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:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the intrinsic coagulation of normal platelet-rich plasma only 11% of the prothrombin is converted to thrombin. Complete conversion of prothrombin to thrombin occurs only via the extrinsic pathway (1). Addition of purified prothrombin to normal plasma to double or triple its concentration, doubled or tripled the amount of the generated thrombin as determined by the thrombin elution assay (1), so that the percentage of the proenzyme which was converted to thrombin remained the same. At the same time the activated partial thromboplastin time (APTT) was prolonged. Proportionality of the amount of the generated thrombin to the amount of prothrombin added and a delay in the appearance of thrombin activity was also observed with the thrombin generation test. Normalization of the APTT was observed when factor IX was added together with prothrombin. Addition of factor IX or X to normal plasma shortened the APTT but did not increase the amount of prothrombin which was converted to thrombin as determined by both the thrombin elution assay and the thrombin generation test. Further experiments indicated that (a) more factor X is activated per mg tissue factor than per mg of activated partial thromboplastin and (b) more thrombin is generated per unit of factor Xa in the presence of tissue factor than in the presence of activated partial thromboplastin. Thus, the two pathways differ not only by the mechanism of factor X activation but also by the extent to which prothrombin is activated by factor Xa.
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PMID:Thrombin generation in normal plasma enriched with purified coagulation factors. 684 84

The thrombogenicity of beta-PL/UV-treated PPSB (factor IX concentrate) was evaluated in chimpanzees. PPSB isolated from beta-propiolactone-treated and UV-irradiated plasma was injected into chimpanzees at a dose of approximately 100 units/kg body weight. An FDA licensed PPSB preparation served as the negative control, and a preparation containing activated as well as precursor clotting factors served as the positive control. 15 minutes, 1 h, 4 h, and 24 h after the PPSB application the following parameters were determined in the chimpanzee blood: factors II, VII, IX, X, VIII, fibrinogen, AT III, thrombin coagulase, Quick value, APTT and platelet count. Neither the untreated control preparation, nor the PPSB isolated from beta-propiolactone-treated and UV-irradiated plasma, showed signs of thrombogenicity in the chimpanzee model. The positive control indicated that the chimpanzee is a suitable model for the thrombogenicity testing of activated clotting factors.
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PMID:Evaluation of thrombogenicity of beta-propiolactone/ultraviolet (beta-PL/UV) treated PPSB in chimpanzees. 686 23

A storage study of factor IX concentrate was performed on 35 randomly selected batches that had been prepared between 1976 and 1980. Vacuum stability, dissolution time, F IX procoagulant activity, NAPTT, and thrombin generation were measured immediately after the manufacturing process and compared in this study with the results obtained from the spare samples analysed in 1981. No significant changes during storage at cold room temperature for up to 5 years were established. The product can thus be considered to be stable for 5 years at + 4 degrees C.
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PMID:The stability of factor IX concentrate during storage. 710 Dec 29

Factor XIa catalyzes an important reaction in the early phase of blood coagulation by converting factor IX to an active enzyme (factor IXa). Although antithrombin-III, an inhibitor of factor XIa, normally accounts for only one-sixth of the plasma inhibitory activity against factor XIa, its effectiveness has been reported to be enhanced by heparin. We have reinvestigated the ability of heparin to potentiate factor XIa inhibition by both purified antithrombin-III and plasma using synthetic tripeptide amide substrates as well as a coagulant assay. No increase in the inactivation rate of factor XIa amidolytic activity by purified antithrombin-III was observed in the presence of therapeutic heparin concentrations (1 U/ml), although inhibition of the amidolytic activity of thrombin by purified antithrombin-III was enhanced at least 20-fold by the same concentration of heparin. Furthermore, despite the ability of heparin (1 U/ml) to increase the inactivation rate of thrombin by plasma, no acceleration of the rate of inhibition of factor XIa by plasma was observed. Similar results were found when the inhibition of factor XIa was monitored with a coagulant assay after first removing the heparin. Only at heparin concentrations of 5 and 10 U/ml, was a 2- and 4-fold increase in the inactivation rate of factor XIa by purified antithrombin III observed. Therefore, in both purified systems as well as plasma, heparin, at concentrations observed in clinical practice, does not accelerate the inactivation rate of human factor XIa by antithrombin-III.
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PMID:Effect of heparin on the inactivation rate of human factor XIa by antithrombin-III. 711 61

Factor VII clotting activity increases about five-fold when blood is clotted in glass. Prior studies suggested that this results from activation induced by activated factor IX (IXa). However, in purified systems containing phospholipid and calcium, activated factor X (Xa) is known to activate factor VII rapidly. Therefore, we studied activation of factor VII by IXa and X, in systems using purified human factors. Concentrations of IXa and Xa were calculated from total activated protein concentrations rather than from active site concentrations. In the presence of phospolipid and calcium, both IXa and Xa activated factor VII 25-fold; however, Xa was roughly 800 times more efficient than IXa. Without added phospholipid, activation of factor VII by both Xa and IXa was markedly slowed, and Xa was roughly 20 times more efficient than IXa. When both phospholipid and calcium were omitted, activation of factor VII by either enzyme was negligible. Adding normal prothrombin, but not decarboxylated prothrombin, substantially slowed activation of factor VII by both Xa and IXa. Adding thrombin-activated factor VIII and antithrombin-III did not change rates of factor VII activation by either enzyme. These results from purified systems do not provide an explanation for the prior data from plasma systems.
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PMID:Activation of human factor VII by activated factors IX and X. 712 68

Using affinity chromatography on heparin-Sepharose, homogeneous prothrombin containing no factor Xa or thrombin was separated into three components differing in their affinities for the bioadsorbent. The major component 2 eluted with 0.35 M NaCl was found to contain prothrombin (Mr 80000) and prethrombin 1 (Mr 60000). Component 1 not bound by heparin contained fragment 1 of prothrombin (Mr 25 000), whereas component 3 with a higher affinity for the bioadsorbent contained factor IX (Mr 52 000). Rechromatography of component 2 provided further evidence for prothrombin modification to prethrombin 1 by heparin-Sepharose. Blocking of endogenous thrombin of prothrombin by diisopropylfluorophosphate did not affect the modification. Heparin-Sepharose probably induced changes in prothrombin conformation and the formation of a catalytic center responsible for prothrombin splitting to prethrombin 1. Heparin-Sepharose can be used for separation of prothrombin proteolytic products by thrombin and for isolation of prethrombin 1 and prothrombin fragment 1.
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PMID:[Activation by heparin-Sepharose of prothrombin conversion to prethrombin 1]. 729 15

Measurement of the total phospholipid (and that portion active in coagulation) in factor IX concentrates revealed no correlation with in vitro tests of potential thrombogenicity, except in the case of the recalcification time and the thrombin generation test which may detect coagulant phospholipid as well as the presence of thrombogenic enzymes. This is probably due to separation of the prothrombin complex proteins from most phospholipid during ion-exchange chromatography. Although low levels of phospholipid remain in the final product these are apparently insufficient to effect appreciable activation of factor IX concentrates despite low levels of antithrombin III. Two tests which measure the formation of thrombin and factor Xa after recalcification of concentrates were affected by the addition of exogenous phospholipid. However this is a relative effect such that differences are quantitative rather than qualitative. Heparin addition during production of factor IX concentrate was found to have only minor effects on the results of in vitro thrombogenicity tests of the final product. This was confirmed in the laboratory by incubation of unheparinised products with heparin for periods of up to 6 hr.
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PMID:In vitro thrombogenicity tests of factor IX concentrates. II: effects of phospholipids and heparin. 736 44

The binding of human factor Xa to fibrinogen and its derivatives was characterized. Factor Xa bound to immobilized fibrin with a concentration at half-maximal binding (C50) of 100 nM. The 4-carboxyglutamic acid (Gla) domain of factor Xa is important in factor Xa binding to fibrin monomer, based on the following observations; the binding requires Ca2+; Gla-domain-lacking factor Xa could not bind to fibrin; factor Xa binding was significantly reduced by prior treatment of factor Xa with factor IX/factor-X-binding protein from the venom of Trimeresurus flavoviridis which specifically binds to the Gla domain of human factors IX and X. Factor Xa also bound to fibrinogen, fibrinogen degradation products (FDP)-D and FDP-E, with a similar affinity (C50 = 75-131 nM). In a solution-phase equilibrated binding assay, approximately 0.76 mol factor Xa bound to 1 mol fibrinogen with a dissociation constant of 180 nM. The binding of 125I-labeled factor Xa to the fibrin monomer was inhibited markedly by unlabeled factor Xa, but only slightly by thrombin, suggesting that the binding site of factor Xa on fibrin monomer differs from that of thrombin. We localized the binding site of factor Xa on fibrinogen: factor Xa bound strongly to the A alpha chain, but weakly to the B beta and gamma chains of fibrinogen. The A alpha chain was then digested with lysyl endopeptidase and separated by reverse-phase HPLC. Among resulting peptides, factor Xa bound specifically to a peptide corresponding to residues Asp82-Lys123 of the A alpha chain. This factor-Xa-binding site is located in the boundary between the central E domain and the terminal D domain of fibrinogen and is apparently distinct from the reported thrombin-binding site.
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PMID:Characterization of the binding of factor Xa to fibrinogen/fibrin derivatives and localization of the factor Xa binding site on fibrinogen. 755 76

Thromboembolic complications of prothrombin complex concentrate (PCC) therapy were first reported by Kasper in 1973 [N Engl J Med 1973;289:160]. The following contaminants were discussed as possible contributors to the thrombogenicity risk: the presence of other zymogens in PCCs, the presence of activated factor IX or activated factor X, or the presence of phospholipids from platelets resulting from insufficient centrifugation of the donor plasma. Activated factor IX is now accepted as a major causative factor. After numerous additional reports of thromboembolic complications in patients treated with PCCs, the International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee (SSC) Thrombogenicity Registry was established in 1988. Lusher collected 72 cases worldwide for the SSC/ISTH in 1988 and 1989. Thromboembolic complications and myocardial infarctions, however, continue to be serious problems associated with PCC therapy--even in the 1990s--underscoring the urgent need for high-purity factor IX products. Results from several studies by Mannucci, Bauer, and other authors demonstrated that patients treated with high-purity products developed no activation of prothrombin or thrombin, as indicated by appearance of thrombogenicity markers such as fibrinopeptide A and the amino-terminal fragments of prothrombin (F1 + 2). Other authors demonstrated that in patients at high risk for thrombotic complications, particularly those with liver disease, or postsurgery, or in those requiring repeated treatments, high-purity concentrates appear to be safe, regarding both thrombosis and risk of virus transmission.
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PMID:The need for highly purified products to treat hemophilia B. 757 91

Five purified concentrates--Nanotiv (Kabi Pharmacia), Immunine (Immuno), Factor IX VHP (Biotransfusion), Alphanine (Alpha Therapeutic Corporation), and Mononine (Armour Pharmaceutical Company)--were characterized biochemically and their in vivo pharmacokinetic and thrombogenic properties evaluated. The results were compared with those for two prothrombin complex concentrates (PCCs): Preconativ (Kabi Pharmacia) and Prothromplex TIM4 (Immuno). The measured values for factor IX coagulant activity (FIX:C) generally agreed with the manufacturers' labeled values. The purified concentrates were virtually devoid of other vitamin K-dependent coagulation factors, the inhibitor proteins C and S, and either fibrinogen, fibronectin, or immunoglobulins. Indicators of thrombin generation (i.e., prothrombin fragments F1 + 2 and thrombin-antithrombin complex) were present in varying amounts in all preparations. The level of specific activity in the purified concentrates exceeded that in the PCCs by a factor of 50- to 100-fold. Pharmacokinetic variables were studied in severe hemophilia B patients: Nanotiv was compared with Preconativ; Immunine was compared with Prothromplex TIM4 in crossover studies; and Mononine was tested in a single-drug study. No differences were apparent between Nanotiv, Preconativ, and Mononine, but recovery rates were lower, clearance rates higher, and FIX:C half-life shorter for Immunine and Prothromplex TIM4, although the disparate results might have been attributable to methodologic differences. Purified factor IX concentrates were used successfully as cover for surgery and in immune tolerance induction without observable adverse effects.
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PMID:Properties of factor IX concentrates. 757 97


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