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)

A deficiency of one of the proteins of the contact system of blood coagulation does not result in a bleeding disorder. For this reason activation of blood coagulation via this system is believed to be an in vitro artefact. However, patients deficient in factor XI do suffer from variable bleeding abnormalities. Recently, an alternative pathway for factor XI activation has been described. Factor XI was found to be activated by thrombin in the presence of dextran sulfate as a surface. However, high molecular weight kininogen (HK), to which factor XI is bound in plasma, and fibrinogen were shown to block this activation suggesting it to be an in vitro phenomenon. We investigated the thrombin-mediated factor XI activation using an amplified detection system consisting of factors IX, VIII and X, which was shown to be very sensitive for factor XIa activity. This assay is approximately 4 to 5 orders of magnitude more sensitive than the normal factor XIa activity assay using a chromogenic substrate. With this assay we found that factor XI activation by thrombin could take place in the absence of dextran sulfate. The initial activation rate was approximately 0.3 pM/min (using 25 nM factor XI and 10 nM thrombin). The presence of dextran sulfate enhanced this rate about 8500-fold. A very rapid and complete factor X activation was observed in the presence of dextran sulfate. Although only minute amounts of factor XIa were formed in the absence of dextran sulfate, significant activation of factor X was detected in the amplification assay within a few minutes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Surface independent factor XI activation by thrombin in the presence of high molecular weight kininogen. 785 91

In order to elucidate the mechanism of thrombus formation in acute myocardial infarction (AMI), coagulation and fibrinolytic and inhibitory proteins were systemically examined in 12 patients with AMI and 29 normal subjects. Activities of factor XII, II and V and concentration of high molecular weight kininogen and Factor II were significantly lower in AMI patients than in normal control subjects. Factor XI activity was also increased in AMI patients as compared with normal controls. Von Willebrand Factor and fibrinogen levels were increased in patients with AMI. Plasma D-dimer concentration was also significantly higher in AMI patients than in controls. Activation of the intrinsic pathway, thrombin generation, fibrin formation and fibrin degradation may be present in patients with AMI just after the onset of coronary thrombus formation.
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PMID:Hemostatic abnormalities in acute myocardial infarction as detected by specific blood markers. 786 79

Activated platelets expose a specific, reversible high affinity (Kdapp congruent to 10 nM) binding site (n congruent to 1500 sites/platelet) for factor XI that requires the presence of high molecular weight kininogen (HK) and ZnCl2 (Greengard, J. S., Heeb, M. J., Ersdal, E., Walsh, P. N., and Griffin, J. H. (1986) Biochemistry 25, 3884-3890). Synthetic, conformationally constrained peptides from four tandem repeat (Apple) domains were tested for their capacity to inhibit 125I-factor XI binding to platelets. A peptide from the Apple 3 (A3) domain (Asn235-Arg266) inhibits factor XI binding to platelets in the presence of HK (42 nM), CaCl2 (2 mM), and ZnCl2 (25 microM), with a Ki congruent to 10 nM which is identical to the Kd for factor XI binding to platelets. A peptide from the A1 domain (Phe56-Ser86) partially inhibits factor XI binding to platelets (Ki congruent to 6 microM) by inhibiting factor XI binding to HK, whereas peptides from the A2 and A4 domains have no effect. Using computer modeling for rational design, conformationally constrained peptides were synthesized (Pro229-Gln233, Thr241-Leu246, and Ser248-Ser261) each of which acted alone and synergistically when added together to inhibit factor XI binding to platelets. Finally, the 125I-labeled A3 domain peptide (Asn235-Arg266) was found to bind to thrombin-activated platelets in a specific, reversible, and saturable manner. Thus, the sequence of amino acids Asn235-Arg266 of the A3 domain of factor XI comprises a contact surface for interaction with a platelet receptor.
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PMID:Identification and characterization of a binding site for platelets in the Apple 3 domain of coagulation factor XI. 789 18

We experienced a successful surgical case, who was a 16-year-old boy suffered from atrial septal defect with congenital factor XI deficiency. This disorder is an inherited disorder of blood coagulation characterized by a defect of the intrinsic pathway of thrombin formation and a mild to moderate bleeding tendency, but it can result in severe bleeding in surgical procedures. Open heart surgery in this disorders is rare. Preoperatively we prepared 4000 cc of fresh frozen plasma, but operated without using it. It would appear that the possibility of open heart surgery with congenital factor XI deficiency suggest in this case.
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PMID:[A successful surgical case of atrial septal defect with congenital factor XI deficiency]. 796 46

Dependence of the citrate human blood plasma clotting kinetics on free calcium concentration under its titration with calcium has been studied in vitro. Activation of factor XI is shown to be independent on calcium, while of thrombin concentration increases non-linearly at calcium concentrations in the range 0.2-0.3 mM. Kinetics of the thrombin generation fits well by the exponential function. Power indexes of the exponents rise steeply as calcium concentration increases from 0.2-0.5 mM and reach plateau at higher concentrations. At free calcium concentrations under 0.2 mM the thrombin level does not increase and remains lower than 10 pmol/ml as seen by our measuring system whose sensitivity threshold is surely less than 10 pmol/ml. Thus, the blood coagulation system behaves in a threshold manner under changes of calcium concentration. The threshold concentration of free calcium is equal to 0.2 mM.
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PMID:[Threshold behavior of the blood coagulation system upon changes in calcium concentration]. 798 Dec 80

Virally inactivated, high-purity factor XI concentrates are available for treatment of patients with factor XI deficiency. However, preliminary experience indicates that some preparations may be thrombogenic. We evaluated whether a highly purified concentrate produced signs of activation of the coagulation cascade in two patients with severe factor XI deficiency infused before and after surgery. Signs of heightened enzymatic activity of the common pathway of coagulation (elevated plasma levels of prothrombin fragment 1 + 2 and fibrinopeptide A) developed in the early post-infusion period, accompanied by more delayed signs of fibrin formation with secondary hyperfibrinolysis (elevated D-dimer and plasmin-antiplasmin complex). These changes occurred in both patients, but were more severe in the older patient with breast cancer when she underwent surgery, being accompanied by fibrinogen and platelet consumption. There were no concomitant signs of heightened activity of the factor VII-tissue factor mechanism on the factor Xase complex (plasma levels of activated factor VII and of factor IX and X activation peptides did not increase). The observed changes in biochemical markers of coagulation activation indicate that concentrate infusions increased thrombin generation and activity and that such changes were magnified by malignancy and surgery. Because some factor XI concentrates may be thrombogenic, they should be used with caution, especially in patients with other risk factors for thrombosis.
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PMID:Activation of the coagulation cascade after infusion of a factor XI concentrate in congenitally deficient patients. 804 46

The activation of prothrombin, factor V, factor VIII, factor IX, and factor X by the tissue factor-factor VIIa complex, in vitro, in a system in which each precursor protein was present at plasma concentration, was evaluated using a combination of activity assays, immunoblots, active-site blots, and autoradiography. The thrombin generation curves observed were distinctly nonlinear and typically displayed a time lag in which little or no thrombin was observed. This was followed by an almost linear propagation phase of thrombin formation. The lag was a function of tissue factor/factor VIIa concentration and represented primarily the interval of factor V and factor VIII activation. The postlag propagation phase of thrombin generation was nearly independent of the initial activator (factor VIIa or tissue factor) concentration over a 10(3)-fold range in factor VIIa-tissue factor concentration. Maximum thrombin generation rates were observed when less than 1% of the factor IX and X present was activated but when nearly 100% activation of the cofactors, factor V and factor VIII, was achieved. Analyses of the activation pattern of factor V indicated that the cofactor is activated by both factor Xa and thrombin which are formed at low levels during the lag phase of the reaction. When the initial reaction mixture contained factor Va instead of factor V, the lag was substantially reduced. When factor V was deleted from the reaction mixture, no thrombin formation was observed. When either factor VII or factor IX was deleted from the reaction system, the propagation phase of thrombin formation (at 5 pM tissue factor-factor VIIa complex) was only one-third that observed for reactions which contained factor VIII and factor IX. The addition of factor XI to the experimental system increased the rate of thrombin formation by 15% during the propagation phase but had no effect upon the lag phase of the reaction. Our data suggest that normal hemostasis may be initiated by the factor VIIa-tissue factor complex and support the concept of multiple feedback reactions which amplify and propagate the hemostatic response.
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PMID:A model for the tissue factor pathway to thrombin. I. An empirical study. 808 41

The important roles of thrombin in the development and propagation of thrombosis are well recognized. In addition to being the enzyme for clotting fibrinogen (the major protein component of blood clots), thrombin accelerates its own generation by activating factor V, factor VIII, factor XI and platelets. It accelerates the stabilization of clots by activating factor XIII to factor XIIIa, the enzyme which crosslinks fibrin. There are probably two major pathways for regulating the availability of thrombin in vivo: inactivation of thrombin (by antithrombin III/vessel wall heparan sulfate and perhaps by other endogenous antithrombins) and the inactivation of factor Va and factor VIIIa by activated protein C. Factor Va and factor VIIIa accelerate the production of thrombin. However, when thrombin becomes bound to fibrin (in clots or possibly on cell surfaces), the ability of antithrombin III/heparin to inactivate thrombin is then reduced significantly. Impairment by fibrin of thrombin inhibition by antithrombin III may account in part for the inability of unfractionated heparin to prevent post-operative deep vein thrombosis in up to 20% of patients who undergo major elective orthopaedic surgery, and may also explain the need for oral anticoagulants after unfractionated and low molecular weight heparins are used to initiate the treatment of established deep vein thrombi. The ineffectiveness of the antithrombin III/heparin pathway for inhibiting thrombin under some circumstances has been a contributory factor for the development, evaluation and identification of other inhibitors of thrombin which are more able than antithrombin III/heparin to inactivate thrombin when the enzyme is bound to fibrin. The focus of this review is to detail how these synthetic agents, by directly or indirectly inactivating thrombin, can also effectively inhibit prothrombin activation in vitro.
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PMID:Mechanisms for the anticoagulant effects of synthetic antithrombins. 815 38

C1-Inhibitor (Berinert, C1 INH), a 104 kDa protein, inhibits complement components (C1 esterase) as well as enzymes of the contact phase of coagulation (Factor XII, Factor XI) and kallikrein, thus regulating kinin generation. C1 INH is used for the treatment of the hereditary angioneurotic edema. This paper will give a survey about the evidence in recent literature concerning the potential efficacy of the compound on other diseases associated with shock, capillary leakage and inflammation as well. In our own experiments we evaluated whether the compound could influence acute inflammatory reactions or the severe systemic inflammatory response syndrome (SIRS) as a consequence of an experimental septic shock. To prevent the sepsis-induced DIC we co-infused the thrombin inhibitors AT III or rec. hirudin in combination with C1 INH. Coinfusion of C1-inhibitor (50-200 U/kg x h) with either rec. hirudin or AT III significantly improved survival rate compared to thrombin inhibitor alone.
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PMID:Influence of C1-inhibitor on inflammation, edema and shock. 817 80

Plasmin, the enzyme responsible for degradation of fibrin in blood clots and thus thrombolysis, is normally formed when its zymogen plasminogen is activated by cleavage of the Arg561-Val562 bond by specific plasminogen activators. We have altered the activation characteristics of plasminogen by substituting the P3, P2, and P1' cleavage site residues with sequences from thrombin-cleavable proteins to produce a novel thrombolytic agent which instead is activated by the blood clotting system. Plasminogen variants with thrombin cleavage sites from fibrinogen, the thrombin receptor, factor XIII, and factor XI were cleaved by thrombin with times to 50% cleavage of 28 h, 2.5 h, 5.7 min, and 3 min, respectively. In vitro clot lysis studies have shown that a variant in which the P3-P1' residues of plasminogen were substituted by the P7-P1' residues (Thr363-Ile370) from factor XI (T51) was sufficiently rapidly cleaved by thrombin to be activated by the endogenous thrombin produced by the coagulation cascade, resulting in rapid clot dissolution. Thrombin-activatable plasminogen therefore has the capacity to short circuit the physiological hemostatic mechanisms and produce fibrinolytic activity localized to the site of thrombin formation, that is, at the thrombus itself. The novel activation mechanism combined with the natural long circulating half-life of plasminogen gives this type of thrombolytic agent the potential for thrombus-selective plasmin generation and an extended duration of action.
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PMID:Plasminogen mutants activated by thrombin. Potential thrombus-selective thrombolytic agents. 820 94


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