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)

Three human volunteers were injected with a range of doses of pentosan polysulphate, SP54, i.v. or s.c. A competitive binding assay (CBA) for sulphated polysaccharides was used to detect circulating SP54 after doses as low as 1 mg i.v. and a linear relationship was observed between the peak plasma concentration of SP54 measured by CBA and the administered dose. A comparison was made between the clearance of SP54 measured by CBA and its anticoagulant and lipolytic activities. SP54 was detectable by CBA after doses which caused no alteration in activated partial thromboplastin time (APTT) or anti-factor Xa activity but after which a small increase of lipase activity was measurable. After SP54 at 10 mg i.v. or 100 mg s.c. anti-factor Xa activity was 4-6 times greater than would be expected from the in vitro activity of the concentrations of SP54 measured by CBA. Like heparin and other heparin analogues, SP54 caused an increase in plasma concentrations of platelet factor 4 (PF4) without a concomitant rise in beta-thromboglobulin (beta-TG). It is concluded that the newly developed CBA will provide a more sensitive means than conventional bioassays for the determination of plasma concentrations of SP54.
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PMID:Metabolism of sodium pentosan polysulphate in man measured by a new competitive binding assay for sulphated polysaccharides--comparison with effects upon anticoagulant activity, lipolysis and platelet alpha-granule proteins. 241 64

Anticoagulant properties of three sulfated compounds prepared from xylans isolated from corn cobs, larchwood and oatspelts were compared with heparin and sodium pentosan polysulfate (SP-54) by studying their effects on activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) using pooled normal human plasma. These compounds were more effective than SP-54 in delaying coagulation by all the three procedures while oatspelts xylan sulfate was as effective as heparin in inhibiting APTT and PT and more effective than heparin in inhibiting TT on a molar basis. The sulfated xylans were more effective than heparin or SP-54 in potentiating the AT-III inhibition of amidolysis of H-D-Phe-Pip-Arg-pNa (S-2238) by thrombin (IIa) or amidolysis of Bz-Ile-Glu-Gly-Arg-pNa (S-2222) by Xa. Study of the high affinity binding of the xylan sulfates to AT-III-Sepharose column showed that the amount of the xylan sulfate recovered in the eluates from this peak was greatly increased with an increase in molecular weight (MW). A buffered mixture of IIa, AT-III and dansylarginine N-(3-ethyl-1,5-pentanediyl) amide (DAPA) was used to study the inactivation of IIa by AT-III. Larchwood xylan sulfate (2-10 micrograms) was found to accelerate this inactivation which was neutralized by human platelet factor 4 (PF4). The results also suggested an interaction between larchwood xylan sulfate and IIa which may potentiate an interaction between AT-III and IIa.
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PMID:Mechanism of potentiation of antithrombin III [AT-III] inhibition by sulfated xylans. 244 30

A new reagent for the determination of heparin in plasma has been developed. In the assay heparin which was bound to platelet factor 4 is also measured. That is why samples, which have to be assayed for heparin with this reagent, do not need any special pretreatment like fast and cooled processing in order to prevent release of platelet factor 4 from platelets. Heparin can be assayed in samples anticoagulated with citrate which are used routinely for the determination of other coagulation parameters like PT or aPTT. Freezing prior to the assay is possible and does not influence the result. The assay is based on the inactivation of factor Xa by antithrombin III which is catalysed by heparin or smaller fragments of it. It can therefore be used for the determination of heparins of low molecular weight, too. The sample is first mixed with AT III in order to compensate for a potentially decreased level in the probe. Then the F Xa reagent is added, which releases bound heparin from plasma proteins like platelet factor 4 by an added polysulfated dextran simultaneously to the onset of the inhibitory reaction towards F Xa. Free and secondarily released heparin are then available for determination. After a defined period of time a substrate for F Xa is added and the remaining activity is measured in a photometer. An incubation time of 1 min or 3 min is used for the normal range of 0.1 to 1 U/ml or the low dose range from 0.01 to 0.3 U/ml heparin, respectively.
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PMID:An improved heparin assay which is insensitive to platelet factor 4. 248 5

Serial determinations of beta-thromboglobulin (BTG), platelet factor 4 (PF4), fibrinopeptide A (FPA), antithrombin III (ATIII), protein C (PC), fibrin (ogen) degradation product (FDP), FDP D-dimer, activated partial thromboplastin time (APTT), prothrombin time (PT), and euglobulin lysis time (ELT) were performed in 18 patients with non-progressing stroke and 14 patients with progressing stroke in order to predict the development of progressing stroke. Increasing levels of BTG, PF4 and FDP with frequent fluctuation were noted in both kinds of stroke. Fluctuation of FPA levels was also noted but was less pronounced. PC levels were found to be slightly decreased with fluctuation but the mean was still in the lower normal limit. BTG, PF4 and PC all elevated at the time of deterioration of physical condition in patients with progressing stroke, whereas FPA had no definite change at that time. From our study, we conclude that both platelet activation and coagulation process do occur in both kinds of stroke. But the latter plays a minor role in the formation of thrombosis. The hemostasis change, especially concerning the thrombosis formation, probably plays a role in the development of progressing stroke, but we cannot predict their development even by the detections of the newly known molecular substances appearing in various steps of the hemostatic mechanism. Development of new tests for understanding the whole dynamic change of the thrombosis process is necessary for accurate prediction of the progressing stroke in the future.
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PMID:The serial hemostasis-related changes in patients with cerebral infarction: comparison between progressing and non-progressing stroke. 253 1

We studied the mode of action of the low molecular weight heparin PK10169 and two of its constituent fractions: EMT 966 High Molecular Weight Fraction and EMT 967 Low Molecular Weight Fraction. EMT 966 like standard heparin, acts primarily on thrombin formed and not on prothrombinase (S type heparin). In contrast EMT 967 has no direct effect on thrombin. At high concentrations, it inhibits the prothrombinase complex (P type heparin). PK10169, that contains the two EMTs shows both activities: antithrombin and antiprothrombinase (mixed type heparin). The addition of increasing amounts of EMT 967 to a constant amount of EMT 966 does not influence the breakdown constant of endogenous thrombin which is determined by the concentration of EMT 966 only. This demonstrates the absence of competition for AT III between the two components of PK10169. In platelet rich plasma, EMT 966 inhibits and postpones thrombin generation more efficiently than unfractionated heparin, probably because it is less sensitive to neutralization by platelet components (platelet factor 4). Amounts of EMT 967 that hardly inhibit thrombin generation in platelet rich plasma enhance the effect of EMT 966 probably by neutralizing platelet factor 4.
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PMID:The mode of action of low molecular weight heparin preparation (PK10169) and two of its major components on thrombin generation in plasma. 254 77

We describe in the present paper the results of the influence of normal and low-molecular-weight heparin on the interaction of human fibrinogen and thrombocytes in human whole blood cotting ex vivo. During the coagulation process sequential measurements of fibrinopeptide A reflect fibrin formation and determination of platelet factor 4 indicate activation of thrombocytes. The data show that low-molecular-weight heparin inhibits plasma thrombin generation in vivo for longer than normal heparin and it affects the fibrinogen platelet binding less. There is good evidence that a lonely factor Xa inhibition mediates this anticoagulant mechanism. Therefore, these data favor the hypothesis that antifactor Xa activity prevents indeed blood clotting.
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PMID:Significance of thrombin-receptors of thrombocytes for the interaction of heparins and low-molecular-weight heparin in human whole blood clotting. 284 Mar 70

Different low-molecular-weight (LMW) heparins are produced by fractionation, enzymatic and chemical methods. Although the manufacturer's assigned molecular weights of these agents are similar (around 5,000 daltons), they exhibit considerable molecular structural heterogeneity due to the variations in the manufacturing process. In vitro standardization of these LMW heparins produces highly variable results due to the variability of assay specificity. In a comparative study with seven LMW heparins, differences were found in molecular weight distribution, antifactor Xa activity, antifactor IIa activity, Heptest activity, USP potency, platelet interactions, protamine and platelet factor 4 neutralization and charge density ratios. Relative antithrombotic actions varied between the seven agents and the ratio of the intravenous:subcutaneous effects were inconsistent with expected results based on in vitro properties or observed ex vivo effects. These products were not bioequivalent in equigravimetric or equipharmacopeial dosages (antifactor Xa, USP). Although the intravenous bioavailability was proportional to the potency for an individual agent, the subcutaneous bioavailability of the same agent showed differences from that of the intravenous regimen. In addition, significant differences between the bleeding profiles of these agents were noted in both intravenous and subcutaneous routes. The bleeding profiles did not correlate well with the relative proportion of the antifactor Xa component. However, some relationship to the bleeding effect was observed with the antifactor IIa and activated-partial-thromboplastin-time activities. These LMW heparins produced different effects on platelets as studied in the heparin-induced thrombocytopenia and platelet activation systems. These observations suggest that the individual composition of each LMW heparin determines its in vivo behavior which may account for the different safety/efficacy ratios observed in clinical trials.
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PMID:Comparative study on the in vitro and in vivo activities of seven low-molecular-weight heparins. 284 Mar 72

A commercial heparin preparation, a heparin fraction with a molecular weight of 12,000 Daltons, heparan sulfate, dermatan sulfate obtained from hog mucosa, and mesoglycan, an heparinoid obtained from calf aortic intima were investigated. Commercial mucous heparin had a stimulatory effect on platelet aggregation induced by ADP, while the others failed to do so. Dermatan sulfate had a dose dependent inhibition and commercial mucosal heparin, a dose dependent stimulation, on serotonin release induced by ADP. Both the commercial mucosal heparin and dermatan sulfate showed an inhibition and the other glycosaminoglycans (GAGs) a negligible effect on collagen induced platelet aggregation. The collagen induced serotonin release was clearly reduced by all GAGs; heparan sulfate had this activity only at the highest doses used. Commercial mucosal heparin produced the highest activity on clotting systems as measured by activated partial thromboplastin time, while mesoglycan had the strongest anti-factor Xa specific activity as measured by a clotting assay. Dermatan sulfate was the weakest on both assays. When we injected intravenously an equivalent amount (about 60 mg) of heparin fraction, heparan sulfate, dermatan sulfate and mesoglycan in three different volunteers with an interval of 20 days after each injection, we had an immediate platelet factor 4 (PF4) release only with heparin fraction, heparan sulfate and mesoglycan. Heparin fraction and mesoglycan, in spite of having a wide discrepancy in anticoagulant effect, caused almost the same PF4 release. GAGs which can neutralize PF4 and which can also have specific anti-factor Xa activity could represent a great advantage in thrombosis prophylaxis.
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PMID:Effects on platelets and on the clotting system of four glycosaminoglycans extracted from hog mucosa and one extracted from aortic intima of the calf. 295 35

Platelet factor 4 is a polypeptide constituent of platelet alpha granules that is released during platelet aggregation and inhibits heparin-mediated reactions. Hageman factor (factor XII) is a plasma proenzyme that, when activated by certain negatively charged agents, initiates clotting via the intrinsic pathway of thrombin formation. In earlier studies using crude systems, platelet factor 4 inhibited activation of Hageman factor by dextran sulfate or cerebrosides, but not activation of Hageman factor by kaolin or ellagic acid. In the present study we examined the mechanisms of inhibition by platelet factor 4, using purified reagents. Platelet factor 4 inhibited activation of Hageman factor by ellagic acid, as measured by amidolysis of a synthetic substrate of activated Hageman factor, an effect inhibited by heparin or by an anti-platelet factor 4 antiserum. Coating glass tubes with platelet factor 4 before addition of normal plasma significantly lengthened the partial thromboplastin time of normal plasma. In addition, the clot-promoting properties of kaolin were inhibited by its prior exposure to platelet factor 4. Thus, the inhibitory properties of platelet factor 4 directed against the activation of Hageman factor were confirmed in a purified system. In this purified system, in contrast to earlier studies using crude systems, platelet factor 4 inhibited activation of Hageman factor by glass, ellagic acid, or kaolin.
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PMID:Inhibition of the activation of Hageman factor (factor XII) by platelet factor 4. 304 34

Membrane assembly of complement proteins C5b-9 on human platelets results in a dose-dependent increase in the binding of coagulation factors Va and Xa to the plasma membrane, concomitant with a marked increase in platelet prothrombinase activity. Factor Va binding increased by 6-15-fold in platelets treated with the C5b-9 proteins as compared to controls. In the presence of near-saturating concentrations of factor Xa, factor Va binding to C5b-9-treated platelets approximately doubled. In the absence of added factor Va, C5b-9-treated platelets bound 1700 molecules of factor Xa versus 50 molecules/cell bound to controls, suggesting that C5b-9 assembly on the platelet surface initiates the release of platelet factor V from the alpha-granules. The capacity of the C5b-9 proteins to initiate the nonlytic release of the platelet alpha-granule storage pool was confirmed by assay for platelet factor 4. When measured in the presence of exogenous factor Va (2 micrograms/ml), factor Xa uptake by C5b-9 platelets increased to approximately 5500 molecules/cell (versus 330 molecules/cell for controls). Removal of external Ca2+ inhibited the C5b-9-initiated release of the alpha-granule storage pool and reduced by approximately 50% the expression of new factor Va binding sites, suggesting that these two events contributing to increased platelet prothrombinase activity are mediated in part by the influx of Ca2+ across the C5b-9 pore.
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PMID:On the mechanism by which complement proteins C5b-9 increase platelet prothrombinase activity. 315 19


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