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)

The activation of factor X in the presence of antithrombin has been studied in order to determine the parameters that control the area under the resulting factor Xa generation curve. Generation curves were analyzed using a model containing three parameters: the total generation of factor Xa, Emax; the rate of factor Xa generation, expressed as a first-order rate constant, kappa 1; and the rate of inhibition, expressed as another first-order rate constant, kappa 2. Using factor IXa-VIIIa to activate factor X, we found the area under the generation curve to be proportional to Emax, which was varied by varying the factor IXa concentration, and inversely proportional to kappa 2, which was varied by varying the antithrombin concentration. With this activator, however, kappa 1 varied in parallel with Emax, resulting in a correlation between integrated area and kappa 1. In order to determine whether Emax or kappa 1, or both, was a controlling parameter, similar activations were done with varying concentrations of the factor X-activating enzyme of Russell's viper venom. With this activator it was possible to vary Emax and kappa 1 independently, again at varying antithrombin concentrations. These results showed the integrated area to be proportional to Emax and inversely proportional to kappa 2, as before, but independent of the activation rate, kappa 1. In this system, therefore, the area under the factor Xa generation curve is controlled by the amount of factor Xa generated and its rate of inhibition but is independent of the rate of factor Xa generation.
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PMID:Analysis of the generation and inhibition of factor Xa. Area under generation curves is independent of enzyme generation rate. 221 47

Patients with acute myeloid leukemia have multiple hemostatic and thrombotic complications, which may or may not result from disseminated intravascular coagulation. Previous studies incorporating routine coagulation analyses failed to detect any clinically useful information in most of these patients. In this study, the first comprehensive evaluation of the various aspects of the hemostatic system in a population of patients with acute myeloid leukemia was performed. Eighteen patients (23-71 years of age) were studied at either diagnosis or relapse. Hemostatic studies were performed at onset and on days 3, 7, and 30 after initiation of therapy. The bone marrow blast counts ranged from 8% to 98%; prothrombin time and activated partial thromboplastin time showed only minor prolongations in a few of these patients. However, in all patients measurement of platelet-associated markers revealed elevated platelet factor 4 and thromboxane B2 and normal 6-keto-prostaglandin F1 alpha levels. Fibrinolytic markers showed an increase in D-dimer and tissue plasminogen activator and a decrease in alpha 2-antiplasmin levels. Plasminogen, plasminogen activator inhibitor, and fibrinogen levels were normal. Coagulation markers demonstrated a decrease in protein C and antithrombin III levels and an elevation of the thrombin-antithrombin complex. The pretreatment values for all hemostatic markers studied were similar to the values obtained on days 3, 7, and 30 during treatment. This investigation demonstrated a subclinical activation of the components of the hemostatic system possibly leading to a hypercoagulable state. Although only six patients (33%) experienced hemorrhagic complications, the risk of bleeding and/or thrombosis was strongly evident in all patients. The significance of finding abnormal levels of specific molecular markers of hemostasis will be established in the future application of such markers in clinical evaluations of leukemic patients known to be at risk for coagulation disorders.
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PMID:Global and molecular hemostatic markers in acute myeloid leukemia. 222 Jun 67

Our purpose was to determine the relative contribution of the antifactor Xa and antithrombin activities of heparin to its antithrombotic potency. The antithrombotic activities of unfractionated heparin (UH), two low molecular weight heparins (LMWH, CY 216 and CY 222) with increasing anti-factor Xa/antithrombin ratio and a synthetic pentasaccharide (PS) with high affinity to antithrombin III and no antithrombin activity were evaluated. In the Wessler-thromboplastin model, the most potent antithrombotic agent, on a weight basis, was UH followed by CY 216, CY 222 and the PS which was 40 times less potent than UH. On an antithrombin unit basis, the antithrombotic potencies of UH, CY 216 and of CY 222 were equivalent. Thus, in this model, the antithrombotic effect results from the catalytic action of UH or LMWH on thrombin inhibition. In the Wessler-serum model, on a weight basis, the antithrombotic effectiveness of UH was unchanged, those of CY 216 and CY 222 were doubled, and that of the PS was increased 10 times. On an anti-factor Xa unit basis, CY 216 was as effective as UH, and PS as effective as CY 222. On an antithrombin unit basis, CY 216 and CY 222 were equivalent and more potent than UH. Thus, in this model, the antifactor Xa activity of heparin becomes important for its antithrombotic property. After a single subcutaneous injection of 1000 antifactor Xa U/kg, the antithrombotic effects of UH were maintained for more than 14 h in the two models. After injection of the same dose of CY 216 significant antithrombotic effects were observed only for 9 h, in the Wessler-thromboplastin model but for 18 h in the Wessler-serum model. At that time, no detectable antithrombin activity was measurable in the plasma while 0.11 units of antifactor Xa activity/ml was detected. Thus, the relative contribution of the anti-factor Xa and antithrombin activities to the antithrombotic effect of a LMWH differs according to the nature of the thrombogenic stimulus.
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PMID:Antithrombotic potencies of heparins in relation to their antifactor Xa and antithrombin activities: an experimental study in two models of thrombosis in the rabbit. 222 52

Factor IX is the zymogen of the serine protease factor IXa involved in blood coagulation. In addition to a catalytic domain homologous to the chymotrypsin family, it has Ca2+, phospholipid, and factor VIIIa binding regions needed for full biologic activity. We isolated a nonfunctional factor IX protein designated factor IXEagle Rock (IXER) from a patient with hemophilia B. The variant protein is indistinguishable from normal factor IX (IXN) in its migration on sodium dodecyl sulfate-gel electrophoresis, isoelectric point in urea, carbohydrate content and distribution, number of gamma-carboxyglutamic acid residues, and beta-OH aspartic acid content, and in its binding to an anti-IXN monoclonal antibody which has been shown previously to inhibit the interaction of factor VIIIa with factor IXaN. Further, IXER is cleaved to yield a factor IXa-like molecule by factor XIa/Ca2+ at a rate similar to that observed for IXN. However, in contrast to IXaN, IXaER does not bind to antithrombin-III (specific inhibitor of IXaN) and does not catalyze the activation of factor X (substrate) to factor Xa. To identify the mutation in IXER, all eight exons of IXN and IXER gene were amplified by the polymerase chain reaction technique and cloned. A single point mutation (G----T) which results in the replacement of Val for Gly363 in the catalytic domain of IXER was identified. Gly363 in factor IXa corresponds to the universally conserved Gly193 in the active site sequence of the chymotrypsin serine protease family. X-ray crystallographic data in the literature demonstrate a critical role of this Gly in stabilizing the active conformation of chymotrypsin/trypsin in two major ways: 1) in the formation of the substrate binding site; and 2) in the development of the oxyanion hole. Our computer structural data support a concept that the Gly363----Val change prevents the development of the active site conformation in factor IXa such that the substrate binding site and the oxyanion hole are not formed in the mutated enzyme.
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PMID:Experimental and theoretical evidence supporting the role of Gly363 in blood coagulation factor IXa (Gly193 in chymotrypsin) for proper activation of the proenzyme. 230 34

Status of thromboplastin, antiheparin and antithrombin characteristics of the native and cryopreserved bone marrow was studied experimentally on 12 rabbits. It is found that both the native and cryopreserved bone marrow possesses a pronounced and dilution resistant thromboplastin activity, whereas antithrombin and heparin activities were statistically unauthentic. In that connection the bone marrow injected into blood circulation may have different effects depending on the initial state of the recipient blood coagulation. The fact should be taken into account in clinics.
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PMID:[Study of tissue coagulation factors of native and cryopreserved bone marrow]. 232 48

Paeonia lactiflora with the action of promoting blood circulation and removing blood stasis had been shown to be able to inhibit thrombosis and platelet aggregation, increase fibrinolytic activity and promote thrombolysis. This paper described the influence of the extract of Paeonia lactiflora in vitro experiments on prothrombin time (PT), activated partial thromboplastin time (PTT), antithrombin effect, activity of plasminogen and urokinase. The experimental results showed that: (1) The extract of Paeonia lactiflora prolonged the time of PT and PTT. (2) The extract of drug was able significantly to inhibit the thrombin. (3) In study of fibrinolysis by fibrin standard plate experiments, the drug possessed activative effect on the plasminogen. (4) The activity of urokinase was reduced, while the extract of Paeonia lactiflora existed. The inhibitory effect on thrombin and effective effect on plasminogen of the drug might be an important mechanism of its action of promoting blood circulation and removing blood stasis.
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PMID:[Effect of an extract of Paeonia lactiflora on the blood coagulative and fibrinolytic enzymes]. 236 61

Changes in clotting time (CT) and fibrinolytic activity (FA) were evaluated in 6 mature, female horses during exercise. Two trials were performed on consecutive days, using a randomized crossover design. Each mare was assigned to either an exercise trial or a control trial on the first day, and to the alternate trial 24 hours later. Mares exercised for 20 minutes on a treadmill at an elevation of 2 degrees and a velocity of 5 m/s. Venous blood samples were collected immediately before exercise, at 4, 8, 12, 16 and 20 minutes during exercise, and 15 minutes after cessation of exercise. Blood was placed into plain glass tubes for determination of CT, and into chilled, citrated tubes for determination of FA, plasminogen/plasmin complex activity (PLG), one-stage prothrombin time (OSPT), activated partial thromboplastin time (APTT), and antithrombin-III (AT-III) activity. There were significant differences (P less than 0.05) between the control and exercise groups for CT, FA, and PLG. During exercise, clotting time decreased from 21.5 +/- 1.6 minutes to 9.9 +/- 1.6 minutes (mean +/- SD; P less than 0.05), without significant changes in OSPT, APTT, or AT-III. Fibrinolytic activity and PLG increased (P less than 0.05) during exercise. Changes in CT, FA, and PLG were significant at 4 minutes of exercise, remained altered until the end of exercise, and returned to baseline values by 15 minutes of recovery. Clotting time, OSPT, APTT, FA, AT-III, and PLG did not change (P greater than 0.05) during control trials.
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PMID:Changes in coagulation and fibrinolysis in horses during exercise. 239 79

The effects of hydroxyethyl starch (HES) on hemostasis were investigated extensively. In order to simulate acute blood loss due to surgery or trauma, one unit (450 ml) of blood was drawn from normal healthy men. This was followed by a 1-liter infusion over 60 minutes of either 6 percent HES, 5 percent albumin, or 0.9 percent sodium chloride (NaCl) as replacement. Coagulation studies were performed before phlebotomy, before infusion and at 0, 4, 20, 27, and 92 hours following infusion. Following infusion of HES and albumin, plasma fibrinogen and antithrombin-III levels fell slightly due to plasma volume expansion and hemodilution. In subjects receiving HES, partial thromboplastin times (PTTs) were significantly (p less than .05) prolonged and factor VIII activities were significantly (p less than .05) decreased when compared to the albumin and NaCl groups. These findings could not be attributed solely to hemodilution. The effects of HES on PTT and factor VIII could not be correlated with plasma HES levels; neither could they be reproduced in vitro by mixing HES with normal plasma. Mean values of the following studies remained normal after infusion of all replacement fluids: prothrombin time, bleeding time, fibrin monomer, fibrin-fibrinogen degradation products, platelet adhesion, circulating platelet aggregates, and platelet count.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of hydroxyethyl starch on blood coagulation, particularly factor VIII. 241 Oct 30

The effects of standard heparin, three low molecular weight derivatives of heparin, dermatan sulphate and pentosan polysulphate on the intrinsic coagulation pathway were compared in order to evaluate the contributions of the anti-factor Xa and anti-thrombin activities to their anticoagulant activities. The anticoagulant potency was measured by the ability of each sulphated polysaccharide to inhibit the generation of thrombin activity in plasma. Similarly, the ability of the six sulphated polysaccharides to enhance the rates of inactivation either factor Xa or thrombin in defibrinated plasma containing calcium chloride and cephalin were also determined. Standard heparin was the only sulphated polysaccharide that could equally inhibit thrombin generation and enhance the inactivation of factor Xa and thrombin by plasma. Dermatan sulphate and pentosan polysulphate were more effective as inhibitors of thrombin generation than potentiators of factor Xa inactivation. The two smallest derivatives of heparin, which had high anti-factor Xa (but low antithrombin) activity, were the poorest inhibitors of thrombin generation. Our results therefore suggest that only sulphated polysaccharides that enhance the inactivation of thrombin by plasma and/or inhibit the generation of thrombin activity in plasma are good anticoagulants. These two activities of sulphated polysaccharides appear to be good predictors of the relative antithrombotic potency in vivo.
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PMID:The importance of thrombin inhibition for the expression of the anticoagulant activities of heparin, dermatan sulphate, low molecular weight heparin and pentosan polysulphate. 241 Dec 83

A method has been developed for detailed kinetic studies of the inhibition of factor Xa in human plasma. Radiolabeled enzyme is not required, and the method can be used at initial factor Xa levels of 1 nM. The method is discontinuous and based on the removal of samples into an amidolytic assay done in the presence of 1% Lubrol-PX detergent. This permits the study of inhibition in mixtures containing phospholipid, platelets, or thromboplastin. The method can be used at inhibition rates in excess of 1 min-1, and by suitable analysis can be used to estimate the contribution of inhibition by alpha 2-macroglobulin, which does not itself inhibit amidolytic activity. The method is at present limited to cases where thrombin is not generated in large excess. Factor Xa inhibition has been studied in citrated plasma as a function of total plasma concentration, and--by the use of antithrombin-depleted plasma--as a function of the antithrombin concentration of the plasma. In all situations inhibition is characterized by second-order behavior: (i) total inhibition rate is proportional to plasma concentration up to 95%, giving a maximum rate in the absence of calcium of 1 min-1; (ii) inhibition in depleted plasma reconstituted with antithrombin shows inhibition rate to remain linearly related to antithrombin concentration; and (iii) the estimated rate due to alpha 2-macroglobulin is proportional to plasma concentration. It is thus confirmed that, as in pure systems, inhibition of factor Xa in whole plasma is linearly related to the concentration of each class of inhibitor.
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PMID:Measurement of the kinetics of inhibition of activated coagulation factor X in human plasma: the effect of plasma and inhibitor concentration. 242 4


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