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At least 343 records · Page 19Linked to original sources
PubMed2001

Direct thrombin inhibitors in acute coronary syndromes and during percutaneous coronary intervention: design of a meta-analysis based on individual patient data. Direct Thrombin Inhibitor Trialists' Collaborative Group.

BACKGROUND: More than 30 randomized trials involving more than 40, 000 patients with acute coronary syndrome and undergoing percutaneous coronary intervention have evaluated the efficacy and safety of direct thrombin inhibitors relative to unfractionated heparin. However, few trials have been large enough to provide reliable estimates of treatment effects on major cardiovascular outcomes. Therefore uncertainty remains regarding the benefits of direct thrombin inhibitors on major cardiovascular outcomes such as death or myocardial infarction and the balance of any such benefits against the risk of major bleeding. OBJECTIVES: By combining data on individual patients from all the major studies, we sought to obtain reliable estimates of the treatment effects of direct thrombin inhibitors on death, myocardial infarction, major bleeding, and secondary outcomes including refractory or recurrent ischemia and need for revascularization. We examined these outcomes at the completion of active treatment and during long-term follow-up, as well as in clinically important subgroups. METHODS: Individual patient data, including baseline demographics, previous history of vascular disease, conventional vascular risk factors, qualifying diagnosis, prognostic markers including biochemical markers of extent of myocardial injury, cointerventions, and fatal and nonfatal cardiovascular outcomes, have been obtained from 14 randomized studies, constituting more than 95% of the available randomized evidence. These data will undergo exhaustive data checking for completeness and consistency and will then be merged into a master database for analysis. Analyses will undergo extensive scrutiny by trialists of the direct thrombin inhibitor studies before incorporation into a manuscript.

Acute Disease↗
PubMed1990

[Comparative analysis of thrombin and anti-thrombin antibody levels in donors and myocardial infarction patients].

Thrombin and natural antithrombin antibody content was comparatively studied in donors and myocardial infarction patients. It was shown that the level of thrombin and antithrombin antibody was stable in the group of clinically normal subjects. In patients with myocardial infarction an increased thrombin level attended by a decrease in the level of natural antithrombin antibody was recorded. The presence of linear correlation between the levels of thrombin and antithrombin antibody, as well as impossibility of the diagnosis of disorders in the blood coagulation system using one of the parameters studied have permitted introduction of an additional diagnostic parameter--"antithrombin index."

Adult↗
PubMed1990

[Thrombin and anti-thrombin antibody levels in the blood of patients with acute myocardial infarction].

Simultaneous levels of thrombin and its natural antibodies were comparatively analyzed in donors and patients with myocardial infarction. Thrombin and its antibody levels were demonstrated to remain unchanged in the healthy subjects. With myocardial infarction development, there was an increase in thrombin concentrations and a decrease in natural antithrombin antibodies at the same time. A linear correlation was established between the levels of thrombin and its antibodies and failure in diagnosing coagulative disorders by one of the parameters studied was also ascertained, which made it possible to introduce a new diagnostic criterion, namely an "antithrombin index" that enabled the groups of donors and patients to be differentiated.

Adult↗
PubMed1988

The contractile response of vascular smooth muscle to thrombin and its inhibition by thrombin inhibitors.

Thrombin (0.1-30 NIH-U/ml) caused a contractile response of rabbit aortic rings. The vasocontraction was independent upon intact endothelium, however in deendothelialized vessels the contractile effect was more pronounced. The thrombin-induced vasocontraction was diminished in calcium-free medium; the same effect was attained by the calcium channel blocker verapamil at high concentrations. In human femoral and saphenous vein strips thrombin produced a contractile effect, too, which was very low and inconsistent in femoral arterial strips. To inhibit the contractile response of vascular smooth muscle to thrombin, higher concentrations of both the specific tight-binding inhibitors hirudin and beta Nas-Gly-(pAM)Phe-Pip were required than for the inhibition of fibrinogen clotting.

Animals↗
PubMed1979

The influence of thrombin on the platelet-aggregating activity of human factor VIII. A study with insolubilized thrombin.

A study was made of the influence of thrombin on the platelet-aggregating activity of human factor VIII with Ristocetin as cofactor. Purified factor VIII and different amounts of a thrombin-Sepharose 2B complex were mixed and incubated for various periods of time. The factor VIII-related platelet-aggregating activities of the filtrates of the incubation mixtures were determined in a test system using formalin-fixed platelets and Ristocetin as cofactor. The results so obtained indicate that thrombin inactivates the platelet-aggregating activity of factor VIII. The filtrates of the incubation mixtures were also tested by a two-stage test system for the clotting activities. Comparison of the influence of thrombin on the clotting- and the platelet-aggregating activities of factor VIII is presented and discussed.

Animals↗
PubMed1982

Thrombin inhibition and thrombin generation by cultured aortic endothelial and smooth muscle cells from minipig.

Endothelial and smooth muscle cells cultured from minipig aorta were examined for their inhibitory activity on thrombin and for their thrombin generating capacity. Endothelial cells showed both a thrombin inhibition and an activation of prothrombin in the presence of Ca++, which was enhanced in the presence of phospholipids. Smooth muscle cells showed an activation of prothrombin but at a lower rate. Both coagulation and amidolytic micro-assays were suitable for studying the thrombin-vessel wall interaction.

Animals↗
PubMed1994

Molecular dynamics simulations of thrombin inhibitors at the S' subsites of thrombin.

Molecular dynamics were carried out to simulate binding interactions between S' subsites of thrombin and hirudin-based thrombin inhibitors. These inhibitors include three segments: an active-site segment, N alpha-acetyl-(D-Phe)-Pro-Arg-Pro-; a fibrinogen-recognition exo-site segment, hirudin 55-65; and a 13-atom-long linker. These linkers have been reported (Szewczuk et al. (1993) Biochemistry 32, 3396) to influence the binding potency while keeping the same active and exo-site segments. The study found that, by combining different omega-amino acids, the potency could be increased 8-fold or decreased 4-fold compared to the native hirudin linker, -Gln-Ser-His-Asn-Asp-Gly-. Five typical linkers were simulated and compared. Analyzing the trajectory files led to the classification of three different dynamic behaviours for the linkers. The flexible linkers had no influence on the antithrombin activity. Other linkers formed hydrogen bonds with the thrombin S' subsite residues Glu39, leu40, and Gln 151. Formations of some hydrogen bonds enhanced the potency of the inhibitor. In other cases, the hydrogen bonds caused the distortion of the inhibitor conformation while affected the binding potency. Based on these observations, a general binding mode in the S' subsites of thrombin is proposed and potential applications are discussed.

Amino Acid Sequence↗
PubMed1993

Enhancement of thrombin receptor activation by thrombin receptor-derived heptapeptide with para-fluorophenylalanine in place of phenylalanine.

Thrombin receptor-derived peptide SFLLRNP (one-letter amino acid code) which corresponds to the N-terminal heptapeptide of tethered ligand is able to activate thrombin receptor and to stimulate the phosphoinositide (PI) turnover. The replacement of Phe-2 by Ala eliminated this activity completely, showing the crucial role of the Phe-phenyl group in receptor activation. It was found that substitution of para-fluorophenylalanine ((p-F)Phe) for Phe-2 enhanced several times the PI-turnover activity of SFLLRNP. This is the first example to date of a substitution with one order of magnitude greater increase in receptor activation. The Phe-2/Tyr substitution diminished the activity drastically (almost 2% of SFLLRNP), indicating the importance of hydrophobicity of Phe2-phenyl. The Phe-2/Leu substitution, however, diminished also the activity (less than 2% of SFLLRNP). These results suggested that highly specific hydrophobic interaction exists between Phe-2 of the tethered ligand and its binding site in thrombin receptor.

Amino Acid Sequence↗
PubMed1986

Reaction of thrombins with human antithrombin III: II. Dependence of rate of inhibition on molecular form and origin of thrombin.

The rate of thrombin inhibition by AT III depends upon the molecular form (alpha, beta, gamma) and species origin of the enzyme. The following apparent second order rate constants (.1000/M.s) were established alpha human 11.24 +/- 0.8; alpha bovine 7.46 +/- 0.27; beta bovine 6.49 +/- 0.34 and gamma human thrombin 2.80 +/- 0.11, 25 degrees C, pH = 7.80, 0.01 M TRIS, 0.01 M HEPES buffer, 0.0025 M EDTA, 0.3 M NaCl, 1 mg/mL PEG 6000. Using these values, the concentration of active AT III in an unknown sample can be calculated from the measured apparent first order rate constant in moles/liter instead of relative units. In contrast to the reactions in the absence of heparin, in the presence of high affinity heparin, the differences between various forms of thrombin are more pronounced and the shape of the progress curves, as well as rates, are highly dependent on the ionic strength. In the presence of heparin, measurement of the rate of inhibition under pseudo first order conditions can be made only when the NaCl concentration is at least 0.3 M. The significance of the presented data for designing a functional assay of AT III is discussed.

Animals↗
PubMed1988

Heparin-like tubings. III. Kinetics and mechanism of thrombin, antithrombin III and thrombin-antithrombin complex adsorption under controlled-flow conditions.

In previous papers, we described treated tubular materials which exhibit an heparin-like antithrombic activity under dynamic conditions. In order to ascertain the heparin-like mechanism of this activity, we have studied the interactions of thrombin, antithrombin III and thrombin-antithrombin III complex with the inner face of these treated tubings under controlled-flow conditions. Moreover, the kinetics of the adsorption of thrombin were studied at different flow rates to establish the rate-determining step.

Adsorption↗
PubMed2006

Thrombin induces tumor growth, metastasis, and angiogenesis: Evidence for a thrombin-regulated dormant tumor phenotype.

The association of idiopathic venous thrombosis with occult cancer is generally recognized. However, it has not been fully appreciated that thrombin generated during thrombosis can augment the malignant phenotype. Thrombin activates tumor cell adhesion to platelets, endothelial cells, and subendothelial matrix proteins; enhances tumor cell growth; increases tumor cell seeding and spontaneous metastasis; and stimulates tumor cell angiogenesis. These mechanisms are reviewed. Evidence is also presented to support the hypothesis that thrombin serves to preserve dormant tumor cells in individuals, preventing host eradication. It is proposed that tumor malignancy may be regulated by a procoagulant/anticoagulant axis.

Animals↗
PubMed1997

Generation of thrombin in blood plasma of non-pregnant and pregnant women studied through concentration of thrombin-antithrombin III complexes.

OBJECTIVE: The main question in this study is how much more thrombin is generated in blood plasma of pregnant women than in non-pregnant women. STUDY DESIGN: Thrombin-antithrombin III complexes (TAT) were used as markers of thrombin generation in vivo. They were measured by the ELISA method in blood plasma of 15 non-pregnant and 43 pregnant, as well as 30 parturient women and 10 women after delivery. RESULTS: With normal menstrual cycles, TAT levels did not change significantly throughout the cyclic phases, and the mean +/- S.D. calculated for all cyclic phases was 1.9 +/- 0.3 micrograms/l. In the 2nd trimester the level of TAT was 16.0 +/- 2.8 micrograms/l and at term 21.5 +/- 11.9 micrograms/l. Throughout the 1st and 2nd stage of labour the level of TAT increased insignificantly, but after placenta separation it was significantly higher than before labour (30.8 +/- 20.4 micrograms/l). In the 3rd and 7th days after delivery the level of TAT was still higher than in non-pregnant women. CONCLUSION: It was found that the level of TAT in normal menstrual cycles is stable, whereas it increases in pregnancy. Relating the values of the cycle to those of pregnancy it was calculated, that at the end of pregnancy there is a ten-fold increase of TAT level and after placenta separation and expulsion--temporarily even fifteen-fold--increase. In the 3rd to 7th day after delivery, the TAT level was still higher than in non-pregnant women.

Adult↗
PubMed1999

Fatal cardiac rupture among patients treated with thrombolytic agents and adjunctive thrombin antagonists: observations from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction 9 Study.

OBJECTIVES: The purpose of this study was to determine the incidence and demographic characteristics of patients experiencing cardiac rupture after thrombolytic and adjunctive anticoagulant therapy and to identify possible associations between the mechanism of thrombin inhibition (indirect, direct) and the intensity of systemic anticoagulation with its occurrence. BACKGROUND Cardiac rupture is responsible for nearly 15% of all in-hospital deaths among patients with myocardial infarction (MI) given thrombolytic agents. Little is known about specific patient- and treatment-related risk factors. METHODS Patients (n = 3,759) with MI participating in the Thrombolysis and Thrombin Inhibition in Myocardial Infarction 9A and B trials received intravenous thrombolytic therapy, aspirin and either heparin (5,000 U bolus, 1,000 to 1,300 U/h infusion) or hirudin (0.1 to 0.6 mg/kg bolus, 0.1 to 0.2 mg/kg/h infusion) for at least 96 h. A diagnosis of cardiac rupture was made clinically in patients with sudden electromechanical dissociation in the absence of preceding congestive heart failure, slowly progressive hemodynamic compromise or malignant ventricular arrhythmias. RESULTS A total of 65 rupture events (1.7%) were reported-all were fatal, and a majority occurred within 48 h of treatment Patients with cardiac rupture were older, of lower body weight and stature and more likely to be female than those without rupture (all p < 0.001). By multivariable analysis, age >70 years (odds ratio [OR] 3.77; 95% confidence interval [CI] 2.06, 6.91), female gender (OR 2.87; 95% CI 1.44, 5.73) and prior angina (OR 1.82; 95% CI 1.05, 3.16) were independently associated with cardiac rupture. Independent predictors of nonrupture death included age >70 years (OR 3.68; 95% CI 2.53, 5.35) and prior MI (OR 2.14; 95%, CI 1.45, 3.17). There was no association between the type of thrombin inhibition, the intensity of anticoagulation and cardiac rapture. CONCLUSIONS Cardiac rupture following thrombolytic therapy tends to occur in older patients and may explain the disproportionately high mortality rate among women in prior dinical trials. Unlike major hemorrhagic complications, there is no evidence that the intensity of anticoagulation associated with heparin or hirudin administration influences the occurrence of rupture.

Adult↗
PubMed1980

Mechanism of action of thrombin on fibrinogen. Size of the A alpha fibrinogen-like peptide that contacts the active site of thrombin.

The following peptides were synthesized by classical methods in solution: Ac-Phe-Leu-Ala-Glu-Gly-Gly-Gly-Val-Arg-Gly-Pro-Arg-Val-Val-Glu-NHCH3 (F-4), Ac-Phe-Leu-Ala-Glu-Gly-Gly-Gly-Val-Arg-Gly-Pro-Arg-Val-NHCH3 (F-5), and Ac-Phe-Leu-Ala-Glu-Glv-Gly-Gly-Gly-Val-Arg-Gly-Pro-NHCH3 (F-6). The rates of hydrolysis of the Arg-Gly bond in these peptides by thrombin were measured, and the values of the specificity constant, kcat/KM, were all found to be approximately 2 X 10(-7) [(NIH unit/L)s]-1, similar to that for a peptide (F-3) having an additional Arg residue between Glu- and -NHCH3 of F-4. The difference between this value and that for the A alpha chain of bovine fibrinogen is attributed to slight conformational differences arising from long-range interactions present in fibrinogen but not in the synthetic peptides. In addition to the requirement for the Phe residue, demonstrated earlier, it is shown here that no residues on the C-terminal side of Pro are required for interaction between thrombin and fibrinogen. The active site of thrombin thus appears to interact with a peptide of the size of F-6, with the Phe residue possibly being in close spatial proximity to the Val-Arg-Gly moiety.

Amino Acid Sequence↗
PubMed2001

Design, synthesis, and modeling of novel cyclic thrombin receptor-derived peptide analogues of the Ser42-Phe-Leu-Leu-Arg46 motif sequence with fixed conformations of pharmacophoric groups: importance of a Phe/Arg/NH2 cluster for receptor activation and implications in the design of nonpeptide thrombin receptor mimetics.

The novel cyclic analogues cyclo(Phe-Leu-Leu-Arg-epsilonLys-Dap) (1) and cyclo(D-Phe-Leu-Leu-Arg-epsilonLys-Dap) (2), which differ only in the absolute conformation of Phe, have been designed and synthesized based upon the minimal peptide sequence Phe-Leu-Leu-Arg which has been found to exhibit biological activity for the thrombin receptor. Compound 1, in which all amino acids have the L-configuration, exhibited higher activity in the rat aorta relaxation and rat longitudinal muscle bioassays compared to compound 2, in which the Phe residue is in the D-configuration. This is attributed to the spatial proximity of the Phe and Arg in compound 1 which does not exist in its diastereomeric compound 2, as is depicted from a combination of NMR studies and computational analysis. Structure-activity studies (SAR) showed that the Phe and Arg side chains along with a primary amino group form an active recognition motif that is augmented by the presence of a second primary amino group in the cyclic peptide. We suggest that a comparable cyclic conformation may be responsible for the interaction of linear TRAPs with the thrombin receptor. The validity of this proposition was tested by the synthesis of four active nonpeptide thrombin receptor mimetics. Substance (S)-N-(6-guanidohexanoyl)-N'-(2-amino-3-phenylpropionyl)piperazine (3), in which the pharmacophoric phenyl, guanidino, and amino groups were incorporated onto a piperazine template, was found to be the most active compared to the other synthesized compounds which lack the amino pharmacophoric group.

Animals↗
PubMed1984

Thrombospondin fragmentation by alpha-thrombin and resistance to gamma-thrombin.

In the presence of 2mM-Ca2+, alpha-thrombin slowly cleaved thrombospondin (Mr 180 000) into 150 000-Mr and 30 000-Mr fragments. In the absence of Ca2+, the platelet glycoprotein was progressively and completely hydrolysed by 3 units of the enzyme/ml to 130 000-Mr, 95 000-Mr and 65 000-Mr fragments. In contrast, the nonclotting enzyme form, gamma-thrombin, did not hydrolyse the platelet protein either in the presence or in the absence of Ca2+, even at 10-fold higher concentrations of enzyme. Protein-interacting regions removed from the catalytic site, like those required for fibrinogen recognition, are necessary for thrombin proteolysis of thrombospondin.

Animals↗