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)

In order to predict a hypercoagulable state in patients with advanced breast cancer receiving medical treatment, the effects of chemoendocrine therapy on the coagulation-fibrinolytic systems were investigated prospectively. The patients were randomly divided into two groups. The ACT group had 38 patients, who received 20 mg/m2 adriamycin (ADM) i.v. on days 1 and 8, 100 mg cyclophosphamide (CPA) p.o. on days 1-14, and 20 mg tamoxifen (TAM) p.o. daily. The ACM group had 44 patients, who received 20 mg/m2 ADM i.v. on days 1 and 8, 100 mg CPA p.o. on days 1-14 and 1200 mg medroxyprogesterone acetate (MPA) p.o. daily. The treatment was repeated every 28 days until there was evidence of progressive disease or until the full ADM dose (550 mg/m2) had been given. The following 9 hematologic parameters were measured every 4 weeks: alpha 2-plasmin inhibitor plasmin complex (PIC), anti-thrombin-III (AT-III), D-dimer (Dd), fibrinogen (Fg), plasminogen (Pg), protein C (PC), thrombin-antithrombin-III complex (TAT-III), tissue plasminogen activator (t-PA), and factor X (FX). Compared to the ACT group, patients in the ACM group showed significantly higher values of AT-III and PC, which exceeded the normal ranges. The levels of Pg, t-PA and FX were significantly higher in the ACM group than in the ACT group, but were still within the normal ranges. The levels of TAT-III, Dd and PIC decreased in the ACT group and were unchanged in the ACM group after the start of treatment. Fg remained unchanged in both groups after the start of treatment. One patient in the ACM group had thrombophlebitis of the lower extremities with high levels of TAT-III, Dd and PIC and a decrease of Fg, but her condition returned to normal after reduction of the MPA dose. Although these data are not directly indicative of a hypercoagulable state in patients receiving chemoendocrine therapy, changes in AT-III, TAT-III, Dd and PIC should be monitored carefully when this type of treatment is given.
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PMID:Effects of chemoendocrine therapy on the coagulation-fibrinolytic systems in patients with advanced breast cancer. Japan Advanced Breast Cancer Study Group and Japan Clinical Oncology Group. 851 13

Using the dog as an animal model, we developed an experimental preparation to compare hemodynamic and hematologic toxicity of anticoagulation reversal. Currently, protamine sulfate reversal of standard unfractionated heparin and low-molecular-weight heparin (LMWH) anticoagulation causes adverse side effects, including decreased systemic mean arterial pressure (MAP), decreased cardiac output (CO), decreased oxygen consumption (VO2), and thrombocytopenia. In addition, standard protamine is only marginally effective at reversing the factor Xa inhibition induced by LMWHs. We have produced protamine-like variant peptides to decrease the adverse responses attributed to standard protamine. The hemodynamic, hematologic, and coagulation effects of standard protamine and the protamine variant (+18RGD) were assessed after reversal of LMWH anticoagulation in anesthetized dogs. Flow probes and vascular catheters were surgically implanted for measurement of hemodynamic parameters including MAP, CO, VO2, and heart rate (HR). Hematologic studies (platelet and white blood cell counts) and coagulation studies (activated clotting time [ACT], activated partial thromboplastin time [aPTT], thrombin clotting time [TCT], antifactor Xa and antifactor IIa values) also were performed. The protamine variant +18RGD was less toxic, induced less thrombocytopenia, and was more effective in anticoagulation reversal than was standard protamine sulfate. Results of this study indicate that the dog may be a useful model for investigating important hemodynamic, hematologic, and coagulation parameters during reversal of LMWH anticoagulation by use of synthetic protamine variants.
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PMID:Comparison of the hemodynamic and hematologic toxicity of a protamine variant after reversal of low-molecular-weight heparin anticoagulation in a canine model. 915 Apr 94

During cardiopulmonary bypass (CPB) mechanical stress and the contact of blood with artificial surfaces lead to the activation of pro- and anticoagulant systems and the complement cascade, and to changes in cellular components. This phenomenon causes the "postperfusion-syndrome", with leukocytosis, increased capillary permeability, accumulation of interstitial fluid, and organ dysfunction. In this study, we focused on the influence of the extracorporeal circulation, sternotomy, and heparin administration on the activation of coagulation and fibrinolysis. In 15 patients we investigated coagulation parameters before, during and post CPB, i.e., fibrinogen, antithrombin (AT) III, thrombin-antithrombin complex (TAT), prothrombin fragments F1 + 2 (F1 + 2), factor (F) XIIa, tissue factor (TF), and parameters of the fibrinolytic system, i.e., plasmin-antiplasmin-complex (PAP), D-dimer, tissue-plasminogen-activator (tPA), urokinase-type plasminogen activator (uPA), and plasminogen-activator inhibitor type 1 (PAI 1). The results demonstrate distinct alterations in the above mentioned parameters. Despite administration of a high dose of heparin (activated clotting time [ACT] > 450s) combined with a low dose of aprotinin, activation of the coagulation and fibrinolytic pathways was observed. We found this activation was mainly caused by CPB and not by sternotomy. The activation of coagulation was due to foreign surface contact (F XII => F XIIa) as well as to an effect of tissue factor release in the late phase of CPB. The enhanced fibrinolytic activity during CPB was, at least in part, caused by tPA and was followed by PAI 1 release.
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PMID:Changes in coagulation and fibrinolytic parameters caused by extracorporeal circulation. 924 50

The exposed Serpin reactive centre loop controls the specificity of the serpin proteinase interaction. Mutations within this region have been used to generate novel potentially therapeutic inhibitors. In this study we examine the effect of the serpin scaffold and reactive centre loop length upon the generation of such inhibitors. The reactive centre loop regions, P7-P3', of alpha1-antitrypsin and alpha1-antichymotrypsin were replaced by the corresponding residues of the viral serpin, Serp1, to form AT/Serp1 and ACT/Serp1, respectively. AT/Serp1 formed SDS stable complexes with a range of proteinases with association rate constants for plasmin, tissue plasminogen activator, urokinase, thrombin and factor Xa of approximately 10(4) M(-1)s(-1) and a stoichiometry of inhibition of approximately 1 for all of them. ACT/Serp1, however, formed SDS-stable complexes with only plasmin and thrombin with association rate constant 100-fold slower than AT/Serp1 and an increased stoichiometry of inhibition. The reactive centre loop of ACT/Serp1 is four amino acid residues longer than AT/Serp1. These four additional residues (VETR) were inserted into AT/Serp1 to form AT/Serp1(VETR). AT/Serp1(VETR) formed SDS stable complexes with plasmin, thrombin and tissue plasminogen activator similar to AT/Serp1, however, the association rate constants were 10-fold slower than those observed with AT/Serp1, while the stoichiometry of inhibition remained around 1. These results suggest that the additional reactive centre loop residues effect the rate of initial complex formation by placing the reactive centre loop in a non-ideal conformation. This study demonstrates that both reactive centre loop length and serpin scaffold are important in defining the inhibitory characteristics of a serpin.
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PMID:Protein engineering of chimeric Serpins: an investigation into effects of the serpin scaffold and reactive centre loop length. 993 Jun 74

During clinical trials with the thrombin inhibitor argatroban, appropriate methods for drug monitoring were identified. Treated patients presented interesting challenges for coagulation laboratory parameter testing in the presence of argatroban. These issues are reported here. Regarding the monitoring of argatroban, the aPTT and ACT were effectively used clinically for low (0-2.5 microg/mL) or high (1-15 microg/mL) doses of argatroban. However, system (reagent and instrument) differences were noted in the time-to-clot values. A clot-based assay using Ecarin as the activator (ECT, Ecarin clotting time) appeared to be useful for monitoring both low and high drug levels with less interference from other drugs or coagulation defects. Also identified were the chromogenic antithrombin assay that could directly quantify argatroban and an HPLC based assay that could specifically quantify argatroban and its metabolites. With regard to assay interference by argatroban, several important effects were observed. The presence of argatroban synergistically interfered with the INR for those patients treated with oral anticoagulants. However, a chromogenic based method was able to determine factor X levels as a monitor of the oral anticoagulation without effect from argatroban. A similar synergistic response on the aPTT with heparin and argatroban was observed. Patients receiving argatroban evaluated for potential coagulation abnormalities could not be tested with the routine functional (clot based) assays for fibrinogen, factor levels or protein C. Argatroban acted as an inhibitor in these assays, causing a dose-dependent false decrease of fibrinogen and factor levels, and a false increase of protein C. Using a chromogenic assay for protein C, values equal to those obtained by an immunologic assay were achieved. These issues will most likely hold true for all thrombin inhibitors.
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PMID:Coagulation laboratory testing in patients treated with argatroban. 1035 54

In this clinical pilot study, the influence of heparin pretreatment on the haemostatic system during and after cardiopulmonary bypass (CPB) was investigated. Thirteen patients scheduled for elective coronary artery bypass grafting (CABG) were divided into two groups: heparin pretreated (HP, n = 6) and non-heparin pretreated (NHP, n = 7). Blood samples were taken for measurements of plasma antithrombin-III (AT-III) activity, plasma heparin levels, activated clotting time with (HACT) and without (ACT) heparinase, whole blood platelet function, platelet count, thrombin-antithrombin-III complexes and D-dimer levels. Also, the mediastinal blood loss within the initial 20 h after surgery, and the blood transfusion requirements were monitored. The mean duration of the heparin pretreatment was 55 h (range 24-161 h). There was no significant difference in plasma AT-III activity and platelet count between the groups. Before and after CPB, the platelet responsiveness was better in the NHP group (p < 0.05). The HACT was prolonged in the NHP group during and after CPB compared to baseline values (p < 0.05), whereas, in the HP group, no significant changes were found. Plasma heparin levels and ACT values suggested adequate anticoagulation during CPB. However, the extent of thrombin inhibition and fibrinolysis increased with time on CPB, but did not differ between the two groups. Twenty hours after surgery, the thrombin inhibition showed to be significantly higher in the NHP group. Furthermore, mediastinal blood loss showed a tendency to be lower in the HP group (p = 0.08). However, there was no difference in blood transfusion requirements between the groups. These data suggest that short-term heparin pretreatment affects the perioperative platelet responsiveness and attenuates the consumption of coagulation factors.
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PMID:Does heparin pretreatment affect the haemostatic system during and after cardiopulmonary bypass? 1119 5

Argatroban is the smallest anticoagulant molecule of direct thrombin inhibitors. The main attributes of this synthetic drug are its rapid onset of anti-thrombin action, the rapid reversibility of its anticoagulant effect, potent inhibition of clot-bound thrombin, the absence of antibody formation and no need for dosage adjustment in patients with renal impairment. It is eliminated by hepatic metabolism. These properties make argatroban a predictable anticoagulant with intravenous use in a routine clinical setting. Argatroban is approved in the US and Canada for both prophylaxis and treatment of thrombosis in patients with heparin-induced throm-bocytopenia (HIT) and in the US as an antithrombotic agent during percutaneous coronary interventions in patients with HIT or a history of HIT. Preliminary reports document the feasibility of using argatroban for anticoagulation during hemodialysis and as adjunct to thrombolysis for treatment of myocardial infarction. Current recommendations for argatroban monitoring are to use the aPTT (activated partial thromboplastin time) for low doses and the ACT (activated clotting time) for high doses. The specific inhibition of thrombin can be measured with the ECT (ecarin clotting time).
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PMID:[Experimental and clinical results with the thrombin inhibitor Argatroban]. 1221 62

Unfractionated heparin (UH) and low-molecular-weight heparins (LMWH) are antithrombotic drugs covering virtually all indications requiring immediately effective anticoagulation. For prevention and treatment of venous thromboembolism (VTE) UH have mainly been replaced by LMWH due to their practical usefulness (one or two subcutaneous daily doses without laboratory test for dose adjustment) and their more favourable risk-benefit profile. With respect to arterial occlusions this statement is also valid for unstable angina pectoris. The risk to develop heparin-induced thrombocytopenia (HIT) appears to be ten times lower with LMWH. In hospitals the use of UH is reserved for complex cases with high bleeding risk and the necessity to interrupt heparin effects rapidly. Therapeutic doses of UH are monitored by the classical coagulation assays, activated partial thromboplastin time (aPTT) and thrombin time (TT), but also by automated chromogenic tests of anti-factor Xa activity. There are no prospective studies directly comparing the efficiency of these three approaches. Disagreements between tests are not rare in individual cases. However, dosing recommendations for UH treatment of VTE (intravenous bolus of 80 IU/kg, followed by 18 IU/kg/h infusion) and average doses used are concordant. 0.30-0.70 anti-Xa IU/ml are considered as therapeutic range for UF infusion. Higher UH activities required during extracorporeal circulation in heart surgery or during coronary angioplasty are usually guided by bedside ACT (activated clotting time). For LMWH tests of anti-Xa activities may only be necessary during weight adjusted treatment of pregnant women, children, or cases with reduced kidney function (glomerular filtration rate < 30 ml/min.) or increased bleeding risk. Expected anti-Xa activities are 0.5-1.1 IU/ml and 1.0-2.0 IU/ml 4 hours after subcutaneous LMWH for dosing intervals of 12 hours and 24 hours respectively.
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PMID:[Heparins]. 1263 71

Heparin has been conventionally used as an anticoagulant for medical and surgical indications. Because factor Xa is an essential component of the prothrombinase complex and leads to the generation of thrombin, its inhibition has become a focus of newer antithrombotic drug development. The in vitro anticoagulant profile of DX-9065a, a synthetic direct factor Xa inhibitor, was studied using activated clotting time assay, thrombelastography, and global clotting tests, such as prothrombin time (PT), activated partial thromboplastin time (aPTT), diluted aPTT, Heptest, Heptest-HI, dilute Russell's viper venom time (dRVVT), thrombin time, ecarin clotting time, and amidolytic anti-Xa assay. In addition, the effect of DX-9065a on platelet aggregation and inhibition of thrombin generation markers (FPA, F1+2, and TAT) were studied. The pharmacokinetic and pharmacodynamic profiles of DX-9065a were also studied in a non-human primate (Macaca mulatta) model. DX-9065a produced a concentration-dependent increase in the Hemochron celite ACT and HemoTec ACT. Clotting times of 538 +/- 19 and 401 +/- 12, respectively, were reached at a concentration of 25 microg/mL signifying that DX-9065a may be useful in interventional cardiological procedures. DX-9065a prolonged the r-time on thrombelastography. DX-9065a did not show any effect on adenosine diphosphate (ADP)-, collagen-, epinephrine-, and arachidonic acid-induced platelet aggregation at concentrations up to 10 microgram/mL. DX-9065a exhibited a concentration-dependent prolongation of the PT, aPTT, diluted aPTT, Heptest, dRVVT, and reached the clotting times of 51.6, 132, 193, 47.9, 129.9 seconds, respectively, at a final concentration of 12.5 microgram/mL; compared to a control value of 10.6, 30.2, 41.9, 14, 32.2 seconds, respectively. DX-9065a did not affect the ecarin clotting time and thrombin time at concentrations up to 12.5 microgram/mL. Because DX-9065a prolonged the dRVVT, this may impact diagnostic screening of patients with systemic lupus erythematosus.
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PMID:Global anticoagulant effects of a synthetic anti-factor Xa inhibitor (DX-9065a): implications for interventional use. 1264 18

Prior to initiation of the ARG-911 and ARG-915 clinical trials, there was no optimal replacement for heparin anticoagulation in patients with heparin-induced thrombocytopenia (HIT) type II. These prospective, historical controlled studies were designed to determine the usefulness of argatroban, a direct thrombin inhibitor (DTI) that is not immunogenic and does not interact with heparin antibody, in answering this clinical need. Clinical outcomes (37-day period) for 568 argatroban-treated and 193 control patients demonstrated significantly reduced risks of the primary efficacy composite endpoint (all-cause death, all-cause amputation, new thrombosis) and the secondary endpoints (death due to thrombosis, new thrombosis) with argatroban. Argatroban patients also experienced a more rapid recovery of platelet count. Bleeding events were similar among both groups. It was concluded that argatroban anticoagulation, compared with historical controls, improves clinical outcomes without increasing bleeding risk in patients having HIT with or without thrombosis. Argatroban has since been approved in the US for both prophylaxis and treatment of thrombosis in patients with HIT. Argatroban has been used in percutaneous coronary interventions in patients with and without HIT, for peripheral vascular procedures in both large and small vessels in HIT patients, and as an adjunct to thrombolytic therapy for the treatment of AMI. Treatment success rates and the same or less bleeding was demonstrated with argatroban compared to heparin controls. These pilot studies suggest that argatroban will provide reliable anticoagulation during interventional procedures. A consistent safety profile of argatroban has been demonstrated in all studies to date. The main attributes of argatroban are its rapid onset of action, fast reversibility of its anticoagulant effect, inhibition of clot-bound thrombin, easily monitored by the aPTT and ACT and no dosage adjustment in renal-impaired individuals. These properties make argatroban a predictable and useful anticoagulant for HIT and non-HIT patients.
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PMID:Argatroban in HIT type II and acute coronary syndrome. 1281 Oct 12


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