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 therapeutic potential of the glycosaminoglycan (GAG), dermatan sulphate (DS), as an antithrombotic agent in humans has yet to be established. We have performed dose ranging studies of DS to determine its effectiveness as an antithrombotic agent in patients (n = 6-8) undergoing haemodialysis for chronic renal failure. In an initial study, Study 1, i.v. bolus doses of 2-4 mg/kg and 5-6 mg/kg DS were given to patients dialysing with polyacrylonitrile hollow fibre (PAN HF) membranes. In a second crossover study, Study 2, performed using cuprophane hollow fibre (CHF) membranes, i.v. bolus doses of 3 mg/kg and 6 mg/kg DS were compared to a standard unfractionated heparin (UFH) regime that has been shown previously to inhibit fibrin formation. Further infusion studies, Study 3 and Study 4 evaluated the antithrombotic efficacy of an i.v. DS bolus of 3 mg/kg plus an i.v. infusion of DS 0.6 mg kg-1 h-1 and a DS bolus of 5 mg/kg plus an infusion of 1 mg kg-1 h-1 over 5 h, respectively. These studies were compared to standard UFH regimes in a randomised crossover design. Plasma levels of fibrinopeptide A (FPA) and thrombin-antithrombin (TAT) were used as markers of fibrin formation and thrombin generation during dialysis using both membranes. The changes in DS concentration following administration of the different doses were similar in Studies 1 and 2. However, the effectiveness of DS as an anticoagulant appeared to depend markedly on the different dialyser types used in the two studies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antithrombotic properties of dermatan sulphate (MF 701) in haemodialysis for chronic renal failure. 145 3

In a controlled pilot study of 32 critically ill patients, we have attempted prospectively to identify laboratory variables which can be used to select and monitor patients on antithrombin (AT) therapy. Patients with plasma AT levels less than 70% of normal were randomized to receive (AT group) or not to receive AT concentrate (non-AT group). The groups did not differ in median age, sex, median APACHE II and TISS scores, number of days spent in the Intensive Care Unit or mortality rate. At the time of inclusion all patients had activated coagulation and fibrinolysis demonstrated as high levels of soluble fibrin, thrombin-antithrombin complexes and fibrin-D-dimers (twice, four and ten times the upper reference range, respectively). In the AT group these levels decreased faster and the prothrombin complex concentration increased more rapidly to normal (i.e. the prothrombin time decreased). The level of C-reactive protein which was high in both groups on inclusion (139 and 98 mg/l, respectively) decreased by 40% in the AT group but did not change in the control group. Our study indicates that laboratory variables normalize faster in seriously ill patients who have activated coagulation and fibrinolysis when they receive AT concentrate and that the variables mentioned above seem to be useful for monitoring the treatment.
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PMID:Effect of antithrombin concentrate on haemostatic variables in critically ill patients. 146 8

We investigated the imbalance between thrombin and plasmin activity in vivo with various grades of severity of disseminated intravascular coagulation (DIC) in relation to the underlying diseases. Plasma thrombin-antithrombin-III complex (TAT) and plasmin-alpha 2-antiplasmin complex (PAP) levels were measured in 133 blood samples obtained from patients with DIC. The TAT/PAP ratio was higher in patients with sepsis or solid cancer than in those with hematologic malignancies. In acute promyelocytic leukemia (APL), the TAT levels were the highest, but the PAP levels were even higher and the TAT/PAP ratio was the lowest. As for the severity of DIC, in mild DIC, both thrombin and plasmin activities were increased. In moderate DIC, the TAT/PAP ratio increased, and thrombin activity was much more predominant. However, in severe DIC, the ratio decreased, and plasmin activity became excessive. In 3 patients with acute myeloblastic leukemia, APL and pancreatic cancer, respectively, the PAP level remained high during heparin therapy although the TAT level was decreased. When tranexamic acid was given, the PAP level was selectively reduced, and the TAT/PAP ratio was markedly decreased along with clinical improvement. These results indicate that monitoring of the TAT/PAP ratio may contribute to decisions regarding the institution and performance of combination therapy for DIC using anticoagulants and antifibrinolytic agents.
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PMID:Imbalance between thrombin and plasmin activity in disseminated intravascular coagulation. Assessment by the thrombin-antithrombin-III complex/plasmin-alpha-2-antiplasmin complex ratio. 146 20

Six different substitution mutations were identified in four different amino acid residues of antithrombin strand 1C and the polypeptide leading into strand 4B (F402S, F402C, F402L, A404T, N405K, and P407T), and are responsible for functional antithrombin deficiency in seven independently ascertained kindreds (Rosny, Torino, Maisons-Laffitte, Paris 3, La Rochelle, Budapest 5, and Oslo) affected by venous thromboembolic disease. In all seven families, variant antithrombins with heparin-binding abnormalities were detected by crossed immunoelectrophoresis, and in six of the kindreds there was a reduced antigen concentration of plasma antithrombin. Two of the variant antithrombins, Rosny and Torino, were purified by heparin-Sepharose and immunoaffinity chromatography, and shown to have greatly reduced heparin cofactor and progressive inhibitor activities in vitro. The defective interactions of these mutants with thrombin may result from proximity of s1C to the reactive site, while reduced circulating levels may be related to s1C proximity to highly conserved internal beta strands, which contain elements proposed to influence serpin turnover and intracellular degradation. In contrast, s1C is spatially distant to the positively charged surface which forms the heparin binding site of antithrombin; altered heparin binding properties of s1C variants may therefore reflect conformational linkage between the reactive site and heparin binding regions of the molecule. This work demonstrates that point mutations in and immediately adjacent to strand 1C have multiple, or pleiotropic, effects on this serpin, leading ultimately to failure of its regulatory function.
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PMID:Pleiotropic effects of antithrombin strand 1C substitution mutations. 146 94

Fibrinopeptide A (FPA), fibrinopeptide B beta 15-42 (FPB beta 15-42) and other coagulation factors (anti-thrombin III, thrombin-antithrombin complex, alpha 2-macroglobulin, plasmin inhibitor complex) were measured in the plasma of 101 patients with diabetes mellitus (DM). The levels in 80 healthy adults were also measured for comparative purposes. The mean levels of FPA, FPB beta 15-42 and the other 4 coagulation factors in the DM patients were significantly higher than in the controls (p < 0.05). The mean levels of FPA and FPB beta 15-42 in patients with diabetic retinopathy (DR) were higher than in those without DR, that is in those with proliferative diabetic retinopathy (PDR) higher than in those with simple diabetic retinopathy (SDR). In patients after panretinal photocoagulation (PRP), the mean level of FPA was higher and that of FPB beta 15-42 was lower than in patients before PRP. In the SDR group, the level of FPB beta 15-42 was significantly correlated with the progression of diabetic retinopathy. We suggest that there was a close correlation between plasma FPA and FPB beta 15-42 levels and activity or progression of disease, and that the investigation of these levels may be useful for the judging of prognosis or effect of therapies of diabetic retinopathy.
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PMID:[Plasma fibrinopeptide A, fibrinopeptide B beta 15-42 and 4 other coagulation factors levels in patients with diabetic retinopathy]. 147 75

A sandwich enzyme-linked immunosorbent assay (ELISA) has been developed to measure plasma levels of thrombin-antithrombin complex (TAT). The assay is performed in a microtitre plate using polyclonal antibodies specific for antigenic determinants on prothrombin and antithrombin. Antibody to prothrombin was immobilized on a solid phase, using a titre predetermined to optimize capture of TAT. The performance of the microtitre plate ELISA for TAT has been extensively investigated and compared with the performance characteristics of a tube-based ELISA for TAT which is available commercially (Enzygnost-TAT, from Behringwerke, Marburg, Germany). Studies with plasma containing various levels of prothrombin showed that the zymogen competed with TAT for capture antibody in both assays. Variations in prothrombin levels between plasma samples present a potential source of artifact, but one which does not critically affect the performance of either assay in detecting large elevations in TAT. A high correlation (r = 0.88) was established between the results of plasma samples assayed by both assays, whether citrate or EDTA anticoagulant was used to prepare plasma. High correlations (r > 0.90) were also established for each assay between the results of plasma prepared with EDTA as compared to citrate anticoagulant. Both assays were able to discriminate completely between a group of 16 normal controls and a group of 31 patients with disseminated intravascular coagulation (DIC).
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PMID:A microtitre plate ELISA to measure thrombin-antithrombin complex using pan-specific antibodies. 148 1

To maintain a closed system during the preparation of blood components, including the removal of buffy coat, many centers use a quadruple blood bag additive solution system which in this study has been reduced to a cheaper triple bag system. The buffy coat and plasma were after centrifugation transferred to the first satellite bag and, after a second spin, the plasma separated from the buffy coat was transferred to the second satellite bag and stored for a fortnight at 4 degrees C. This resulted in a statistically significant increase in platelet factor 4 and elastase activity levels. No significant changes were found in the levels of C1-esterase inhibitor and kallikrein inhibiting activity, thrombin-antithrombin complexes, soluble fibrin, fibrinopeptide A and spontaneous proteolytic activity. The changes observed must be regarded as clinically insignificant. The platelet count is low enough to meet the requirements for platelet poor plasma. Using this blood component separation technique, one can reduce the CPD/additive solution 4-pack blood bag system to a less expensive 3-pack blood bag system.
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PMID:Blood component processing technique and plasma quality. 149 50

This study was made to evaluate assays for monitoring of low dose heparin thromboprophylaxis and to evaluate its efficacy in reduction of hypercoagulation. Patients with medical diseases scheduled for routine thromboprophylaxis were subcutaneously treated with either 5.000 anti XaU low molecular weight (LMW) heparin once daily (n = 20) or 5.000 IU standard (ST) heparin 3 times daily (n = 19). On days 1,2,3, before, 1 and 4 hours after heparin injection APTT, TCT, anti Xa, Heptest, thrombin-antithrombin complexes (TAT), and D-Dimer levels were measured. In the LMW heparin group, median values of APTT and TCT slightly increased after heparin and the ranges of pre- and postinjection values showed extensive overlap. However, values of anti Xa and Heptest markedly increased, showing complete separation of ranges. In the ST heparin group neither APTT, TCT, anti Xa, nor Heptest were significantly different comparing pre- and postheparin values. Half of the patients in both groups had subclinical hypercoagulation at baseline (TAT greater than 5 ng/ml, D-Dimer greater than 200 ng/ml). On day 3 of prophylaxis this percentage was not significantly decreased. Moreover, several patients in both groups increased in TAT and D-Dimer. In the LMWheparin group, negative correlations between body weight and 4 h postinjection heparin levels were found (anti Xa R = -0.50, Heptest R = -0.31) and between 1 h postinjection heparin and TAT and D-Dimer levels 3 h later (TAT-anti Xa R = -0.58, TAT-Heptest R = -0.64, D-Dimer-anti Xa R = -0.32, D-Dimer-Heptest R = -0.33).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Laboratory monitoring of thromboprophylaxis with low molecular weight and standard heparin. 151 32

An ELISA assay for quantitation of the thrombin-heparin cofactor II complex (T-HC II) in plasma was developed. Plasma was incubated with immobilized, specific antibodies to human thrombin. The second, biotinylated antibody was directed against human HC II. The assay was insensitive to thrombin-antithrombin complex (TAT) and to uncomplexed HC II. In plasma samples from 31 normal individuals (aged 21-68, mean 43.3 years), the T-HC II ranged 0.3-6.1 ng/ml; median 1.5, mean 2.0, and SD 1.6 ng/ml. In plasma samples from 13 patients with disseminated intravascular coagulation (DIC), T-HC II ranged 0.4-30.0 (median 13.5) ng/ml. In plasma samples from 6 patients in which the clinical suspicion of DIC was not verified, T-HC II complex ranged 1.4-14.3 (median 3.6) ng/ml. In plasma samples with elevated T-HC II levels, TAT was usually elevated, and on the average more than was T-HC II. These results indicate that HC II contributes significantly to the inactivation of in vivo generated thrombin.
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PMID:Elevated levels of thrombin-heparin cofactor II complex in plasma from patients with disseminated intravascular coagulation. 152 13

Blood coagulation and fibrinolytic inhibitors and the balance between and within the two systems were investigated in 26 normal pregnant women during pregnancy and the puerperium. The concentration of the coagulation inhibitors antithrombin and protein C remained within normal levels, whereas the mean level of free protein S showed a significant decrease from 0.26 U/mL in early pregnancy to 0.14 U/mL in week 35. At the same time, soluble fibrin levels increased from 9.2 to 13.4 nmol/L and thrombin-antithrombin complexes increased from 3.1 to 7.1 micrograms/L; both are indicators of thrombin activity. A concurrent increase in the levels of the fibrinolytic inhibitors plasminogen activator inhibitor-1 and -2 from 7.4 to 37.8 AU/mL and 31 to 160 micrograms/L, respectively, suggests a decrease in fibrinolytic activity. However, the levels of fibrin D-dimer, ie, fibrin split products, also increased in parallel from 91 to 198 micrograms/L, suggesting that fibrinolysis is present. Thus, a balance normally exists, which is probably why thrombotic events are rare during pregnancy.
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PMID:Enhanced thrombin generation and fibrinolytic activity in normal pregnancy and the puerperium. 153 80


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