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

---

Query: EC:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study compares the ability of unfractionated heparin, of dermatan sulfate, and of their simultaneous administration delivered as continuous intravenous infusion or as a single bolus injection to inhibit the growth of a standardized venous thrombosis in the rabbit. When delivered as continuous intravenous infusion for 4 h, heparin and dermatan sulfate inhibited thrombus growth in a dose dependent manner. The maximum antithrombotic effect of heparin was achieved at the dose of 0.15 mg kg-1 h-1 (25 U kg-1 h-1) which generated a mean plasma concentration of 1.8 micrograms ml-1 (0.31 U ml-1) and a 1.8 fold prolongation of the activated partial thromboplastin time (APTT) in comparison to the pretreatment value. A comparable antithrombotic effect was obtained with dermatan sulfate at the dose of 2 mg kg-1 h-1. This dose generated a mean plasma concentration of 30 micrograms ml-1 and a 1.3 fold APTT prolongation. Increasing these doses up to 10 fold did not improve the antithrombotic effect which did not overpass 60-70% of the controls. When the compounds were delivered simultaneously, the maximum antithrombotic effect (64%) was obtained with the following association: 0.06 mg kg-1 h-1 (10 U kg-1 h-1) for heparin and 1 mg kg-1 h-1 for dermatan sulfate. Increasing these doses up to 4 to 5 fold did not improve the antithrombotic effect. Heparin, dermatan sulfate and the association of both were also delivered as single bolus injections and the resultant antithrombotic effect was determined 4 h after saline infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Effects of heparin, dermatan sulfate and of their association on the inhibition of venous thrombosis growth in the rabbit. 128 77

Protein C inhibitor is a plasma protein whose ability to inhibit activated protein C, thrombin, and other enzymes is stimulated by heparin. These studies were undertaken to further understand how heparin binds to protein C inhibitor and how it accelerates proteinase inhibition. The region of protein C inhibitor from residues 264-283 was identified as the heparin-binding site. This differs from the putative heparin-binding site in the related proteins antithrombin and heparin cofactor. The glycosaminoglycan specificity of protein C inhibitor was relatively broad, including heparin and heparan sulfate, but not dermatan sulfate. Non-sulfated and non-carboxylated polyanions also enhanced proteinase inhibition by protein C inhibitor. Heparin accelerated inhibition of alpha-thrombin, gamma T-thrombin, activated protein C, factor Xa, urokinase, and chymotrypsin, but not plasma kallikrein. The ability of glycosaminoglycans to accelerate proteinase inhibition appeared to depend on the formation of a ternary complex of inhibitor, proteinase, and glycosaminoglycan. The optimum heparin concentration for maximal rate stimulation varied from 10 to 100 micrograms/ml and was related to the apparent affinity of the proteinase for heparin. There was no obvious relationship between heparin affinity and maximum inhibition rate or degree of rate enhancement. The affinity of the resultant protein C inhibitor-proteinase complex was also not related to inhibition rate enhancement, and the results showed that decreased heparin affinity of the complex is not an important part of the catalytic mechanism of heparin. The importance of protein C inhibitor as a regulator of the protein C system may depend on the relatively large increase in heparin-enhanced inhibition rate for activated protein C compared to other proteinases.
...
PMID:Heparin binding to protein C inhibitor. 131 38

An open 5-day study was conducted in 12 healthy male volunteers to determine the potential for drug interaction between low dose standard heparin and temafloxacin, a new fluorinated quinolone antibiotic. Heparin 5000IU was administered subcutaneously on the morning of the first and last study days and temafloxacin 600mg was administered twice daily for 4 days. The mean change in activated factor X (antifactor Xa) concentration relative to baseline 2h after coadministration was similar to that after heparin alone. Likewise, changes in activated partial prothrombin time, prothrombin time and thrombin time were similar after either heparin alone or concomitant temafloxacin administration, indicating the absence of interaction between temafloxacin and low dose standard heparin in healthy volunteers.
...
PMID:Absence of drug interaction between temafloxacin and low dose heparin. 131 77

Patients over 40 years of age who undergo elective orthopaedic surgery have a relatively high risk for developing post-surgical deep vein thrombosis (DVT). Prophylactic use of heparin or low molecular weight heparins can reduce the incidence of post-operative DVT by up to 80%. It is not known whether prophylaxis is achieved by inhibition of prothrombin activation or catalysis of thrombin inhibition in vivo. We determined the changes in concentrations of factor VII zymogen and thrombin-antithrombin III (the latter as an index of prothrombin activation) in the plasmas of 129 patients randomized to receive two daily subcutaneous injections of placebo or 30 mg of Enoxaparin after elective knee surgery. Enoxaparin reduced the frequency of post-surgical DVT by 70%. The concentration of factor VII zymogen had decreased by approximately 50% within 24 h after the knee surgery, followed by a gradual increase to near presurgical values. Additionally, post-Enoxaparin plasmas had statistically significant higher concentrations of factor VII zymogen than post-placebo plasmas. Post-Enoxaparin plasmas had significantly lower concentrations of endogenous thrombin-antithrombin III than comparable post-placebo plasmas. Finally, post-Enoxaparin plasmas inactivated exogenous factor Xa and thrombin more effectively than comparable post-placebo plasmas. As Enoxaparin moderated the generation of endogenous thrombin-antithrombin III after elective knee surgery, inhibition of prothrombin activation in vivo by Enoxaparin may be important for its prophylactic antithrombotic effect.
...
PMID:The low molecular weight heparin Enoxaparin inhibits the consumption of factor VII and prothrombin activation in vivo associated with elective knee replacement surgery. 132 19

This study compared how Enoxaparin and unfractionated (UF) heparin influenced in vivo coagulation in patients randomized to receive, by twice daily subcutaneous injections, either 30 mg of Enoxaparin or 7500 I.U. of UF heparin after elective hip surgery. These two regimens were equally effective in reducing the incidence of post-operative deep vein thrombosis DVT. We compared the concentrations of endogenous thrombin-antithrombin III in pre- and post-surgical plasmas to determine how each prophylactic regimen influenced prothrombinase activity in vivo, and found the same concentrations of endogenous thrombin-antithrombin III in post-heparin and post-Enoxaparin plasmas. However, significantly higher concentrations of endogenous thrombin-antithrombin III were found in pre- and post-surgical plasmas of patients who developed post-operative DVT than the levels found in comparable plasmas of patients who remained DVT-negative, regardless of the drug received for prophylaxis. Human factor Xa was added to an equal volume of each patient's plasmas and the amount of added enzyme inactivated by antithrombin III measured using an enzyme-linked immunosorbent assay for factor Xa-antithrombin III. Post-heparin and post-Enoxaparin plasmas inactivated approximately 4 times more factor Xa than the pre-surgical plasmas, regardless of the clinical outcome. Thus, before and after surgery, a higher than normal in vivo prothrombinase activity may be a significant risk factor for developing post-operative DVT.
...
PMID:Prophylactically equivalent doses of Enoxaparin and unfractionated heparin inhibit in vivo coagulation to the same extent. 132 20

Two cases of thrombocytopenia due to a low molecular weight heparin (Fraxiparine) are reported. The first case was a 35-year-old alcoholic man with acute mild pancreatitis. After having been treated with Fraxiparine for 12 days to prevent venous thrombosis, routine laboratory studies revealed a thrombocytopenia (49 G.l-1). At the same time, a minor haemorrhage occurred in the nasogastric tube. Prothrombin time, partial thromboplastin time, fibrin degradation products and D-dimers remained normal. There were no soluble fibrin monomers. Fraxiparine was discontinued. The thrombocyte count continued to decrease (12 G.l-1) up to the thirteenth day, it raised 3 days later to 110 G.l-1, and returned to normal after 9 days more (395 G.l-1). The second patient was a 58-year-old man given prophylactic Fraxiparine between the 5th and 16th days after admission for a severe asthma attack. Here again, after 12 days of treatment, the thrombocyte count decreased to 74 G.l-1. There were no other abnormalities, neither clinically nor in laboratory findings. Heparin administration was discontinued and the thrombocytopenia had resolved 3 days later. In both patients, the diagnosis of thrombocytopenia elicited by low molecular weight heparin was confirmed by finding, in vitro, a platelet aggregating factor in the presence of Fraxiparine. The literature concerning this topic is reviewed and discussed.
...
PMID:[Thrombocytopenia induced by low molecular weight heparin]. 133 4

Citrated samples from 100 patients on i.v. heparin and 20 normal patients were tested with three batches each of three activated partial thromboplastin time (APTT) reagents: Thrombosil I (Ortho); Automated APTT (Organon Teknika) and Actin FSL (Baxter). The ratio of APTT over the geometric mean normal APTT for each heparinized sample was calculated. One batch of reagent arbitrarily chosen as a reference gave the ratios APTRREF (y). The remaining reagents to be standardized against the reference system gave the ratios APTRTEST (x). The best correlation between systems was given by log vs log x. Standard curves were prepared from the APTT ratios of the 20 normal patients and 65 of the heparinized samples. On plotting log APTRTEST vs log APTRREF the y intercept was close to zero so x was expressed in terms of y using; log x = HSI. log y, where HSI (Heparin Sensitivity Index) = slope. The APTRTEST results of the remaining 35 heparinized samples were transformed using; APTRTRANS = (APTRTEST)HSI.APTRTRANS was then compared to APTRREF to determine whether the transformation brought the results closer to the reference. We conclude that although some improvement was found by using the transform, it was not possible to mathematically relate APTT results due to a high degree of variation between results using different reagents. A standard APTT reagent for the monitoring of heparin therapy is recommended. A separate APTT reagent may be required for the screening of factor deficiencies and lupus anticoagulants.
...
PMID:An attempt to standardize APTT reagents used to monitor heparin therapy. 133 84

Native heparin (CAS 9005-49-6) and its two new fragments, low molecular weight heparin (LMW-H, 5 kDa) and oligo-heparin (oligo-H, 2 kDa) obtained by radical degradation were characterized as to their physicochemical properties. Heparin fragments differ from unfractionated heparin only in molecular weight. The pharmacokinetics and some pharmacological effects, bleeding and antithrombotic activity, of the three different molecular weight heparins were investigated. The plasma concentrations were determined by an amidolytic method which measures inhibiting effect on factor Xa. The blood levels of each substance were derived from their in vitro calibration curves. The examination of the pharmacokinetics parameters allowed to evaluate the differences in the bioavailability, absorption rate and elimination mechanisms between the three different heparins. The bioavailability, the absorption rate and the distribution of the molecules of heparins in biological compartments depend on the molecular weight. LMW-H and oligo-H exhibit greater antithrombotic activity than unfractionated heparin when administered subcutaneously. The pharmacokinetic behaviour of oligo-H considerably differs from that of unfractionated heparin and LMW-H. This new drug is able to bind cells and plasma proteins differently from heparin and LMW-H. The capacity of oligo-H to bind smooth muscle cells and to interact with myosin is discussed in relation to the bleeding effect.
...
PMID:Different pharmacokinetics, antithrombotic activity and bleeding effects of heparin and two new fragments administered in rat by subcutaneous route. 133 49

Plasminogen activator inhibitor 1 (PAI-1), a member of the serpin superfamily of proteins, has been demonstrated previously to interact functionally with the glycosaminoglycan heparin (Ehrlich, H.J., Keijer, J., Preissner, K. T., Klein Gebbink, R., and Pannekoek, H. (1991) Biochemistry 30, 1021-1028). Heparin specifically enhances the rate of association between PAI-1 and thrombin about 2 orders of magnitude, whereas no effect is detected with other serine proteases (e.g. factor Xa). For the heparin-dependent serpins antithrombin III and heparin cofactor II, basic amino acid residues in and around the helix D subdomain were proposed to be involved in the binding of glycosaminoglycans. Here we employed site-directed mutagenesis of full-length PAI-1 cDNA to identify the amino acid residues that mediate heparin binding. To that end, 15 single-point mutants of PAI-1, each having individual arginyl, lysyl, or histidyl residues replaced by a neutral (alanyl) residue ("ala-scan"), and one double mutant were constructed, expressed in Escherichia coli, and purified to apparent homogeneity. The purified biologically active proteins were subjected to the following analyses: (i) heparin-dependent inhibition of thrombin; (ii) heparin-dependent formation of sodium dodecyl sulfate-stable complexes with thrombin; and (iii) binding to and elution from heparin-Sepharose. Based on the data presented, we propose that the amino acid residues Lys65, Lys69, Arg76, Lys80, and Lys88 constitute major determinants for heparin binding of PAI-1. These residues are located in and around the helix D domain and are conserved in the other heparin-dependent thrombin inhibitors, antithrombin III and heparin cofactor II.
...
PMID:Elucidation of structural requirements on plasminogen activator inhibitor 1 for binding to heparin. 137 44

Orgaran (Org 10172), which has antithrombotic activity in man with apparently minimal bleeding side effects, is a mixture of low-molecular-weight heparan, dermatan, and chondroitin sulfates. The degrees to which the minimum concentrations of Orgaran, its fraction with high affinity for antithrombin III (Org 10849; AT III) and unfractionated heparin, which double the activated partial thromboplastin time (APTT) of pooled normal plasma, inhibit intrinsic activation of factor IX, factor X, and prothrombin were compared. Specific ELISAs were used to quantify the activation of each clotting factor. Factor IX activation, which began without a lag phase, preceded factor X and prothrombin activation by approximately 15 and approximately 25 s, respectively. When used at these functionally equivalent concentrations, heparin (2 micrograms/ml plasma), Orgaran (50 micrograms/ml plasma), and Org 10849 (20 micrograms/ml) could delay the onset of factor IX activation. Compared to control plasma, however, only Orgaran reduced the initial rate of factor IX activation. Heparin and Orgaran delayed the onset of factor X activation by 20 and 15 s, respectively, while Org 10849 could not delay the onset of factor X activation. In addition, each anticoagulant delayed the onset of prothrombin activation. Thus, at concentrations which double the APTT of normal plasma, the combined actions of heparan and dermatan sulfate present in Orgaran can apparently suppress factor IX activation more effectively than heparin, and delay the onset of factor X activation nearly as effectively as heparin. The coordinated inhibition of factor IX and factor X activation by Orgaran may contribute to its antithrombotic effectiveness.
...
PMID:Anticoagulant mechanisms of Orgaran (Org 10172) and its fraction with high affinity to antithrombin III (Org 10849). 137 66


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---