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)

Tinzaparin, a low molecular weight (LMW) heparin with an average molecular weight of 4.5 +/- 1.5 kD, has greater bioavailability and a longer duration of action than unfractionated heparin, allowing it to be administered once daily by subcutaneous injection for both prophylaxis and treatment of deep venous thrombosis (DVT). Like other members of its class, tinzaparin has a greater ratio of antifactor Xa/anti-factor IIa activity than unfractionated heparin, providing the theoretical advantage of similar antithrombotic efficacy with a diminished risk of haemorrhagic complications. In a small number of clinical trials, tinzaparin was found to be more effective than intravenous dextran or oral warfarin sodium as prophylaxis against DVT in high-risk patients undergoing orthopaedic surgery, and more effective than subcutaneous heparin in both general surgical patients and medical patients with an immobilising illness. When used for the treatment of established DVT, tinzaparin was more effective in preventing DVT recurrence than intravenous heparin, both initially and during a 3-month follow-up period when patients received warfarin sodium. Tinzaparin was also used successfully in one small study to maintain the patency of haemodialysis circuits over a 6-month period, with favourable effects on the lipid profile of such patients. Tinzaparin is well tolerated, the most frequent complication being injection site haematoma. In comparative trials, tinzaparin was associated with fewer major haemorrhagic complications than intravenous heparin (when used for treatment of venous thrombosis), but more than warfarin sodium. Other adverse events which have been reported in tinzaparin-treated patients include elevated liver enzyme levels and thrombocytopenia. Thus, although clinical experience is limited at present, available data suggest that, in common with other LMW heparins, tinzaparin is likely to prove an effective alternative to unfractionated heparin for both the prevention and treatment of DVT, with the advantage of more convenient administration and decreased monitoring requirements.
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PMID:Tinzaparin. A review of its pharmacology and clinical potential in the prevention and treatment of thromboembolic disorders. 752 34

The activation of the clotting cascade leading to deep venous thrombosis begins during total hip arthroplasty, but few studies have assessed changes in coagulation during surgery. A better understanding of thrombogenesis during total hip arthroplasty may provide a more rational basis for treatment. In 3 separate studies, the following observations were made. Circulating indices of thrombosis and fibrinolysis: prothrombin F1.2, thrombin-antithrombin complexes, fibrinopeptide A, and D-dimer, did not increase during osteotomy of the neck of the femur or during insertion of the acetabular component, but rose significantly during insertion of the femoral component. Thrombin-antithrombin complexes, fibrinopeptide A, and D-dimer were higher after insertion of a cemented component than insertion of a noncemented femoral component. A significant decline in central venous oxygen tension was observed after relocation of the hip joint and after insertions of cemented and noncemented femoral components, providing evidence of femoral venous occlusion during insertion of the femoral component. In patients receiving a cemented femoral component, mean pulmonary artery pressure increased after relocation of the hip joint, indicating intraoperative pulmonary embolism. No changes in mean pulmonary artery pressure were noted with noncemented total hip arthroplasty. Administration of 1000 units of unfractionated heparin before insertion of a cemented femoral component blunted the rise of fibrinopeptide A. The results of these studies suggest that (1) the greatest risk of activation of the clotting cascade during total hip arthroplasty occurs during insertion of the femoral component; (2) femoral venous occlusion and use of cemented components are factors in thrombogenesis during total hip arthroplasty; and (3) measures to prevent deep venous thrombosis during total hip arthroplasty (such as intraoperative anticoagulation) should begin during surgery rather than during the postoperative period and be applied during insertion of the femoral component.
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PMID:The John Charnley Award. Thrombogenesis during total hip arthroplasty. 755 26

Various experimental models have been developed in order to more clearly understand deep vein thrombosis, the mechanisms involved and its treatment. These models are based on venous stasis, either alone or combined with the injection of thrombogenic substances or endothelial lesions. Other models only use endothelial lesions. Thrombogenic substances are mostly composed of activated factor X or thrombin, which raises the problem of purity of the substances and determination of the antithrombotic activities of the substance tested, especially heparin and hirudin and their derivatives, and consequently their efficacy. Endothelial lesions can be induced by chemical, physical or electrical agents or by repeated application of clamps, or cellular crushing. These models result in the formation of various forms of venous thrombus. The development and improvement of experimental models is very important in every case. Experimental models of thrombosis constitute the best tool for the study of thrombosis, in which many points remain to be elucidated. They also allow the study and development of various antithrombotic substances the improvement of their efficacy. These models must be validated, standardized, reproductible and in agreement with local legislation in each country.
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PMID:[Experimental models of venous thrombosis]. 757 61

A 70-year-old woman on maintenance hemodialysis for 3 years was admitted to our hospital because of deep vein thrombosis (DVT) in the right femoral vein. Seven days before admission, she suddenly noticed severe pain in her right inguinal region while she was walking on the street. A wide range of stenosis from the iliac to the distal femoral region was detected by both CT scanning and venography. Her hematocrit reading was 30% and her serum erythropoietin level was 10.5 MU/ml, which was within the normal range, on the day of admission. The results of routine coagulation tests, including prothrombin time, activated partial thrombin time and plasma fibrinogen values, were normal. Plasma anti-thrombin III and plasminogen were also normal. In contrast, beta-thromboglobulin, platelet factor IV, fibrinogen degradation product, D-dimer, thrombin-antithrombin III complex (TAT) and fibrinopeptide A were abnormally elevated. In the venous occlusion test which was performed in the forearm of the opposite side of the arterio-venous shunt, plasma tissue type plas-minogen activator values showed little response to occlusion indicating that the vessel endothelium may have been partially damaged. These data suggest that the DVT had been induced by imbalance of increased blood coagulation and decreased fibrinolytic activity. Damaged vascular wall may also have contributed to the production of DVT. Furthermore, it is surprising that the patient had elevated values of D-dimer and TAT for many years without recurrence of the DVT. Spontaneous DVT in an apparently healthy individual on maintenance hemodialysis seems to be rare, compared with arterial thrombosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[A long-term hemodialysis patient with spontaneous deep vein thrombosis, showing high levels of coagulo-fibrinolytic markers]. 760 31

Recombinant hirudin is currently being developed as a potential prophylactic and therapeutic antithrombotic drug in various clinical indications such as angina and deep venous thrombosis. In this report, we have discussed the production of specific polyclonal antibodies to recombinant hirudin (rH) and the development of two ELISA methods to measure rH concentrations in biological fluids: a sandwich and a competitive ELISA method. Intra- and inter-assay variations in the two methods are extremely low (3-7%). The competitive ELISA method is rapid, simple and highly reproducible. Saturation binding curves, selection of appropriate incubation times, recovery of different hirudin variants and reactivity in the presence of thrombin are discussed. The methods can be easily adapted to monitor hirudin concentrations in the clinical laboratory for diagnostic purposes as well as for performing pharmacokinetic studies.
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PMID:Development and validation of two enzyme-linked immunosorbent assay (ELISA) methods for recombinant hirudin. 766 Jan 41

Management of thromboembolic disease involves administration of anticoagulants, thrombolytics or antiplatelet agents to lyse or prevent thrombus extension. Despite widespread use and decades of experience with some of these agents, much is unknown about the effects of dose and plasma concentration on patient response. Unfractionated heparin (UFH) improves outcome in many thromboembolic disorders when administered to a target activated partial thromboplastin time (aPTT) or plasma heparin concentration. UFH exhibits dose-dependency both with absorption from subcutaneous sites and elimination. Doses based on bodyweight or estimated blood volume attain therapeutic aPTTs faster than fixed or standard doses. Low molecular weight heparins (LMWHs) were developed to increase the anti-factor Xa:anti-factor IIa activities. Several different LMWHs are as effective as UFH in treating deep venous thrombosis. Evidence fails to support a relationship between anti-factor Xa activity and either thrombosis evolution or bleeding. No comparisons have been made between bodyweight-based and anti-factor Xa activity-based doses. The dose of orally administered warfarin is adjusted to achieve a target International Normalised Ratio (INR). Maintenance doses are estimated on the basis of the patient's INR during the first 3 days of therapy: the dose required to achieve an optimal INR decreases with age > 50 years. The thrombolytic agents are administered in standard doses to achieve rapid thrombolysis with minimal alteration in systemic haemostasis. Accelerated intravenous alteplase may result in the highest rate of coronary artery reperfusion. Nevertheless, standard doses of streptokinase, anisoylated plasminogen streptokinase complex and alteplase result in similar 1-month mortality rates. The minimal advantage seen with alteplase is offset by higher rates of stroke. Future trials will focus on administration strategies achieving rapid thrombolysis, while minimising the risk of serious bleeding. With the antiplatelet agents, unpredictability in the pharmacokinetic parameters of different products has confounded interpretation of published reports. Optimal aspirin (acetylsalicylic acid) administration would include administration of an initial dose of 160 to 325mg after an acute vascular event, followed by maintenance dosages of approximately 75 mg/day for prophylaxis or treatment. Ticlopidine does not exhibit a relationship between either plasma concentration or dose and adverse effects, while pharmacodynamic effects may be dose-, but not plasma concentration-, dependent. The correlation between the concentration of dipyridamole and some of its antiplatelet effects may be the strongest amongst all the antiplatelet agents. However, unfortunately all clinical trials used standard doses and the current consensus is that dipyridamole alone is not an effective antiplatelet agent.
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PMID:Pharmacokinetic optimisation of the treatment of embolic disorders. 771 62

Dermatan sulphate catalyses thrombin inhibition by heparin cofactor II; it has a lower haemorrhagic to antithrombotic ratio than that of heparin in animal models. Consecutive patients aged forty years or more, electively undergoing total hip replacement under general anaesthesia, were randomly allocated to one of three dosage regimens of dermatan sulphate (MF701, Mediolanum Farmaceutici) given intramuscularly. These were 200 mg once daily (n = 50), 200 mg twice daily (n = 52) and 300 mg twice daily (n = 51), administered from twenty-four hours pre-operatively until the tenth postoperative day. The overall incidence of DVT assessed by bilateral venography was 53%, 51% and 34% respectively (Chi-square test for trend p = 0.06). The incidence of major proximal DVT was 10.6%, 8.5% and 2.1% respectively. Pulmonary embolism (PE) and bleeding were assessed in all 153 patients. There was one case of PE in each dose group. The incidence of bleeding episodes, volume of blood lost and blood transfusion requirements were low and showed no increase with increasing dose. The patients were followed up 4-8 weeks after discharge. We conclude that the two lower doses were subtherapeutic in this population, however dermatan sulphate given 300 mg twice daily, proved to be efficacious with an incidence of proximal major DVT of 2.1% and a low incidence of bleeding complications. A trial of dermatan sulphate 300 mg twice daily compared to standard prophylactic agents is needed.
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PMID:A dose ranging study to evaluate dermatan sulphate in preventing deep vein thrombosis following total hip arthroplasty. 774 Apr 43

The physiologic mechanisms that protect children from thromboembolic complications are not known. We investigated the regulation of thrombin in children because of its central importance to thrombosis. The capacity to generate thrombin in vitro (chromogenic assay) was decreased by 26% in plasmas from children (1-16 yrs; n = 102) compared to adults ([20-45 yrs; n = 20; p < 0.001]). The addition of purified prothrombin to plasmas from children increased thrombin generation to adult values. The capacity of plasmas to inhibit 125I-alpha-thrombin was increased by 21% in children compared to adults (p = 0.020), with significantly more thrombin complexed to alpha 2-macroglobulin (alpha 2M) in children. When DVT occur in children, adult guidelines for heparin therapy are used. At low heparin concentrations (0.1 and 0.2 U/ml), thrombin generation was decreased by 30% in children compared to adults (p < 0.001). At high heparin levels (0.4 U/ml), thrombin generation was negligible in all plasmas. ATIII inhibited over 95% of thrombin in all plasmas in the presence of heparin. In summary, thrombin regulation differs in children from adults and may protect children from thromboembolic complications. When DVT do occur, heparin requirements may differ in children compared to adults.
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PMID:Thrombin regulation in children differs from adults in the absence and presence of heparin. 774 Apr 51

Abnormal antithrombin III (AT III) was found in a 30-year-old woman who suffered from recurrent thrombosis during pregnancy and the postpartum period. Among her family members, only her father had recurrent episodes of deep vein thrombosis of the lower extremities, from his youth. The antithrombin and antifactor Xa heparin cofactor activities of the proposita's plasma were 61% and 42% of normal, respectively. The progressive antithrombin and antifactor Xa activities were also decreased to 55% and 58% of normal, respectively. The immunoreactive level of AT III was within the normal range (23.1 mg/dl). Analysis of the proposita's plasma by crossed immunoelectrophoresis in the presence or absence of heparin and by affinity chromatography on heparin-Sepharose revealed that the proposita's AT III had apparently normal affinity for heparin. Nucleotide sequencing of 7 exons of the proposita's AT III gene amplified by polymerase chain reaction (PCR) disclosed that the second base of codon 393 comprised both G and A, indicating Arg393-His conversion. The base sequences of exons 1, 2, 3a, 3b, 4, and 5 were normal, excluding any other mutation. These findings indicated that the proposita's AT III was a variant of AT III at the thrombin binding site and that the proposita was a heterozygote for the abnormality. Heparin affinity of purified abnormal AT III from the proposita's plasma was demonstrated to be increased upon affinity chromatography using heparin-Sepharose, suggesting that the mutation (Arg393-His) per se could possibly increase the affinity of antithrombin III for heparin. For this variant AT III (Arg393-His), the name AT III Kumamoto II is proposed.
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PMID:Antithrombin III Kumamoto II; a single mutation at Arg393-His increased the affinity of antithrombin III for heparin. 783 87

In order to evaluate the usefulness of determining D-dimer and thrombin-antithrombin III complex (TAT) in the diagnosis of deep venous thrombosis (DVT), three D-dimer assays were tried: one ELISA and one latex test from Diagnostica Stago and one new latex method from Biopool. TAT was assessed using an ELISA (Behringwerke). We studied 96 consecutive outpatients with suspected DVT, of whom 36 had phlebographically confirmed DVT. Statistical calculations showed high sensitivity and a negative predictive value for the D-dimer ELISA (97% for both), confirming the results obtained by others. The new latex method (Biopool) showed similar figures (96% for both). The latex method from Diagnostica Stago and TAT showed lower sensitivity and negative predictive values. No differences in the D-dimer results were found with or without antifibrinolytics in the tubes for blood sampling. Our data suggest that negative results when using the new simple and cheap latex method (Biopool) may reduce the number of phlebographic examinations.
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PMID:D-dimer and thrombin/antithrombin III complex--diagnostic tools in deep venous thrombosis? 784 46


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