inhibitor (EPI). 227 17

The plasma inhibitor(s) of factor VIIa-tissue thromboplastin cooperates with factor Xa. This "Extrinsic Pathway Inhibitor" has been quantitated with a sensitive chromogenic substrate assay. Gel filtration of plasma separates 3 EPI peaks. Postoperatively, both EPI and the other coagulation inhibitors decrease. Unlike the other inhibitors, EPI is usually normal in severe liver cirrhosis. In disseminated intravascular coagulation, EPI levels vary considerably.
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PMID:The inhibitor of F VIIa in plasma measured with a sensitive chromogenic substrate assay: comparison with antithrombin, protein C and heparin cofactor II in a clinical material. 246 15

We have extended earlier studies (Blood 66:204, 1985) of a mechanism of inhibition of factor VIIa/tissue factor activity that requires a plasma component (called herein extrinsic pathway inhibitor or EPI) and factor Xa. An activated peptide release assay using 3H-factor IX as a substrate was used to evaluate inhibition. Increasing the tissue factor concentration from 20% to 40% (vol/vol) overcame the inhibitory mechanism in normal plasma but not in factor VII-deficient plasma supplemented with a low concentration of factor VII. A second wave of factor IX activation obtained by a second addition of tissue factor to plasma with a normal factor VII concentration was almost abolished by supplementing the reaction mixture with additional EPI and factor X. Factor Xa's active site was necessary for factor Xa's contribution to inhibition, but preliminary incubation of factor Xa with EPI in the absence of factor VIIa/tissue factor complex or of factor VIIa/tissue factor complex in the absence of EPI did not replace the need for the simultaneous presence of factor Xa, factor VIIa/tissue factor, calcium, and EPI in an inhibitory reaction mixture. Inhibition of factor VIIa/tissue factor was reversible; both tissue factor and factor VIIa activity could be recovered from a dissociated, inhibited factor VIIa/tissue factor complex. EPI appeared to bind to a factor VIIa/tissue factor complex formed in the presence of factor Xa but not to a factor VIIa/tissue factor complex formed in the absence of factor Xa.
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PMID:Studies of a mechanism inhibiting the initiation of the extrinsic pathway of coagulation. 349 26

We report a procedure to purify partially from plasma (approximately 1200 fold) the factor Xa-dependent inhibitor of factor VIIa/tissue factor (i.e., the extrinsic pathway inhibitor or EPI) and describe some of its properties. An assay for EPI was developed based upon inhibition of factor VIIa/tissue factor induced release of activation peptide from tritiated factor IX by a test sample in the presence but not in the absence of factor Xa. Approximately 50% of the total EPI activity in plasma was found in the lipoprotein fraction, which was used as the starting material for purification. Total lipoproteins (isolated by density ultracentrifugation) were delipidated and the urea soluble apoproteins gel filtered on Sephacryl S-200. The inhibitory activity co-eluted with the major protein peak, which primarily contained apoprotein A-I. Inhibitory activity was separated from apoprotein A-I by anion-exchange chromatography on Q-Sepharose and was further resolved from higher and lower molecular weight contaminating proteins by polypreparative disc gel electrophoresis in the presence of 0.1% SDS. Functional inhibitory activity eluted from the polypreparative disc gel in two discrete pools of different molecular weights (approximately 34,000 and approximately 43,000 D). Apoprotein E was identified by immunological techniques as the major protein present in both of these pools. However, incubation with a monospecific polyclonal antibody to human apoprotein E did not decrease EPI activity either in plasma or in the partially purified polypreparative disc gel fractions. A rabbit antiserum was prepared against material from the polypreparative disc gel. The IgG fraction neutralized approximately 95% of the total inhibitory activity present in plasma. Therefore, EPI in the lipoprotein fraction and in the non-lipoprotein fraction of plasma appears to be antigenically similar.
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PMID:Partial purification and characterization of extrinsic pathway inhibitor (the factor Xa-dependent plasma inhibitor of factor VIIa/tissue factor). 350 Nov 73

Clinical and experimental data have recently accumulated for antithrombotic action of angiotensin-converting enzyme inhibitors (ACE-1s). We have shown previously that captopril (which contains a thiol group in the moiety) exerts more pronounced antithrombotic activity than does an equipotent dose of enalapril (the drug devoid of the thiol group). To clarify the relative importance of the presence of the thiol group in the molecule versus angiotensin-converting enzyme (ACE) inhibitory properties in the antithrombotic action of captopril, rats were treated with captopril (5 mg/kg twice daily; CAP), epicaptopril (stereoisomer of captopril devoid of ACE-inhibitory properties; 5 mg/kg twice daily; EPI), N-acetylcysteine (3.75 mg/kg twice daily; ACC), enalapril (3 mg/kg once daily; ENA), or distilled water (VEH) for 10 days, per os. After ligation of the vena cava, the incidence of the venous thrombosis and/or the thrombus weight decreased significantly in all but the ENA-treated groups when compared with control rats. The effect of CAP, EPI, and ACC was accompanied by a marked reduction of euglobulin clot lysis time and, with the exception of ACC, by an increase in prothrombin time in the blood collected from the site of the thrombus formation. Antithrombotic activity of EPI was completely abolished by nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) or indomethacin, with the parallel reversal of fibrinolytic and coagulation parameters toward normal. Activated partial thromboplastin time, mean blood pressure, and bleeding time were not altered by either of the administered drugs. Thus, we demonstrated that thiol compounds exert antithrombotic activity by increasing fibrinolysis and/or suppression of the extrinsic pathway of the coagulation cascade in a nitric oxide/prostacyclin-dependent manner.
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PMID:Thiol repletion prevents venous thrombosis in rats by nitric oxide/prostacyclin-dependent mechanism: relation to the antithrombotic action of captopril. 1102 53

The aim of this study was to investigate whether supplementation with nattokinase, which is considered one of the most active functional ingredients found in natto, alters hemostatic factors. Subjects presenting with hypercholesterolemia (serum cholesterol: 200-280 mg dL-1) were randomly divided into nattokinase and placebo groups (n = 50, respectively). No significant between-group differences were found at baseline in collagen-epinephrine closure time (C-EPI CT), prothrombin time (PT), or activated partial thromboplastin time (aPTT). After 8 weeks of treatment, the nattokinase group exhibited significant increases in C-EPI CT, PT, and aPTT. The nattokinase group showed significantly greater increases in C-EPI CT (P = 0.001) and aPTT (P = 0.016) than the placebo group. Moreover, at 8 weeks, the nattokinase group showed a significantly higher C-EPI CT than the placebo group (P = 0.001). Additionally, a significant correlation between PT and aPTT was observed (r = 0.491, P < 0.001). In conclusion, nattokinase supplementation was associated with prolonged C-EPI CT and aPTT in nondiabetic and borderline-to-moderate hypercholesterolemic subjects.
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PMID:The effects of nattokinase supplementation on collagen-epinephrine closure time, prothrombin time and activated partial thromboplastin time in nondiabetic and hypercholesterolemic subjects. 3128 55