Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Low molecular weight (LMW) heparin preparations have unknown distributions of ATIII-binding material, so mean molecular weights as such might bear little information on their anti-factor Xa and anti-thrombin activities, and on the neutralization of these activities by platelet factor 4 (PF4). These properties were investigated in pure systems with proteins of human origin. Pseudo-first order rate constants of inactivation of factor Xa and thrombin by antithrombin III were determined as function of heparin concentration, in the presence of 4.0 mM CaCl2. Despite a large variation in the mean molecular weights, the ratios of the anti-factor Xa over the anti-thrombin activities were essentially the same for the 4th International Standard for heparin (0.46), the 1st International Standard for LMW heparin (0.32), CY216 (0.42) and enoxaparin (0.50). The ultra LMW heparin CY222 had only a 2-times higher ratio (0.98). Analysis of CY216 subfractions, obtained by gel filtration, showed that the heparin molecules of the upper region of the molecular weight distribution are responsible for the anti-thrombin, but also to a large extent for the anti-factor Xa activities. The results indicate that depolymerization of unfractionated heparin does not result in an increased anti-factor Xa/anti-thrombin ratio, because in the presence of Ca(2+)-ions the rate constants of inactivation of factor Xa are lowered as compared to those of native heparin. PF4-dependent neutralization of anti-factor Xa and anti-thrombin activities of fixed concentrations of the LMW heparins was studied by measuring rate constants as function of PF4 concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Low molecular weight heparin-catalyzed inactivation of factor Xa and thrombin by antithrombin III--effect of platelet factor 4. 166 94

In this prospective study, the effect of the antiproteinase aprotinin on anticoagulation during cardiopulmonary bypass was compared with placebo treatment in a randomized double-blind fashion. The kallikrein-inhibiting capacity was significantly increased in aprotinin-treated patients and decreased in the control patients. The intrinsic clotting system was also inhibited by aprotinin. We demonstrated during cardiopulmonary bypass and in vitro a significantly prolonged activated clotting time and a remarkable prolongation of the activated partial thromboplastin time by aprotinin at low heparin concentrations, whereas the antithrombin III consumption was significantly reduced. Aprotinin synergistically enhanced the anticoagulation by heparin, which allowed reduced heparinization. This is of clinical importance for use in both heparin-resistant and heparin-sensitive patients undergoing cardiopulmonary bypass and may also have advantages for routine use during bypass to reduce the adverse effects of heparin-protamine complexes.
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PMID:Increased anticoagulation during cardiopulmonary bypass by aprotinin. 171 4

We have found that rat plasma corrected the non-activated PT of human normal or factor-X deficient plasma, and the factor Xa-like activity being constantly detected in every 1 ml of blood collected via the cannulated carotid artery of rats. The present study was undertaken to characterize the factor Xa-like activity in rat plasma by preparing rat factor X and a monoclonal antibody against it. Factor X was purified from a BaCl2 eluate of rat plasma by chromatographies on columns of DEAE-Sepharose CL-6B and Sulfate Cellulofine or on a column of Affi-Gel 10 conjugated with a monoclonal antibody against rat factor X. Factor Xa-like activity in rat plasma was eliminated by the treatment of rat plasma with a monoclonal antibody which recognized the heavy chain portions of rat factors X and Xa. A kinetical study demonstrated that rat factor Xa was strongly inhibited by rat antithrombin III, with a Ki of 2.2 x 10(-11) M, in the presence of heparin. However, in the absence of heparin, the second order rate constant for the inhibition of rat factor Xa by rat antithrombin III was 2.6 x 10(4) M-1.min-1, which was one forty-third that for the inhibition of human factor Xa by human antithrombin III. Furthermore, rat factor Xa was resistant to the inhibition by rat alpha-1-antitrypsin and alpha-2-macroglobulin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of rat factors X and Xa: demonstration of factor Xa in rat plasma. 171 49

This article reports on the pharmacologic properties of an O-acylated butyryl derivative (C4-UH) of unfractionated heparin (UH). In a purified system, the ability of C4-UH to catalyze the inhibition of thrombin and of factor Xa in the presence of antithrombin III was similar to that of UH. Addition of albumin (10 mg/ml) to the reagents reduced the antithrombin and antifactor Xa catalytic potency of C4-UH 68-fold and 20-fold, respectively, and did not alter those of UH. As judged from the prolongation of the activated partial thromboplastin time and the thrombin clotting time, the anticoagulant activities of C4-UH were two times weaker than those of UH. After calibration against UH, the antifactor Xa-specific and antithrombin-specific activities were two and 6.6 times lower, respectively. After bolus intravenous injection into rabbits, the apparent clearances of C4-UH were reduced 2.4 (antifactor Xa activity) and 3.2 times (antithrombin activity) in comparison with those of UH. This property accounted for the higher plasma concentrations generated during a constant infusion of the same dose. In the Wessler thromboplastin model, the minimum doses providing the maximum antithrombotic effect after bolus injection were equivalent for both compounds when expressed as antifactor Xa units; the duration of the antithrombotic effect of this derivative was prolonged, whereas the hemorrhagic potential was unaffected. This study opens a new concept for heparin derivatives having lower clearances and long-lasting effects. These properties could be linked to nonspecific binding of C4-UH to plasma proteins, thereby reducing the amount of free compound available to interact with antithrombin III.
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PMID:Pharmacologic properties of an unfractionated heparin butyryl derivative with long-lasting effects. 174 Jun 33

We investigated whether the inactivation of factor IXa contributes to the partial inhibition of thrombin formation that is observed at therapeutic concentrations of heparin. The action of standard unfractionated heparin (0.05 U/ml) on thrombin formation in the intrinsic system was compared to that of a mixture of dermatan sulfate (DS) and a synthetic pentasaccharide (PS). DS enhances the action of heparin cofactor II which inhibits thrombin only. PS specifically enhances the anti-factor Xa activity of antithrombin III (AT III). The concentrations of DS and PS were chosen so as to obtain equal anti-thrombin and anti-factor Xa activities as in 0.05 U/ml heparin. An extra inhibitory effect of heparin over the mixture is observed in situations where free factor IXa, not bound to factor VIIIa and phospholipid, limits the rate of thrombin formation, notably in contact activated plasma. We conclude that the inactivation of free factor IXa by heparin contributes importantly to the inhibition of thrombin formation in the intrinsic system such as e.g. measured in the activated partial thromboplastin time.
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PMID:Factor IX a inhibition contributes to the heparin effect. 174 1

The authors evaluated the potential for thrombotic complications arising from implantation of a ventricular assist device (Sarns/3M-VAD) in four calves. Coagulation screening tests (prothrombin time [PT], partial thromboplastin time [PTT], thrombin time [TT]), fibrinogen levels, and antithrombin III functional activity were found to be of little value as predictors of the degree of activation of the hemostatic system. However, platelet counts, adenosine diphosphate (ADP)- and collagen-induced platelet aggregation, and thromboxane (TXB2) levels were good indicators of changes in platelet reactivity. Platelet counts (initial value 6 x 10(5) rose, and were associated with increased rate and extent of ADP- and collagen-induced platelet aggregation, which remained elevated during the entire 25 day postimplantation period. The first 5 days postimplantation revealed a typical acute inflammatory response, with increased platelet levels, but with TXB2 levels significantly decreased during this period. A monoclonal antibody based bovine D-dimer assay and Western blot studies indicated a small but significant increase in circulating bovine D-dimer, indicating localized fibrin formation and its dissolution.
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PMID:Hemostatic evaluation of Sarns/3M-VAD implantation in calves. 175 Nov 63

Two different preparations of hepatic triglyceride lipase (HTGL) with comparable lipolytic activities, purified from post-heparin human plasma, were assessed for their anti-Xa activities by two clotting and one chromogenic method. Preparation 1, prepared by heparin affinity followed by ion exchange chromatography, did not contain antithrombin III and exhibited no anti-Xa activity in any of the assay systems. Preparation 2, prepared by two consecutive heparin affinity chromatography steps, was active in all three assay systems, and was shown to contain antithrombin III (AT III). Addition of purified AT III to preparation 1 did not result in the anti-factor Xa activity of preparation 2, and monoclonal antibodies to AT III did not antagonize the activity of preparation 2. These results show that the anti-Xa activity of some HTGL preparations is neither due to the lipase itself nor to the content of AT III, but suggest, that it could be due to contamination with another protein, which binds to heparin sepharose columns but is removed during ion exchange chromatography. Most likely the effect is due to the extrinsic pathway inhibitor (EPI), also called lipoprotein-associated coagulation inhibitor (LACI), which has recently been shown to be released by heparin.
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PMID:Anti-Xa clotting activities in different hepatic-triglyceride lipase preparations from post-heparin plasma. 175 3

Blood rheologic properties and homeostasis system were comprehensively examined in 23 patients with fibrous-cavernous pulmonary tuberculosis and 58 patients with various chronic nonspecific pulmonary diseases complicated by respiratory failure. The patients were found to have signs of erythrocyte edema, their more rapid depletion, lower resistance and higher aggregation which was accompanied by increased hematocrit and normal erythrocyte count. The thromboelastograms showed that all all phases of blood coagulation were shortened and fibrinolysis was deeply depressed. There was an increase in activated partial thromboplastin and thrombin time, a reduction in the values of the prothrombin indices and antithrombin III activity and higher heparin levels. The fibrinogen level was either normal or reduced despite an increase in other acute phase reactants, followed by the appearance of large amounts of blocked fibrinogen in the blood. Analysis of the findings enabled one to regard a combination of the above changes as signs of the latent DIC syndrome. Determination of fibrin and fibrinogen degradation products in a deep and long-term inhibition of fibrinolysis loses its diagnostic significance.
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PMID:[Status of the hemostatic system in patients with chronic lung diseases]. 175 60

A simulation model for the production of thrombin in plasma is presented. Values of the reaction rate constants as determined in purified systems are used and the model is tested by comparison of simulations of factor Xa, factor Va and thrombin generation curves with experimental data obtained in thromboplastin-activated plasma. Simulations of the effect of hirudin indicate that factor V is predominantly activated by thrombin and not by factor Xa. The model predicts a threshold value for the factor Xa production which, if exceeded, results in explosive and complete activation of prothrombinase. The dependence of this threshold value on different negative feedback reactions, e.g. the inactivation of thrombin and factor Xa by antithrombin III (+ heparin), is investigated. The threshold value, for control plasma in the range of 1-10 pM total factor Xa production, can be raised two orders of magnitude by accelerated inactivation of factor Xa and prothrombinase but is hardly affected by a tenfold increase in the rate of thrombin inactivation or by increased production of activated protein C. This latter effect, however, results in a more gradual input-response relation between factor Xa input and the extent of prothrombinase activation.
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PMID:Simulation model for thrombin generation in plasma. 179 46

The generation of thrombin in citrated, r-hirudinized and heparinized whole blood (final concentrations 10, 25, 50 micrograms/ml) was studied in the presence or absence of various activators. Whole blood from healthy volunteers was activated either by glass or dextran sulfate (contact activation; CA) as well as by thromboplastin/calcium chloride (extrinsic activation; EA) and by ellagic acid/cephaloplastin/calcium chloride (intrinsic activation; IA) and incubated 10 (CA, EA, IA) and 30 (CA) min at 37 degrees C. After the incubation period plasma levels of prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin III complex (TAT) were measured utilizing ELISA methodology. After EA or IA no blood clotting occurred in all r-hirudinized samples and in heparinized blood at the highest concentration used. Despite inhibition of clotting F1 + 2 levels were increased both in r-hirudinized and in heparinized blood. However, in blood anticoagulated with heparin F1 + 2 levels after EA, IA and especially after CA were markedly lower than in r-hirudinized blood. Furthermore, in r-hirudinized blood an increase of TAT levels was found. The enhancement of F1 + 2 and TAT levels by r-hirudin was concentration-dependent and was lower in the higher r-hirudin concentration. The results indicate that in r-hirudinized whole blood significant amounts of thrombin can be generated which may elicit thrombin-mediated feedback mechanisms.
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PMID:In vitro studies on thrombin generation in citrated, r-hirudinized and heparinized whole blood. 180 63


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