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)

Recent development of microassays and determination of age-specific normal ranges have shed new light on the components and functioning of the neonatal fibrinolytic system. Plasminogen and tissue plasminogen activator levels are low in neonates, who generate plasmin more slowly and in smaller amounts than adults. Quantitative and qualitative changes occur as the fibrinolytic system matures. This is also true of the coagulation system responsible for the production of thrombin, which is the target for plasmin. These data are essential to assess the risk of thrombosis in neonates and, if appropriate, to guide management decisions including selection of a thrombolytic agent, of the optimal dosage, and of the best laboratory tests for monitoring purposes. Ongoing studies are investigating the mechanisms involved in neonatal lysis of thrombin clots occurring naturally or as the result of thrombolytic therapy.
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PMID:[Characteristics of the fibrinolytic system in the newborn]. 845 35

Reproducible disseminated intravascular coagulation in rabbits was provoked by two intravenous injections 24 hours apart of endotoxin from Salmonella enteritidis. There were mild symptoms of DIC before the second injection which considerably increased thereafter. In detail there was a sharp drop of the platelet count and a considerable diminution of Antithrombin III, of Protein C, Plasminogen and Antiplasmin as well as an appearance of fibrin monomer complexes and an increase of the aPTT. When PEG-hirudin in a single dose of 1 mg/kg BW was given simultaneously with the second injection of endotoxin the following alterations were observed: The drop of the platelet count and of the activities of Antithrombin III, Protein C, Plasminogen and Antiplasmin was significantly less pronounced. The fibrin monomer complexes were lower and the aPTT was less prolonged. The thrombin time, however, as a sign of a direct action of hirudin on thrombin was considerably more prolonged than in the controls. The combined effect of these alterations strongly points in the direction of a favourable influence of PEG-hirudin on the course of DIC. It is of special interest that 6 h after the intravenous injection of PEG-hirudin its full effect on the thrombin time was still detectable. This is apparently due to a longer half-life in circulation of PEG-hirudin than of natural hirudin.
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PMID:The effect of a long-acting recombinant hirudin (PEG-hirudin) on experimental disseminated intravascular coagulation (DIC) in rabbits. 847 80

Three distinct alpha 2PI (alpha 2-antiplasmin) degrading and alpha 2M (alpha 2-macroglobulin) inhibiting enzymes, named proteinase a, b and c, have been purified from the venom of Crotalus basiliscus (the Mexican west coast rattlesnake) by fast protein liquid chromatography (anion-exchange chromatography and gel filtration chromatography). SDS-PAGE revealed that proteinase a and b had similar mol. wts (approximately 23,500), whereas proteinase c displayed a mol.wt of approximately 24,200. Their isoelectric points were found to be acidic, ranging from pH 4.8 to 5.7. The proteinase activity of all three enzymes was inhibited in the presence of EDTA. Dependent on enzyme concentration, a progressive and catalytic inactivation of alpha 2PI was induced, leading to an almost complete loss of the plasmin inhibitory activity at a molar ratio of enzyme: alpha 2PI = 0.1 within 60 min. The ability of alpha 2M to protect the esterolytic activity of trypsin from inhibition by soybean trypsin inhibitor was only reduced at a molar ratio of enzyme: alpha 2M = 0.5, whereas no inactivation could be observed when the three venom proteinases were incubated with an excess of alpha 2M, suggesting that the inactivation occurred by complex formation but not by degradation of the intact alpha 2M molecule. In SDS-PAGE, inactivation of human alpha 2PI (mol. wt 68,000) correlated with the appearance of two cleavage products with an approximate mol. wt of 56,000 and 11,000, respectively. The three proteinases had no thrombin-like activity. Plasminogen and factor X were not activated and no platelet aggregation was induced. They degraded the A alpha- and B beta-chain of fibrinogen and showed plasma extravasation-inducing activity following intradermal injection into the abdominal skin. None of the enzymes showed any activity against a series of chromogenic p-nitroanilide substrates.
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PMID:Purification and characterization of three alpha 2-antiplasmin and alpha 2-macroglobulin inactivating enzymes from the venom of the Mexican west coast rattlesnake (Crotalus basiliscus). 859 84

Plasminogen activator inhibitor-1 (PAI-1) is a member of the serpin superfamily of proteins and is the fast acting inhibitor of both urinary plasminogen activator and tissue-type plasminogen activator. We have assessed the functional significance of reactive center residues on the carboxy-terminal side of the cleavage site of recombinant human PAI-1. Using site-directed mutagenesis, the P1'-P5' residues (P1' is the first residue on the carboxy-terminal side of the protease cleavage site) of the wild-type PAI-1 reactive center sequence were replaced with the corresponding sequences of plasminogen activator inhibitor-2, antithrombin, alpha 2-antiplasmin and protease nexin I. Rate constants of inhibition of the serine proteases urinary plasminogen activator, tissue-type plasminogen activator, plasmin and thrombin by the variants were determined. The results suggest a crucial role for both reactive center length and sequence in the inhibition of plasminogen activators by PAI-1. Analysis of substitutions at positions P4' and P5' both confirms and extends our previous work demonstrating a favorable electrostatic interaction between these residues and tissue-type plasminogen activator. None of the variants show dramatic increases in the rate constants of inhibition of other serine proteases, suggesting that these residues alone are not sufficient to confer protease specificity on PAI-1. Apparently, the determinants of the rapid inhibitory specificity of PAI-1 are localized to the P1'-P5' region of the reactive center and these residues act synergistically to produce the exquisite specificity of PAI-1 for plasminogen activators.
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PMID:Sequence requirements in the reactive-center loop of plasminogen-activator inhibitor-1 for recognition of plasminogen activators. 862 Aug 72

A new type of gamma Gly-268 (GGA) to Glu (GAA) substitution has been identified in a homozygous dysfibrinogen by analyses of the affected polypeptide and its encoding gene derived from a 58 year-old man manifesting no major bleeding or thrombosis. The functional abnormality was characterized by impaired fibrin assembly most likely due to failure to construct properly aligned double-stranded fibrin protofibrils. This presumption was deduced from the following findings: (1) Factor XIIIa-catalyzed cross-linking of the fibrin gamma-chains progressed in a normal fashion, indicating that the contact between the central E domain of one fibrin monomer and the D domain of another took place normally; (2) Nevertheless, factor XIIIa-catalyzed cross-linking of the fibrinogen gamma-chains was obviously delayed, suggesting that longitudinal association of D domains of different fibrin monomers, ie, D:D association was perturbed; (3) Plasminogen activation catalyzed by tissue-type plasminogen activator was not as efficiently facilitated by polymerizing fibrin monomer derived from the patient as by the normal counterpart. Therefore, gamma Gly-268 would not be involved in the 'a' site residing in the D domain, which functions as a complementary binding site with the thrombin-activated 'A' site in the central E domain, but would be rather involved in the D:D self association sites recently proposed for human fibrinogen. Thus, the gamma Glu-268 substitution newly identified in this homozygous dysfibrinogen seems to impair proper alignment of adjacent D domains of neighboring fibrin molecules in the double-stranded fibrin protofibril, resulting in delayed fibrin gel formation.
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PMID:A gamma Gly-268 to Glu substitution is responsible for impaired fibrin assembly in a homozygous dysfibrinogen Kurashiki I. 863 38

It is increasingly realised that fibrin deposition and fibrin lysis are major factors in vascular pathology. In addition to thrombotic occlusion fibrin is a component of atherosclerotic lesions, but the increased interest in components of the haemostatic system was mainly triggered by clinical use of fribrinolytic agents, and the problems of re-stenosis following angioplasty. This review focuses on the main components of the fibrinolytic system--tissue plasminogen activator (tPA), urokinase (uPA) and plasminogen activator inhibitor (PAI-1)--and on thrombin. These factors are not only involved in fluid phase clotting and clot lysis; they react specifically with cells and matrix components. During the last 5 years, the main period under review, there have been numerous studies on their interactions with endothelial and smooth muscle cells in culture, in whole tissues and in vivo, and with arterial extracellular matrix of which a major component is fibrin. Plasminogen activators bind to cell surface receptors, influence cell migration and release active thrombin from fibrin. Thrombin emerges as a pluripotent factor which modulates many aspects of endothelial and smooth muscle cell behaviour, including release and synthesis of fibrinolytic components, and stimulation of cell proliferation.
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PMID:Haemostatic factors and atherogenesis. 883 Sep 27

Nineteen patients with symptoms of chronic venous insufficiency (CVI) were treated with 13-week cycles of intermittent pneumatic compression (IPC) during 2 h sessions twice weekly, with most treatments at home. At study completion, quantitative subjective scores for total symptomatology were improved in 16/19 patients (84%). Enhancement of fibrinolytic potential in vivo was detected in 86% of observations on specimens from CVI patients over 2 h of IPC, with accelerated euglobulin clot lysis times (ELT) noted within 15 min of initiating compression. The enhanced fibrinolytic potential was attributed to increased urokinase plasminogen activator (u-PA), probably released from perturbed endothelial cells by IPC. Significant decreases in total t-PA antigen (mass concentration) but not t-PA activity, were produced by IPC in CVI patients only (P = 0.0001), with greater effects noted in the non-anticoagulated versus the anticoagulated cohort. Plasminogen activator inhibitor type 1 (PAI-1) levels rose rapidly after IPC only in the controls and non-anticoagulated CVI patients. PAI-1 decreased in those receiving anticoagulation. No platelet perturbation was detected during IPC by measuring levels of beta-thromboglobulin or the thromboxane A2 metabolite, 11-dehydrothromboxane B2; however, significant (P < 0.003) decreases in plasma prostacyclin (PGI2) levels (measured as the stable 6-ketoprostaglandin F-1-alpha-metabolite) were observed after 15 min of IPC in non-anticoagulated CVI patients only. There was no evidence of increased thrombin generation by IPC, determined by urinary excretion of fibrinopeptide A and prothrombin fragment 1. Concurrent anticoagulation appears to mediate more favorable biochemical alterations in CVI, although subjective improvement did not correlate with anticoagulation. The mechanism(s) by which these physiologic changes compliment the mechanical effects of IPC remain to be elucidated and will require adequately controlled and powered studies.
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PMID:Intermittent pneumatic compression in chronic venous insufficiency favorably affects fibrinolytic potential and platelet activation. 883 95

Hemorrhagic diathesis and widespread microthrombosis are common in heatstroke. To assess the early stages of coagulopathy in heatstroke, thrombin-antithrombin III (TAT), fibrin monomers, plasmin-alpha 2-antiplasmin (PAP), plasminogen and D-Dimer were measured in 16 heatstroke patients (means +/- SE rectal temperature 42.3 +/- 0.2 degrees C) pre- and postcooling and compared with 8 heatstressed and 23 normal controls. Comparing heatstroke patients with normal controls, TAT, fibrin monomers, PAP and D-Dimer were elevated to (median (range)) 16.5 (4-1000) versus 3.5 (2-7.2) micrograms/l p < 0.001, 16 (4-113) versus 2 (2-9) nM p < 0.001; 3300 (1000-36500) versus 255 (136-462) micrograms/l p < 0.001 and 0.72 (0.22-64.8) versus 0.15 (0.05-0.25) microgram/ml p < 0.01 respectively. Plasminogen decreased to 81% (34-106); PAP, TAT and D-Dimer correlated significantly with hyperthermia (r = 0.577, p = 0.02; r = 0.635, p = 0.01; r = 0.76, p = 0.003). Postcooling PAP decreased to 545 (260-850) micrograms/l p < 0.005, TAT 10 (6-70) micrograms/l, and fibrin monomers 22 (18-86) nM remained unchanged. Heatstressed controls showed mild but significant increase in all markers. Activation of coagulation and fibrinolysis occurs early and is profound and sustained in heatstroke. Cooling seems to attenuate the activation of fibrinolysis only, however, this requires confirmation in a larger study population.
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PMID:Activation of coagulation and fibrinolysis in heatstroke. 897 10

Plasminogen activator inhibitor type 1 (PAI-1), a member of serine proteinase inhibitor superfamily, is known to inhibit thrombin in the presence of either heparin or vitronectin. We analyzed possible inhibitory activity of PAI-1 on human factor Xa. PAI-1 inhibited factor Xa in the presence of calcium ion (Ca2+), whereas no inhibition was observed in the absence of Ca2+. Half maximal enhancement by Ca2+ was obtained at 0.8 mM. An equimolar complex formation between factor Xa and PAI-1 in the presence of Ca2+ was observed by SDS polyacrylamide gel electrophoresis. Both unfractionated heparin and vitronectin enhanced the inhibition only in the presence of Ca2+. Apparent second-order rate constant (ki) for the inhibition of factor Xa by PAI-1 at 5 mM Ca2+ was 1.6 x 10(4) M-1 s-1, and was enhanced 3-fold by 2 u/ml of heparin (4.6 x 10(4) M-1 s-1) and 10-fold by 100 nM vitronectin (1.6 x 10(5) M-1 s-1), respectively. The interaction between Ca(2+)-bound factor Xa and PAI-1 could be important from the view of PAI-1 neutralization and enhancement of fibrinolysis.
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PMID:The inhibition of human factor Xa by plasminogen activator inhibitor type 1 in the presence of calcium ion, and its enhancement by heparin and vitronectin. 898 Jun 46

Cirrhosis is associated with compromised hemostasis and coagulopathy during orthotopic liver transplantation (OLT). It has been suggested that hemostasis is better preserved during OLT in primary biliary cirrhosis (PBC) than other cirrhotic states. The aim of this study was to compare coagulation and fibrinolysis in 15 patients with PBC with 31 patients with other liver disease before and during OLT. Preoperatively, both groups had subnormal mean levels of prekallikrein, factor XIIa, antithrombin III (ATIII), plasminogen, and alpha2-antiplasmin. C1 esterase inhibitor and kallikrein inhibition in PBC was higher than the normal range (P < .01), but not in non-PBC. Non-PBC had lower median fibrinogen levels and shorter euglobulin clot lysis times (ECLT) (P < .05). Tissue plasminogen activator (tPA) antigen levels did not differ between groups but were elevated from the normal range, as were median thrombin-antithrombin complexes (TAT). Plasminogen activator inhibitor (PAI) activity was significantly higher in PBC (0.0041). Perioperatively in the PBC group during the early anhepatic phase of OLT, there was more thrombin generation, as evidenced by higher TAT levels (P = .0455) and less hyperfibrinolysis with longer ECLTs. We hypothesize that there is a preserved capacity to generate thrombin and less fibrinolytic activation during the anhepatic phase of OLT, and we suggest that, in PBC, the use of antifibrinolytic agents may have an adverse effect.
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PMID:Coagulation and fibrinolysis in primary biliary cirrhosis compared with other liver disease and during orthotopic liver transplantation. 904 19


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