Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have developed a specific and sensitive ELISA for the measurement of the TAT in human plasma. The assay follows the sandwich principle and uses two different antibodies directed against human thrombin and human antithrombin III, respectively. The anti-thrombin antibody population used for coating was purified by immunoadsorption on immobilized prothrombin and thrombin, respectively. Antithrombin III antibodies were conjugated with peroxidase. Plasma samples containing TAT were incubated in polystyrene tubes coated with anti-thrombin antibodies; after washing, peroxidase-conjugated antithrombin III antibodies were added and bound enzyme activity was subsequently measured using o-phenylenediamine. The assay was calibrated with definite concentrations (2.0 to 60 micrograms/l) of preformed purified TAT added to TAT-poor plasma. Plots of absorbance at 492 nm against TAT concentrations revealed a linear correlation (r = 0.98). A reference range from 0.85 to 3.0 micrograms/l was calculated from TAT concentration in plasma samples from 88 healthy donors (mean value +/- SD: 1.45 +/- 0.4 micrograms/l). In patients with deep vein thrombosis confirmed by phlebography (n = 15), TAT was found up to 7-13 micrograms/l. Patients with septicemia associated with a consumption coagulopathy (n = 10) showed markedly increased TAT values (greater than or equal to 10 micrograms/l). From these data it can be concluded that measurement of TAT might be a parameter for detection of a latent clotting pathway activation.
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PMID:Determination of human thrombin-antithrombin III complex by enzyme immunoassay. 246 14

The purpose of this pilot study was to determine the effect of recombinant hirudin (r-hirudin) on coagulopathy and the relationship between concentrations of thrombin-antithrombin III (ATIII) complex (TAT) and thrombin-hirudin complex (THC) in patients with disseminated intravascular coagulation (DIC). Five patients with haematological malignancy associated with DIC were studied. r-Hirudin was administered by continuous intravenous infusion at a dose of 0.005 mg/kg/h for 4-9 days to each patient. Fibrin/fibrinogen degradation products (FDP), D-dimer, TAT and plasmin-alpha 2 antiplasmin complex (PAP) concentrations decreased after treatment with r-hirudin in four patients studied. However, in one patient, serum creatinine increased to 1.7 mg/dl and aPTT was prolonged to 74.4s. Statistical analysis disclosed significant positive correlations between plasma concentrations of hirudin and THC, and between concentrations of THC and TAT. The concentrations of THC were much higher than those of TAT. In conclusion, these findings indicate that r-hirudin more strongly inhibited thrombin than did ATIII without heparin, and that administration of r-hirudin to renal insufficiency required individual adjustment of dosage. The present findings also suggest that r-hirudin can be considered a new agent for the treatment of DIC.
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PMID:Recombinant hirudin for the treatment of disseminated intravascular coagulation in patients with haematological malignancy. 754 Aug 78

Synovial cell proliferation is one of the pathological bases of rheumatoid arthritis (RA). Several cytokines including IL-1 and IL-6 and growth factors have been shown to be involved in the synovial cell proliferation in RA. Thrombin is a multifunctional protease and acts as a mitogen for several cell types through its specific receptor. To assess whether thrombin is involved in overproliferation of rheumatoid synovial cells, we measured the concentration of thrombin-anti-thrombin III (ATIII) complex (TAT) in synovial fluid obtained from patients with RA or osteoarthritis (OA). We also examined the effect of thrombin or thrombin receptor agonist peptide (TRAP) on cell growth of synovial cell clones (SCCs) established from an RA patient. The concentrations of TAT in the synovial fluid from patients with RA were significantly higher than in those with OA. Moreover, both thrombin and TRAP enhanced proliferation of synovial cells in vitro. We also characterized the expression of thrombin receptor mRNA by reverse transcription-PCR. The expression of mRNA for thrombin receptor was up-regulated by thrombin or TRAP stimulation. Thrombin receptor antigen was also detected on both SCCs and synovial tissue from RA patients by immunostaining using a monoclonal antibody against thrombin receptor. These findings indicate that thrombin may act as a mitogen for synovial cells through thrombin receptor and may play some role in synovial overproliferation and remodeling in RA.
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PMID:Thrombin receptor-mediated synovial proliferation in patients with rheumatoid arthritis. 755 43

In a double-blind, randomized, crossover study, we investigated in 15 healthy male volunteers the effects of recombinant (r-) hirudin (HBW 023, 0.35 mg/kg body wt SC), unfractionated heparin (UFH, HeparinNovo; 150 IU/kg body wt SC), and a low-molecular-weight heparin preparation (LMWH, Fragmin; 75 IU/kg body wt SC) on coagulation and platelet activation in vivo by measuring specific coagulation-activation peptides (prothrombin fragment 1 + 2 [F1 + 2], thrombin-antithrombin-III complex [TAT], and beta-thromboglobulin [beta-TG]) in bleeding-time blood (activated state) and venous blood (basal state). In bleeding-time blood, r-hirudin and the heparin preparations significantly inhibited formation of both TAT and F1 + 2. However, the inhibitory effect of r-hirudin on F1 + 2 generation was short-lived and weaker compared with that of UFH and LMWH, and the TAT-to-F1 + 2 ratio was significantly lower after r-hirudin than after UFH or LMWH. Thus, in vivo, when the coagulation system is in an activated state, r-hirudin exerts its anticoagulant effects predominantly by inhibiting thrombin (factor IIa), whereas UFH and LMWH are directed against both factors Xa and IIa. A different mode of action for UFH and LMWH was not detectable. In venous blood, r-hirudin caused a moderate reduction in TAT formation and an increase (at 1 hour) rather than a decrease in F1 + 2 generation. Formation of TAT and F1 + 2 was suppressed at various time points following both UFH and LMWH. There was no difference in the TAT-to-F1 + 2 ratio after r-hirudin and heparin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of recombinant hirudin (r-hirudin, HBW 023) on coagulation and platelet activation in vivo. Comparison with unfractionated heparin and a low-molecular-weight heparin preparation (fragmin). 760 Jan 20

Clotting abnormalities are well-recognized complications that occur with high frequency in patients suffering from underlying malignant diseases. New and highly sensitive molecular markers of hemostasis, thrombin-antithrombin III complex (TAT III), D-dimer fragments (DD), and plasmin-alpha 2-antiplasmin complex (PIC) were measured in 58 consecutive lung cancer patients. Significant elevation in the blood concentrations of DD, PIC, and TAT was found in lung cancer patients, with either extensive or limited disease compared with values obtained in a healthy control group and in another group of patients with chronic obstructive pulmonary disease. Patients with distant metastasis exhibited significantly higher levels of these parameters as compared to those without metastasis. These data indicated that there was a subclinical activation of blood coagulation and fibrinolysis in lung cancer from the early clinical stages of the disease. In addition, there appeared to be different levels of clotting activation according to histologic type of tumor and response to chemotherapy.
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PMID:Evaluating prethrombotic state in lung cancer using molecular markers. 767 80

Radiolabeled antithrombin III (ATIII) was incubated at 37 degrees C with purified vitronectin (VN) or fibrinogen-deficient plasma before thrombin was added to initiate complex formation. Incorporation of radiolabeled ATIII was detected using polyacrylamide gel electrophoresis (PAGE) and autoradiography. The PAGE conditions appeared to be crucial for the detection of VN.TAT complexes. In the absence of SDS, ternary complexes formed instantaneously, whereas in the presence of SDS, only 50% of the TAT was associated with VN after a 60-min incubation. Formation of ternary complexes could be confirmed by gel filtration of the plasma to which thrombin was added. Furthermore, TAT in patient plasmas (disseminated intravascular coagulation and sepsis) was found to bind to heparin-Sepharose, indicating that this endogenously formed TAT was also associated with VN. The amino-terminal region of VN and the thrombin moiety of the TAT complex were found to be responsible for their interaction, which was stabilized by disulfide bridges. These results indicate that in normal plasma all TAT is complexed with VN. This association alters the conformational state of plasma VN, which appears to be responsible for the clearance of thrombin complexes from the circulation.
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PMID:Ternary vitronectin-thrombin-antithrombin III complexes in human plasma. Detection and mode of association. 767 52

Human hepatocyte growth factor (hHGF) has considerable sequence homology with plasminogen and both proteins can be activated by plasminogen activators. The aim of this study was to investigate the relationship between plasma hHGF and fibrinolysis in patients with fulminant hepatic failure (FHF), in whom proteases of coagulation are known to be activated and hHGF levels have been shown to be raised as a consequence of hepatic regeneration. Serum hHGF measured by ELISA was increased in FHF (median 6.67 ng/ml, range 1.2-62 ng/ml), but the values did not correlate with the decreased plasminogen level (median 9%., range 0.7-35.5%) or the level of t-PA which was normal. There was a significant correlation between serum hHGF and increased plasma D-dimer (median 2,163 microgram/l, range 39-7 311 microgram/l), produced by the action of plasmin on fibrin and increased plasma thrombin-antithrombin III complexes (TAT, median 31.7 microgram/l, range 3.7-105 microgram/l). These relationship could be indicative of an involvement of blood coagulation, possibly a specific serine protease, in hHGF activity. After liver transplantation, plasma hHGF was rapidly cleared to almost normal levels, whereas D-dimer and TAT continued to be at elevated levels.
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PMID:Hepatocyte growth factor and plasminogen activation in fulminant hepatic failure. 784 6

New markers of intravascular activation of coagulation have been developed, based on advance in our understanding of the biochemistry of the haemostatic mechanism. These are sensitive methods for measuring of peptides liberated with the generation of thrombin (factor IX activation peptide, factor X activation peptide, peptide F1 + 2), for measuring concentration of enzyme-inhibitor complexes (eg. thrombin-antithrombin III-TAT complexes), as well as for investigating the effect of thrombin on fibrinogen (fibrinopeptide A-FPA) or on protein C (protein C activation peptide). Studies employing these markers indicate that a state of hypercoagulability can be detected in the blood of humans prior to the appearance of thrombotic phenomena. However, further studies will be required to determine whether these methods can identify individuals who are entering a clinically relevant hypercoagulable state as well as to monitor an antithrombotic treatment.
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PMID:[Markers of intravascular activation of coagulation]. 799 71

Recently, an increased frequency of thromboembolic events has been reported after the administration of anticancer drugs. The precise mechanism by which these vascular phenomena occur is unknown. The current work aims at evaluating the alterations of the coagulation and the fibrinolysis systems during the administration of antineoplastic agents by means of newly developed markers of haemostasis. This investigation comprised 25 lung cancer patients treated with multidrug combination chemotherapy. D-dimer, plasmin-alpha 2-antiplasmin complex, fibrin degradation products, fibrinogen, antithrombin III, thrombin-antithrombin III complex, prothrombin time and activated partial thromboplastin time were measured from samples taken before and on days 2, 5, 7, 14 and 21 after the administration of antineoplastic drugs. A significant reduction in plasma concentration of fibrinolytic activity markers, DD and PAP, was observed on days 5 and 7, and on days 2, 5, 7 and 14, respectively, following the administration of chemotherapeutic drugs. Statistically significant shortening of PT and APTT on days 2, 5, 7 and 14, as well as significant elevation of the thrombin generation marker TAT were observed on days 5 and 7 after chemotherapy. These results show that relatively higher levels of coagulation activation and a lower fibrinolytic activity occur during cytotoxic drug therapy compared with basal values. Small variations of haemostatic values and a short follow-up period may explain why no thrombotic events were observed during this study. Although further studies must be done to clarify these findings, the results of this investigation suggest that an imbalance of the coagulation-fibrinolysis system might be a contributing factor in the pathogenesis of thrombotic complications during chemotherapy.
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PMID:Alteration of coagulation and fibrinolysis systems after multidrug anticancer therapy for lung cancer. 799 12

The clinical relevance of determination of plasma antithrombin III(ATIII) and alpha 2-plasmin inhibitor (alpha 2 PI) activities in patients with disseminated intravascular coagulation (DIC) was analyzed. Although the plasma ATIII activity was decreased in patients with DIC, no significant correlation was observed between plasma level of ATIII and that of thrombin-antithrombin III complex or prothrombin fragment 1+2. The extent of the decrease of ATIII in DIC was the most marked in cases associated with septicemia. The plasma level of ATIII in septicemia without DIC was significantly lower than that in DIC cases without septicemia, suggesting that the decrease of ATIII level could not be related to the pathophysiology of DIC, but to that of septicemia. The plasma half-life of ATIII in septicemia without DIC was significantly shortened in the absence of the increase of TAT level, suggesting that the extravasation of ATIII might be induced probably due to the endothelial damage in septicemia. The alpha 2-Plasmin inhibitor level was decreased in DIC patients. The decrease was the most marked (lower than 60% of normal) in patients with excessive fibrinolysis in which fibrinogen degradation was induced. The plasma level of alpha 2PI was significantly higher in the DIC cases with septicemia than in those without septicemia. The ATIII/alpha 2PI ratio was significantly lower in DIC cases with septicemia than in those with solid tumor or acute leukemia. Moreover, the ATIII/alpha 2PI ratio was significantly lower in MOF cases than in non-MOF cases in septicemia. The mortality of the MOF cases did not correlate with the ATIII/alpha 2PI ratio, but with the plasma level of PAI-1, suggesting that the decrease of ATIII/alpha 2PI ratio might not reflect the irreversible endothelial cell damage. Based on these observations, the calculation of ATIII/alpha 2PI in DIC patients would provide the following information; (1) a low ATIII/alpha 2PI ratio (less than 0.6) was frequently observed in septicemia, which could be related to the occurrence of organ dysfunction; (2) a high ATIII/alpha 2PI ratio (higher than 1.0) with the marked decrease of alpha 2PI level (lower than 60% of normal) suggests the occurrence of excessive fibrinolysis in which anti-fibrinolytic therapy should be considered when clinical bleeding was present; (3) The ATIII/alpha 2PI ratio near 1.0 was observed in DIC associated with the pathological conditions other than described above, such as solid tumors, in which the coagulation and fibrinolysis was almost equally activated.
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PMID:[Clinical relevance of determination of plasma ATIII and alpha 2 PI activities in patients with DIC--application of the molecular markers for the analysis of pathophysiology of DIC]. 810 83


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