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 current study was designed to evaluate tubing sets with either polymeric phospholipids or ionically bound heparin in six bovine experiments (body weight, 70 +/- 5 kg). No heparin was given systemically. Left heart bypass was started with 300 ml of clear priming solution and maintained over 6 hours (50 ml/kg/min). Coagulation studies included platelet counts, activated coagulation time (ACT), thrombin time (TT), fibrinogen (Factor I), antithrombin III (AT III), and fibrinopeptide A (FPA). Normalized platelet levels dropped from 100 +/- 12% before to 86 +/- 13% after 6 hours of left heart bypass for heparin, compared with 100 +/- 46% to 90 +/- 44% for phospholipid coating (NS). The ACT increased from 146 +/- 7 sec at 10 min to 159 +/- 16 sec after 6 hours for heparin, compared with 122 +/- 4 to 126 +/- 5 sec for phospholipid (p < 0.05). Thrombin time changed from 18 +/- 0 sec before to 19 +/- 1 sec after 6 hours for heparin, as compared with 16 +/- 1 sec to 18 +/- 1 sec for phospholipid (NS). Factor I levels decreased from 1.5 +/- 0.3 g/L to 1.3 +/- 0.1 g/L for heparin, compared with 1.5 +/- 0.2 g/L to 1.4 +/- 0.3 g/L for phospholipid. Antithrombin III levels changed from 102 +/- 26% to 91 +/- 7% for heparin, compared with 123 +/- 12% to 118 +/- 12% for phospholipid. Fibrinopeptide A levels changed from 100 +/- 60% to 130 +/- 13% for heparin, compared with 100 +/- 11% to 99 +/- 6% for phospholipid (P < 0.05). No macroscopic red clots were found in either group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Coagulation patterns in bovine left heart bypass with phospholipid versus heparin surface coating. 843 79

Coagulation abnormalities occurring in patients with acute promyelocytic leukemia (APL) are partially corrected by heparin administration. This study was undertaken to verify if "supra-normal" levels of antithrombin III (AT-III) are similarly able to quench intravascular thrombin generation triggered by APL cells. Eight patients with APL were randomly assigned to receive either 50 U/kg (Group A) or 100 U/kg (Group B) of an AT-III concentrate, starting on the first day of chemotherapy and continuing for 7 days thereafter. Fibrinopeptide A (FPA), prothrombin fragment F1+2 and thrombin-AT III complexes, measured before and 15 minutes after each AT-III infusion, decreased significantly after each infusion, but the effect was minimal and short-lived, despite the achievement of post-infusion levels of AT-III activity well above 150% (Group A) or 200% (Group B). Small amounts of heparin were consistently detected in AT-III concentrates and post-infusion plasma samples. The short-lived quenching of thrombin generation after AT-III concentrate could be partially explained by the infusion of heparin, rather than by supranormal AT-III levels.
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PMID:Supranormal antithrombin III levels induced by concentrate administration are ineffective in quenching thrombin generation in acute promyelocytic leukemia. 847 59

The hypothesis that heparin-coated perfusion circuits reduce thrombin formation and activity; fibrinolysis; and platelet, complement, and neutrophil activation was tested in 20 consecutive, randomized adults who had cardiopulmonary bypass. Twenty identical perfusion systems were used; in 10, all blood-contacting surfaces were coated with partially degraded heparin (Carmeda process; Medtronic Cardiopulmonary, Anaheim, Calif.). All patients received a 300 U/kg dose of heparin. Activated clotting times were maintained longer than 400 seconds. Cardiopulmonary bypass lasted 36 to 244 minutes. Blood samples for platelet count, platelet response to adenosine diphosphate, plasma beta-thromboglobulin, inactivated complement 3b, neutrophil elastase, fibrinopeptide A, prothrombin fragment F1.2, thrombin-antithrombin complex, tissue plasminogen activator, plasminogen activator inhibitor-1, plasmin alpha 2-antiplasmin complex, and D-dimer were obtained at these times: after heparin was given, 5 and 30 minutes after cardiopulmonary bypass was started, within 5 minutes after bypass was stopped, and 15 minutes after protamine was given. After cardiopulmonary bypass, tubing segments were analyzed for surface-adsorbed anti-thrombin, fibrinogen, factor XII, and von Willebrand factor by radioimmunoassay. Heparin-coated circuits significantly (p < 0.001) reduced platelet adhesion and maintained platelet sensitivity to adenosine diphosphate (p = 0.015), but did not reduce release of beta-thromboglobulin. There were no significant differences between groups at any time for fibrinopeptide A, prothrombin fragment F1.2, or thrombin-antithrombin complex or in the markers for fibrinolysis: D-dimer, tissue plasminogen activator, plasminogen activator inhibitor-1, and alpha 2-antiplasmin complex. In both groups, concentrations of prothrombin fragment F1.2 and thrombin-antithrombin complex increased progressively and significantly during cardiopulmonary bypass and after protamine was given. Concentrations of D-dimer, alpha 2-antiplasmin complex, and plasminogen activator inhibitor-1 also increased significantly during bypass in both groups. Fibrinopeptide A levels did not increase during bypass but in both groups increased significantly after protamine was given. No significant differences were observed between groups for levels of inactivated complement 3b or neutrophil elastase. Radioimmunoassay showed a significant increase in surface-adsorbed antithrombin on coated circuits but no significant differences between groups for other proteins. We conclude that heparin-coated circuits used with standard doses of systemic heparin reduce platelet adhesion and improve platelet function but do not produce a meaningful anticoagulant effect during clinical cardiopulmonary bypass. The data do not support the practice of reducing systemic heparin doses during cardiac operations with heparin-coated extracorporeal perfusion circuitry.
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PMID:Surface-bound heparin fails to reduce thrombin formation during clinical cardiopulmonary bypass. 880 Jan 82

Dietary intake of fish oils, rich in the polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has given inconsistent results as to their influence on the plasma fibrinogen level (1, 2, 3, 4, 5, 6). In the present study we have examined the effects of various fatty acids, the PUFAs and the saturated fatty acid palmitic acid (PA), alone or combined with the antioxidant vitamin E (Vit.E), on the fibrinogen concentration in the growth medium of human hepatoma (HepG2) cells. Vit.E alone decreased the amount of fibrinogen in the medium in a dose dependent fashion, where fibrinogen was measured as Fibrinopeptide A (FPA) releasable by thrombin. EPA and Vit.E decreased the amount of fibrinogen additively. PUFAs alone increased the fibrinogen concentration in a dose dependent manner. PUFAs combined with a fixed dose of Vit.E decreased the fibrinogen concentration, also dose dependently. OA and PA had an inhibitory effect, both alone and combined with Vit.E. These results indicate that Vit.E may be necessary for PUFAs to have a fibrinogen lowering effect, whereas both OA and PA apparently may decrease the fibrinogen concentration in the cell medium of HepG2 cells, both alone and combined with Vit.E. Possibly, peroxidation of the PUFAs may increase the fibrinogen production, that may be counteracted and reversed by the simultaneous presence of Vit.E.
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PMID:Effects of various fatty acids alone or combined with vitamin E on cell growth and fibrinogen concentration in the medium of HepG2 cells. 857 40

The aim of the present study was to investigate the reactivity of immunoreagents developed for clinical applications in humans in different animal species (hen, mouse, rat, rabbit, guinea-pig, dog, pig, sheep, baboon). Prothrombin fragment 1 + 2, thrombin-antithrombin III complex and fibrinopeptide A were tested for coagulation, platelet factor 4 and beta-thromboglobulin for platelet activation, glycoprotein IIb-IIIa, glycoprotein Ib and P-selectin for platelet membrane glycoproteins, D-dimers for fibrinolysis, thrombomodulin for activation of endothelial cells and thrombospondin and von Willebrand factor for adhesive proteins. Prothrombin fragment 1 + 2, platelet factor 4, beta-thromboglobulin and D-dimers were revealed only in baboons. Fibrinopeptide A was well detected in baboons but weakly in mice, dogs, pigs and sheep. Whereas glycoprotein IIb-IIIa was revealed on guinea-pig, dog and sheep platelets and glycoprotein Ib on rabbit and dog platelets, P-selectin and thrombomodulin were never detected. Thrombospondin was revealed in hens, mice, rats, guinea-pigs, pigs, sheep and baboons and von Willebrand factor in mice, rats, guinea-pigs, dogs, pigs, sheep and baboons. Interestingly, thrombin-antithrombin III complex (TAT) was detected in all species tested except the hen. A time- and dose-dependent increase in TAT was observed when rats, dogs or pigs were infused with thromboplastin (4.5-450 microliters/kg/h), while administration of hirudin (1 mg/kg) abolished this TAT generation. Thus, the TAT immunoassay could provide a tool for the screening of antithrombotic drugs in a number of animal species. However, the possibility of using a wider panel of human immunoreagents would appear to be restricted to baboons which display good species cross-reactivity.
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PMID:Cross-reactivity of human molecular markers for detection of prethrombotic states in various animal species. 858 12

Studies suggest that thrombosis is important in the progression of atherosclerotic lesions. The biochemical markers prothrombin fragment 1-2 and fibrinopeptide A reflect in vivo thrombin generation and activity, respectively. As such, they are markers that might be associated with cardiovascular risk. From the Cardiovascular Health Study, a cohort study of 5201 persons over 65 years of age, 399 persons free of clinical cardiovascular disease (CVD) at the baseline examination were selected for study of specialized markers of hemostasis. We report the cross-sectional relationships of the thrombin markers to CVD risk factors and measures of subclinical CVD. The range of fragment 1-2 2 was 0.12 to 0.85 nmol/L. The range of fibrinopeptide A was 0.9 to 44.1 micrograms/L. High levels of fragment 1-2 and fibrinopeptide A were associated with age, with levels higher in women than men. Fragment 1-2 was associated with smoking; high levels of triglyceride, creatinine, and C-reactive protein; and low levels of glucose. Fibrinopeptide A was associated with high C-reactive protein and apolipoprotein(a) and lower ankle-brachial index. There were no significant associations of the thrombin markers with race, fibrinogen, alcohol consumption, diabetes, or most measures of subclinical CVD. Study findings support a hypothesis that there are physiological interrelationships between cardiac risk factors, hemostasis, inflammation, and progression of atherosclerosis.
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PMID:Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease. 879 70

In order to determine changes in hemostasis occurring during continuous venovenous hemofiltration (CVVH), we made a prospective study of 14 patients with acute renal failure. Fibrinopeptide A, thrombin-antithrombin III complex, beta-thromboglobulin and platelet retention were determined serially. Fibrinopeptide A (x +/- SD: 33 +/- 20 ng/ml, ref. < 3.0) and thrombin-antithrombin III complex (11 +/- 5 ng/ml, ref. 1.0-4.0) were enhanced prior to commencement of treatment but showed no further increase during therapy. Platelet retention (Hellem II, ref. 60-99%) fell from 39 +/- 32% before treatment to 16 +/- 15% after treatment, while the beta-thromboglobulin/creatinine ratio (ref. 0.23-0.41) rose from 0.39 +/- 0.20 to 0.64 +/- 0.44. Via platelet activation, CVVH leads to a reinforcement of the existing platelet dysfunction (thrombocytopathy), without influencing plasmatic coagulation. In order to analyze the influence of pre-existing hemostatic alterations on filter running time during CVVH, 60 patients were examined retrospectively in a second study. Filter running time, global coagulation tests, fibrinogen, antithrombin III, platelet count and hematocrit were registered daily. There was no significant correlation between filter running time and fibrinogen concentration, thrombin time, platelet count or hematocrit. Apart from filter occlusion, no thrombotic complications were observed. The frequency of filter occlusion increased with falling activated clotting time (ACT) (p < 0.05). Rising platelet count led to an increase in heparin dose (p < 0.05), primarily due to the anti-heparin effect of platelet factor 4.
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PMID:Hemostatic alterations during continuous venovenous hemofiltration in acute renal failure. 887 56

To examine whether fibrin N-terminal Aalpha 17-23 and Bbeta 15-25 may contain high-affinity polymerization sites, GPRVVER and GHRPLDKKREE analogs were prepared, and their abilities to inhibit fibrin monomers from repolymerizing were compared in turbidity and clottability assays. Within Aalpha 17-23, GPR is the most active site (IC30 of 0.95-1.36 mM). Its extension into GPRVVER (IC30 of 1.75-2.3 mM) reduced activity. Within Bbeta 15-25, acyl-DKKREE (IC30 of 0.30-0.53 mM) can account for GHRPLDKKREE activity (IC30 of 0. 33-0.44 mM). Comparison of the assays showed that calcium, whose presence induces thick fibrin fibers, elicited a higher turbidity than clottability inhibition. Similarly, the lateral-association-promoting GHRP (IC30 of 1.25-1.43 mM) gave a high turbidity vs clottability inhibition ratio (137%). In contrast, low ratios were found for the linear-association-initiating GPR (73%) and for acyl-DKKREE (34%). Structure-activity correlation showed that fibrinogen-like acyl-GPRP and acyl-GHRP could inhibit D. E association at the millimolar range, but in a manner different from fibrin-related GPR peptides did, which required the NH2 as well as Arg presence. To explain Bbeta 20-25 masking, it is proposed that DKKREE in fibrinogen may engage in ionic and hydrogen bonds with KDSDW, the Aalpha 29-33 sequence implicated in thrombin binding. To explain acyl-GPRP and acyl-GHRP inhibition of D.E association, it is proposed that fibrinogen packing may be mediated by E domain association with alphaC (Aalpha 220-609) fragments of adjacent molecules, and by alphaC-alphaC association. A modified polymerization mechanism is deduced by taking into account fibrinogen N-terminal conformation as well as E domain binding to thrombin vs alphaC fragments. This model proposes the following. (1) Upon thrombin binding to fibrinogen KDSDW, DKKREE may become exposed. (2) Fibrinopeptide A cleavage further unmasks the NH2 and Arg group of GPR, leading to DKKREE and GPR initiation of polymerization. (3) The micromolar-effective thrombin-fibrin(ogen) binding may initiate a partial alphaC repulsion. Subsequent DKKREE and GPR binding to D domains of other fibrin(ogen) will lead to the formation of the trimer and bring additional molecules to fibrin N-terminal region, and the combined steric congestion may lead to a complete alphaC repulsion from the overcrowded E domain. (4) Repulsion of the large Aalpha 220-609 fragments may unmask multiple polymerization sites beyond the fibrin N-terminal region.
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PMID:Localization of an effective fibrin beta-chain polymerization site: implications for the polymerization mechanism. 923 81

Fibrinopeptide A and thrombin-antithrombin III complex were used respectively as markers for in vivo thrombin formation and beta-thromboglobulin as a marker for platelet activation. In cases of acute renal failure (ARF) a heightened plasma concentration in the hemostasis activation markers may occur, because of a renal elimination disturbance, without a previous activation of the hemostasis. In order to check the validity of fibrinopeptide A, thrombin-antithrombin III complex and beta-thromboglobulin as markers for the hemostasis activation in cases of ARF we examined 32 patients prior to renal replacement therapy. A significant rise in fibrinopeptide A (x +/- SD: 34 +/- 22 ng/mL, ref < 3.0), thrombin-antithrombin III complex (19 +/- 15 ng/mL, ref 1.0-4.0) and beta-thromboglobulin (149 +/- 58 U/mL, ref 10-40) was found. None of the parameters examined showed a correlation to the serum creatinine. A correlation was observed respectively between fibrinopeptide A (r = 0.34, p < .05), beta-thromboglobulin (r = 0.39, p < .05) and the beta-thromboglobulin/creatinine coefficient (0.50 +/- 0.30, r = 0.72, p < .001) on the one side and the thrombin-antithrombin III complex on the other. A greater rise in the concentration of all parameters in patients with disseminated intravascular coagulation (DIC) was established, in contrast to patients without DIC (fibrinopeptide A: 44 +/- 31 vs. 32 +/- 20 ng/mL, beta-thromboglobulin: 169 +/- 57 vs. 144 +/- 60 U/mL, thrombin-antithrombin III complex 40 +/- 21 vs. 14 +/- 7 ng/mL, p < .05). Fibrinopeptide A and beta-thromboglobulin/creatinine coefficient in combination with the thrombin-antithrombin III complex can be employed as markers for the activation of hemostasis in cases of ARF there is no direct relationship between restricted kidney function in ARF and the plasma concentration of these markers, which behave similarly in spite of their varying elimination patterns.
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PMID:Hemostasis activation markers in acute renal failure. 950 68

Tissue factor (TF)-induced coagulation was compared in contact pathway suppressed human blood from normal, factor VIII-deficient, and factor XI-deficient donors. The progress of the reaction was analyzed in quenched samples by immunoassay and immunoblotting for fibrinopeptide A (FPA), thrombin-antithrombin (TAT), factor V activation, and osteonectin. In hemophilia A blood (factor VIII:C <1%) treated with 25 pmol/L TF, clotting was significantly delayed versus normal, whereas replacement with recombinant factor VIII (1 U/mL) restored the clot time near normal values. Fibrinopeptide A release was slower over the course of the experiment than in normal blood or hemophilic blood with factor VIII replaced, but significant release was observed by the end of the experiment. Factor V activation was significantly impaired, with both the heavy and light chains presenting more slowly than in the normal or replacement cases. Differences in platelet activation (osteonectin release) between normal and factor VIII-deficient blood were small, with the midpoint of the profiles observed within 1 minute of each other. Thrombin generation during the propagation phase (subsequent to clotting) was greatly impaired in factor VIII deficiency, being depressed to less than 1/29 (<1.9 nmol TAT/L/min) the rate in normal blood (55 nmol TAT/L/min). Replacement with recombinant factor VIII normalized the rate of TAT generation. Thus, coagulation in hemophilia A blood at 25 pmol/L TF is impaired, with significantly slower thrombin generation than normal during the propagation phase; this reduced thrombin appears to affect FPA production and factor V activation more profoundly than platelet activation. At the same level of TF in factor XI-deficient blood (XI:C <2%), only minor differences in clotting or product formation (FPA, osteonectin, and factor Va) were observed. Using reduced levels of initiator (5 pmol/L TF), the reaction was more strongly influenced by factor XI deficiency. Clot formation was delayed from 11.1 to 15.7 minutes, which shortened to 9.7 minutes with factor XI replacement. The maximum thrombin generation rate observed ( approximately 37 nmol TAT/L/min) was approximately one third that for normal (110 nmol/L TAT/min) or with factor XI replacement (119 nmol TAT/L/min). FPA release, factor V activation, and release of platelet osteonectin were slower in factor XI-deficient blood than in normal blood. The data demonstrate that factor XI deficiency results in significantly delayed clot formation only at sufficiently low TF concentrations. However, even at these low TF concentrations, significant thrombin is generated in the propagation phase after formation of the initial clot in hemophilia C blood.
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PMID:Blood coagulation in hemophilia A and hemophilia C. 961 54


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