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)

The changes in relevant haemostatic parameters during the course of ten orthotopic liver transplantation were studied when aprotinin was given intra-operatively. Increases of tissue-type (P = 0.008) and urokinase-type (P = 0.009) plasminogen activators during the anhepatic phase could be correlated with hyperfibrinolysis. Thrombin-antithrombin III complexes (TAT) increased after revascularization of the liver graft (P = 0.003). Parallel studies in the perfusate showed that TAT concentrations were 350% and protease inhibitor activities (antithrombin III, protein C) only 52% of the systemic circulation before reperfusion, suggesting that thrombin activation together with protease inhibitor consumption occurs during graft liver reperfusion. The relatively smaller increases in profibrinolytic parameters and a lower blood loss when compared with other groups may be explained by aprotinin administration in our patients.
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PMID:Coagulation changes and the influence of the early perfusate in the course of orthotopic liver transplantation (OLT) when aprotinin is used intra-operatively. 172 11

The plasma levels of protein C, AT III, the perioperative administration of fresh frozen plasma (FFP) and AT III concentrate were compared under the use of various drugs in a randomized, prospective double-blind study in 40 patients in whom an aortocoronary bypass operation was carried out. We formed four groups of ten patients: group A served as a control group, group B received a prostacyclin (PGI2) infusion of 10 or 20 ng/kg/min, group C high-dose aprotinin substitution, and group D was treated with a combination of prostacyclin and aprotinin. After an initial short-term rise in the inhibitors protein C and AT III, there was a fall in all groups in the further course of extracorporeal circulation. The initial preoperative values were reached again on the morning of the first postoperative day. This indicates a raised turnover and in association with this a raised rate of elimination of these factors caused by an increased thrombin activation during the extracorporeal circulation which cannot be prevented by the usual heparinization. Whereas prostacyclin had no effect on our results mediated by thrombocytic mechanisms, use of aprotinin led to a significant saving in the requirement for perioperative fresh frozen plasma and AT III substitution therapy. A clinical advantage of prostacyclin and aprotinin combination was not observed. In view of our results (individual analyses were mainly in the normal range), we consider that AT III and fresh frozen plasma should not be substituted routinely during or after extracorporeal circulation.
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PMID:The role of protein C as an inhibitor of blood clotting during extracorporeal circulation. 172 2

The structural and functional features of thrombin are under discussion: combination of restricted specificity and a central regulatory role in hemostasis. Thrombin specificity is mainly connected with special regions of the enzyme molecule--an additional recognition binding site for high molecular substrates. One can consider the additional site of thrombin as a kind of the allosteric centre changing thrombin-catalyzed functions at binding with modulator. Specific site of substrate (inhibitor or receptor) is used in the role of modulator. A computer search of that modulator was fulfilled by means of the program DOTHELIX. The peptides thymosin I and substance P which have regions similar to those of hirudin were shown to inhibit thrombin activity. The kinetic data point to the noncompetitive type of inhibition. The data on the high reactivity of the thrombin-activated protein C system confirm the idea of protein C to be the first defensive mechanism when thrombin is generated in blood and interacts with thrombomodulin.
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PMID:[Regulation of thrombocyte stimulating and other activities of thrombin by modulators of the recognition site]. 172 58

Detailed haemostatic changes were investigated during eight liver transplantations. The patients were divided into two groups; group 1 had minor operative bleeding (four cases) and group 2 had major bleeding (four cases). Group 2 had lower levels of platelets, fibrinogen, factor V (FV), and alpha 2-antiplasmin than group 1, and the thromboelastography showed fibrinolysis. In both groups, plasma tissue-plasminogen activator levels rose slightly. After revascularization of the graft liver, reductions in the values of PT, fibrinogen, FV and FVII were noted, along with a prolongation of the PTT and an increase in thrombin-antithrombin III complex levels. Plasma levels of protein C, protein S, antithrombin III, and plasminogen remained relatively stable throughout the operation. These results show that the preceding fibrinolysis and subsequent superimposed activation of the clotting system are the main causes of coagulopathy during liver transplantation, which correlate with the amount of operative haemorrhage and the abnormalities found in haemostatic tests.
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PMID:Coagulation disorder during liver transplantation. 177 95

Thrombin has both beneficial and harmful effects. In order of importance, at very low concentrations, alpha-thrombin firstly amplifies its own generation through the activation of factors V and VIII, which are the primary targets of antithrombotic agents. It secondly functions at the cellular level where, at low concentrations it activates platelets, and at higher concentrations, induces endothelial cell changes (e.g., shape changes, albumin transport release of plasminogen activators and other substances). It thirdly converts fibrinogen into clottable fibrin and becomes actively incorporated into the forming thrombus. In addition, it activates protein C, which in turn degrades factors V and VIII (and/or their activated forms) and causes the shutdown of thrombin generation. When compared to other serine proteinases of the blood coagulation and fibrinolytic systems, alpha-thrombin is unique in that it loses most of its proenzyme activation fragment and has developed multisite short-ranged bridge-binding interactions, which appear to explain thrombin specificity. To understand thrombin is to understand haemostasis.
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PMID:Thrombin structure and function: why thrombin is the primary target for antithrombotics. 177 99

The effect of sera and purified IgG isolated from plasma of 46 patients with systemic lupus erythematosus (SLE) and 9 healthy donors on the endothelial cell (EC) mediated protein C activation was investigated. Out of the 46 SLE sera used, 19 were antiphospholipid antibodies (aPL) positive. From 12 patients IgG was isolated, of which 6 contained aPL. EC were first incubated with IgG (7 mg/ml) or serum (1:1 diluted) for 1 h and then tested for their ability to promote protein C activation by thrombin, with the cells either in a monolayer or in a suspension. The normal range (mean of control values +/- 2 SD) of protein C activation was 80-120%. In contrast to others, we could not detect an inhibition of protein C activation by any of the patient IgG's or sera. The recently described cofactor for binding of antiphospholipid antibodies to phospholipids, beta 2-glycoprotein I, was purified and added to the purified IgG's. A combination of these two components did not inhibit the EC mediated protein C activation by thrombin. This study suggests that the inhibition of the protein C activation, mediated by EC, is not a general mechanism by which aPL related thrombosis can be explained.
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PMID:In vitro studies of antiphospholipid antibodies and its cofactor, beta 2-glycoprotein I, show negligible effects on endothelial cell mediated protein C activation. 179 12

Phospholipids bearing a proportion of anionic species such as phosphatidylserine are necessary to promote the anticoagulant potential of the protein C pathway. Factor Xa (200 or 350 pM) was found to activate protein C in a thrombomodulin-independent reaction requiring only phospholipids in Al(OH)3,-adsorbed plasma resupplemented with physiological concentrations of protein C (70 nM) and protein S (130 nM). All experiments were performed in the presence of an excess of hirudin. The activity of activated protein C was assessed by the survival of factor Va. The optimal phospholipid concentration range was 5 to 25 microM with a proportion of phosphatidylserine of 50% (mol/mol) resulting in a half-life of factor Va of 7.5 min in the absence of protein S and 4.2 min in its presence. Dns-EGR-Xa, an inactive derivative of factor Xa, behaved as an apparent protector of factor Va. When replacing factor Xa, thrombin at 10 nM was not an efficient protein C activator in the absence of purified human placenta thrombomodulin. In the presence of 100 pM activated protein C, factor Va half-life was 2 min in the absence of protein S and 1.1 min in its presence in the above optimal phospholipid concentration range. The presence of protein S allowed reduction of phospholipid requirements. Annexin-V (placental anticoagulant protein-I), a potent phospholipid antagonist, fully protected factor Va from degradation by phospholipid-dependent mechanisms. Factor Va was partially protected in the plasma of a patient having experienced thrombosis associated with lupus-like anticoagulant and anti-phospholipid auto-antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The catalytic role of anionic phospholipids in the activation of protein C by factor Xa and expression of its anticoagulant function in human plasma. 179 56

After a bite by the aglyphous red-necked keelback snake Rhabdophis subminiatus a complete defibrinogenation syndrome with severe hemorrhagic diathesis developed in a 25-year-old man. In vitro studies showed that the venom gland extract of the snake contains a very active prothrombin (Factor II) activator. The thrombin generated is inhibited neither by antithrombin III nor the antithrombin-III-heparin complex. The venom gland extract stimulated also the tissue plasminogen activator; however, it did not cause direct activation of plasminogen, protein C, Factor X or direct degradation of fibrinogen.
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PMID:Hemostatic changes due to the venom gland extract of the red-necked keelback snake (Rhabdophis subminiatus). 180 26

The main characteristics of the blood coagulation system is its high potential of autoamplification. Cascade reactions consisting of successive activations of zymogens into their respective serine-proteinase active form culminate in the generation of thrombin, the central enzyme of the system. Blood coagulation is under control of two major natural regulatory mechanisms limiting the extension of the thrombus. The first one with antithrombin III as the central element, directly inhibits thrombin and other activated clotting factors in cooperation with heparans synthetized by the vascular wall. The second one, the protein C pathway, limits thrombin generation, through its ability to block the amplification potential of feedback reactions. The physiological significance of these regulatory mechanisms is clearly emphasized by the frequency of recurrent thrombotic episodes affecting subjects presenting an inherited deficiency of one of these components, estimated between 50 and 70%. Patients with protein S deficiency, the essential cofactor of activated protein C, exhibit a surprisingly high tendency to arterial thrombosis. The biological investigation of thromboembolic disease must be focused on antithrombin III, protein C and protein S deficiency using functional assays when available or feasible in order to detect both qualitative and quantitative defects.
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PMID:[Congenital deficiencies of natural anticoagulant systems responsible for recurrent thromboembolism]. 182 3

We measured concentrations of the natural anticoagulant protein C; its cofactor, protein S; and the carrier protein C4b-binding protein (C4BP), in 24 patients with severe infection and 13 with septic shock. Decreased antithrombin III levels were found in 16 of 24 infection patients and all shock patients; high thrombin-antithrombin (TAT) complexes were present in 16 of 24 infection and 12 of 13 shock patients. Protein C concentrations were significantly reduced compared to healthy blood donors, to 60 +/- 14% (infection) and 47 +/- 20% (septic shock) (mean +/- 1 SD). Total protein S levels were not reduced (119 +/- 36.7 and 88 +/- 20.0%, normal value 96 +/- 15%). Free protein S was also normal (27 +/- 9.4 and 30 +/- 8.7%, normal value 29 +/- 9%). The percentage free of total protein S was normal in shock patients (35 +/- 8.5%), but significantly reduced in patients without shock (23 +/- 5.3%). C4BP was significantly higher than normal in the latter group (135 +/- 43%), but not in the shock group (118 +/- 40%), possibly due to increased consumption. Thus, no deficiency of total or free protein S was found in these patients, who had evidence of activated coagulation but no clinical DIC.
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PMID:Protein C, protein S and C4b-binding protein in severe infection and septic shock. 182 15


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