Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:005171 (prothrombin)
 14,518 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By devising and applying quantitative methods for the assay of thrombin and autoprothrombin C and by developing techniques for their purification, it was possible to obtain information about the function and properties of antithrombin. The inhibitor is a protein for which the initial purification steps consist of removing fibrinogen from plasma by heating to 56 degrees for 3 min, removing prothrombin complex by absorption on barium carbonate, absorbing the antithrombin on aluminum hydroxide, and eluting with phosphate buffer. Antithrombin is limited in its capacity to neutralize thrombin activity, and, under some conditions, the rate of inhibition was accelerated, but equivocal results were involved. Heparin cofactor was found to be essential for retarding the formation of thrombin, and, by inference, it is essential for retarding the formation of autoprothrombin C. Heparin cofactor and antithrombin III are the same. Thrombin absorbs on fibrin, and this has been referred to as the "antithrombin I effect." Interference with the thrombin-fibrinogen reaction by mixtures of antithrombin III and heparin is called the "antithrombin II henomenon." The acceleration of thrombin inactivation at the time thrombin forms is called the "antithrombin IV effect." It was discovered that antithrombin III neutralizes thrombin, as well as autoprothrombin C. The inhibitor and the enzyme form a mutual depletion system. To assay for antithrombin III, a standard quantity of thrombin (about 1,100U/ml) was reacted with antithrombin III for 2 hr. The percent thrombin inactivated was then measured. In random samples of human blood, a wide range of antithrombin III concentration was found. The inhibitor is relatively stable in plasma and serum. It is not changed in concentration when Dicumarol therapy is instituted. Ether extraction of plasma reduces antithrombin III activity. Seitz filtration of plasma did not remove activity. Under special conditions, antithrombin III enhances esterase activity of thrombin. Under special conditions, thrombin regenerates from the thrombin-antithrombin III complex. Antithrombin III neutralizes the activity of prethrombin-E and thrombin-E; consequently, an active histidine center found in the B1 chain of thrombin is not essential for the binding of antithrombin. Autoprothrombin II-A activity was neutralized by antithrombin III. Autoprothrombin C was found to be neutralized by antithrombin III; the amounts required varied with the molecular forms of autoprothrombin C. Thrombin and autoprothrombin C apparently occupy the same binding sites on antithrombin III. An equation was developed to account for all the known characteristics of antithrombin III functions. The kinetic aspects of thrombin neutralization were found to correspond exactly with those of autoprothrombin C. Antithrombin III is a high-capacity inhibitor of the two most powerful enzymes in blood coagulation.
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PMID:Antithrombin III: a backward glance o'er travel'd roads. 4 4

The interaction of heparin with chemically modified thrombin and heparin cofactor is studied. Amidinated heparin cofactor does not bind to heparin-agarose and the reaction rate of the amidinated inhibitor with unmodified thrombin is not affected by heparin. Likewise, thrombin modified with 1,2--cyclohexanedione does not bind to heparin agarose and the reaction rate of the modified enzyme with unmodified inhibitor is not affected by heparin. In the absence of heparin, the modified and unmodified proteins react at the same rate in all possible combinations. Affinity chromatography of diisopropylphosphoryl thrombin on heparin cofactor coupled to Sephadex G--50 is used to study the binding of heparin cofactor and thrombin to heparin. The thrombin for all experiments is tritium-labeled and then inactivated with diispropylfluorophosphate. Thrombin is not bound to heparin cofactor-Sephadex columns. However, after treatment of the columns with a heparin solution, thrombin binds tightly, and is eluted at high ionic strength. Bound thrombin can also be eluted with either excess non-radioactive thrombin or excess free heparin. Heparin-dependent binding of thrombin does not occur if the heparin cofactor-Sephadex is heat-denatured. The ability of heparin to couple solution-phase thrombin to solid-phase heparin cofactor indicates that a ternary complex is formed. Analysis of the binding of the proteins to heparin by a dye displacement method suggests that at least one site on heparin binds to thrombin but not to heparin cofactor. Further support for a catalytic role for heparin derives from the ability of catalytic concentrations of heparin to enhance the rate of hydrolysis of prothrombin by thrombin, another protein pair which bind mutually to heparin.
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PMID:A catalytic role for heparin. Evidence for a ternary complex of heparin cofactor thrombin and heparin. 7 28

The inhibitory effects of a newly synthesized protease inhibitor, Gabexate mesilate (FOY), on experimental disseminated intravascular coagulation were studied as compared with those of aprotinin or heparin. Thrombin, tissue thromboplastin, and endotoxin were used as DIC trigger substances. As parameters on DIC, platelet counts, white blood cell counts, neutrophilic leukocyte counts, fibrinogen, fibrin degradation products, platelet retention, platelet aggregation, prothrombin time, partial thromboplastin time were served. The drug efficacy in each parameter were expressed by the score system and analyzed statistically. The results were summarized as follows; (1) In thrombin-induced DIC, FOY was apparently superior to the other drugs (p less than 0.05). (2) In thromboplastin-induced DIC, heparin was slightly more effective than FOY or aprotinin. (3) In endotoxin infusion, there were no significant differences among them. In conclusion, the results of the present study suggest that FOY was more effective than heparin or aprotinin on experimental DIC.
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PMID:Inhibitory effects of gabexate mesilate (FOY) on experimental DIC. 22 8

When human 125I-labeled Factor Xa is incubated with washed platelets, prothrombin, and Ca2+, a small amount of thrombin is formed which causes the platelet release reaction after a period of time that decreases as the Xa concentration is increased from 0.9 to 19 ng/ml. After a further lag period, the Xa binds reversibly to receptors on the platelet surface and rapid thrombin formation follows (3 units or 1 mug of thrombin formed per min per ng of Xa bound to 10(8) platelets). When platelets are treated with either htrombin (0.5 units/ml) or calcium ionophore A23187 prior to addition of Xa, binding begins immediately. Thrombin formation occurs at the platelet surface at rates that correlate with the amount of Xa bound. Dibutyryl cyclic AMP inhibits the release reaction, Xa binding, and rate of thrombin generation in parallel. The platelet Xa receptor is distinct from the previously described thrombin receptor and appears to be a protein because treatment of platelets with thrombin at 50 units/ml destroys Xa binding sites. The results suggest that specific receptors for Xa appear on the platelet surface after the release reaction occurs. The bound Xa catalyzes thrombin formation 1000-fold faster than does Xa added to reactions in which phospholipids are substituted for platelets.
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PMID:Interaction of coagulation factor Xa with human platelets. 33 55

Antithrombin III is one of the main inhibitors in the blood coagulation mechanisms. Thrombin and factor Xa are slowly inactivated by it, as well as other serine proteinases of the coagulation mechanisms. Heparin tremendously accelerates the inhibitory function of antithrombin III. In the process antithrombin III activity is also reduced. Heparin retards the thrombin-fibrinogen reaction, but otherwise the effectiveness of heparin as an anticoagulant depends on antithrombin III in laboratory experiments, as well as in therapeutics. The activation of prothrombin is inhibited, and any thrombin or other vulnerable protease that might generate becomes inactivated. The measurement of antithrombin III concentration in blood is now achieved by research methods, as well as by methods that are practical for routine use. The tests require either thrombin or factor Xa as substrate, and could be specific for antithrombin III. There are congenital as well as acquired deficiencies of antithrombin III. The inhibitor is also found in tissues.
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PMID:Antithrombin III. Theory and clinical applications. H. P. Smith Memorial Lecture. 34 19

Thrombocytin, a serine protease from Bothrops atrox venom, caused platelet aggregation and release of platelet constituents at a concentration of 10(-7) M and clot retraction at a concentration of 2 x 10(-9) M. Thrombocytin was slightly more active when tested on platelets in plasma than on washed platelets suspended in Tyrode--albumin solution. Thrombin was 5 times more active than thrombocytin when tested on platelets in plasma and 50 times more active when tested on washed platelets. The patterns or release induced by thrombocytin and thrombin were similar. Prostaglandin E1 (10(-5) M) produced complete inhibition of platelet release induced by thrombocytin and thrombin. Indomethacin (10(-4) M) was without any effect. Antithrombin III, in the presence of heparin, inhibited the action of thrombocytin on platelets and on a synthetic peptide substrate (Tos-Gly-Pro-Arg-pNA.HCl). formation of an antithrombin III--thrombocytin complex was demonstrated on NaDodSO4--polyacrylamide gel electrophoresis. Hirudin and alpha 1-antitrypsin did not inactivate thrombocytin. Thrombocytin had a low fibrinogen-clotting activity (less than 0.06% that of thrombin). Thrombocytin also caused progressive degradation of the alpha chain of human fibrinogen, and it cleaved prothrombin, releasing products similar to intermediate 1 and fragment 1 produced by thrombin. Thrombocytin activated factor XIII by limited proteolysis and increased the procoagulant activity of factor VIII in a manner analogous to that of thrombin.
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PMID:Thrombocytin, a serine protease from Bothrops atrox venom. 2. Interaction with platelets and plasma-clotting factors. 47 69

Thrombin first activates and then inactivates factor VIII and for this reason thrombin has been considered responsible for the inactivation of factor VIII which occurs during clotting. Experiments described in this paper indicated that the activity of factor VIII is not reduced in factor IX or factor X deficient sera, while on the other hand this factor becomes inactivated in blood anticoagulated with high concentrations of hirudin which inhibit thrombin activity completely. This suggests that some other factor, besides thrombin, which is generated only in trace amounts in factor IX or factor X deficient plasmas, is also able to inactivate factor VIII. Purified factor X activated with insolubilized trypsin was added to purified preparations of factor VIII, which were free of both fibrinogen and prothrombin. Factor X a was allowed to act for 5-60 minutes and then inactivated with phenylmethanesulfonyl fluoride. Depending on the duration of the action of factor X a partial or complete inactivation of factor VIII was observed. This inactivation was also observed in the presence of hirudin, thus excluding the possibility that the effect was due to contamination with trace amounts of thrombin.
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PMID:Inactivation of factor VIII by a mechanism independent of the generation of thrombin. 50 1

The procoagulant activity of cells from some experimental tumours isolated in culture or in single-cell suspensions from ascitic fluid was investigated. Cells from Lewis lung carcinoma (primary and metastasis), Ehrlich carcinoma ascites and JW sarcoma ascites were able to shorten markedly the recalcification time of normal, Factor VIII- and Factor VII-deficient but not of Factor X-deficient human plasma. The same cells generated thrombin when mixed with a source of prothrombin and Factor X, absorbed bovine serum (as a source of Factor V), phospholipid and calcium chloride. Thrombin formation was not influenced by the presence of Factor VII. Cells from Sarcoma 180 ascites were completely inactive in both test systems. It is concluded that cells from some experimental tumours have the capacity to activate Coagulation Factor X directly. These findings suggest the existence of an alternative "cellular" pathway in the initiation of blood clotting distinct from both the intrinsic and extrinsic mechanisms.
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PMID:Evidence that cells from experimental tumours can activate coagulation factor X. 57 31

Thrombogenicity of the factor IX concentrate and its clinical use for stoppage of the bleeding in the case of hemophilia A with inhibitor were reported. (1) Factor IX concentrate contained the coagulation factors as prothrombin complex (factors II, VII, IX and X); Thrombin and factor Xa. (2) Prothrombin in the factor IX concentrate could be converted to thrombin without any additional procoagulant such as thromboplastin or factor V, but in just 2.5M glycine solution by the effect of factor Xa. (3) The infusion of factor IX concentrate into a rabbit induced DIC promptly which was proved by autopsy and coagulation-fibrinolytic studies. (4) Factor IX concentrate showed a great efficacy in stopping the bleeding in the case of hemophilia A with inhibitor.
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PMID:Characteristics and thrombogenicity of factor IX concentrate. 61 88

Low concentrations of a polyoxyethylene detergent, Brij 58, inhibited the secondary phase of platelet aggregation induced by ADP in human citrated platelet-rich plasma but had no effect on primary aggregation. Thrombin-induced aggregation of washed human platelets suspended in Tyrode's buffer was inhibited after incubation of cells with 4.10(-6) M detergent. Efflux of [14C]serotonin, 45Ca2+ and labile aorta contracting substance (thromboxane A2) and development of prothrombin-converting activity (platelet factor 3) were abolished concomitantly. Aggregation of washed platelets either by sodium arachidonate or by collagen was also inhibited by the same concentration of Brij 58 which inhibited thrombin aggregation. This concentration did not itself produce any release of a cytoplasmic marker, lactate dehydrogenase, from platelets. Higher concentrations of Brij 58, exceeding 4.10(-5) M, lysed the cells liberating lactate dehydrogenase, serotonin and Ca2+. When albumin was included as a platelet stabilizer in the suspending medium the concentration of detergent required for the inhibitory effects was increased ten-fold. This could be attributed to competitive binding of the detergent to albumin, demonstrated with [14C]acetylated Brij 58. A variety of other polyoxyethylene detergents, at concentrations from 8.10(-4) to 5.10(-3) M, also inhibited platelet aggregation induced by thrombin. It is concluded that low concentrations of Brij 58 stabilize the platelets against the action of aggregating agents, while higher concentrations produce membrane destabilization and cell lysis.
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PMID:Effects of a polyoxyethylene detergent (Brij 58) on platelet aggregation, release and clotting activity. 62 96


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