Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment monitoring based on a laboratory parameter increases the efficacy and safety of standard heparin therapy, but it is not known if this also applies to low-molecular-weight heparin (LMWH) therapy of acute deep vein thrombosis (DVT). In a prospective randomized trial involving 122 consecutive patients, group A (58 patients) received a weight adjusted dose of Fragmin (100 IU/kg) subcutaneously twice a day throughout the treatment period (10 days +/- 1), while in group B (64 patients) the dosage was based on the results of an anti factor Xa (anti Xa) amidolytic assay to obtain a target concentration from 0.5 to 1 IU/ml. AntiXa and antithrombin activities were also measured retrospectively on frozen plasma from all patients. The two regimens were comparable in terms of hemorrhagic complications (4 in group A and 3 in group B). Bilateral ascending phlebography was performed before inclusion and at the end of LMWH treatment. Treatment efficacy, based on Marder's score, did not differ between the two groups (p = 0.3). Dosage adjustment to between 0.5 to 1 IU anti-Xa/ml does not therefore appear to improve the efficacy or safety of LMWH treatment. However, correlations between the change in Marder's score and both anti-Xa (p < 0.001) and antithrombin activity (p < 0.001) were observed, suggesting a relationship between the degree of FXa or thrombin inhibition and antithrombotic activity.
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PMID:Adjusted versus fixed doses of the low-molecular-weight heparin fragmin in the treatment of deep vein thrombosis. Fragmin-Study Group. 797 34

Resistance to activated protein C (RAPC) has been described recently as a cause of trombophilia; this may justify up to 50% of thromboembolic disease without predisposing cause in patients under 45 years. A 29 years-old male with a previous deep venous thrombosis (DVT) in the lower left limb three years earlier, developed a DVT in the right lower limb after a trauma of the knee that required immobilization, was associated to pulmonary thromboembolism diagnosed by gammagraphic methods. The phlebographic study showed femoro-iliaco-caval venous thrombosis. The proband's father and a younger brother had a previous history of thrombotic episodes. The following tests, were performed in the proband and relatives: prothrombin time, aPTT, thrombin time, fibrinogen, (Von Clauss), antithrombin III (chromogenic), protein C and protein S (coagulometry and ELISA), plasminogen (chromogenic) and lupus anticoagulant (ITT, dRVVT, aCL). RAPC was evaluated in two different samples. The proband study was performed under oral anticoagulation treatment (OAT). Control groups were: 21 blood donors and 12 OAT patients. The results showed a decreased response to APC in the proband (ratio 1.5) and relatives: father (1.4), brothers (1.5 and 1.5), while the mother was within the normal range (> or = 2). In normal controls and OAT patients the ratio was over 2. No other abnormalities were detected in the assays performed. It is concluded that RAPC is the cause of this familial trombophilia. RAPC should be included in the evaluation study of trombophilia.
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PMID:[Familial thrombophilia due to resistance to activated protein C]. 798 58

A quantitative and non-occlusive deep vein thrombosis model was developed in rabbits. We used this model to test the antithrombotic activity of the prothrombinase complex inhibitors factor rXai and its chemical analog glutamyl-glycyl-arginyl chloromethyl ketone inactivated human factor Xa (EGR-Xai), along with the thrombin inhibitors D-phenylalanyl-prolyl-arginyl chloromethyl ketone (PPACK) and heparin. Dose dependent effects of the inhibitors during constant infusion were monitored. Measurements included thrombus weights, hemostatic parameters and both cuticle and ear bleeding times. In this model, factor rXai and EGR-Xai had comparable in-vivo efficacy, and showed 80%-93% inhibition at plasma levels of 6.5 nM (rXai) and 8 nM (EGR-Xai). Effects on ex-vivo clotting times varied among the inhibitors. At 80-100% thrombus inhibition, factor rXai and EGR-Xai had no statistically significant effect, while PPACK extended thrombin clotting time (TCT) times 2.3-fold, and heparin prolonged both activated partial thromboplastin time (APTT), prothrombin time (PT) and TCT ex-vivo clotting times 6.9-, 1.2-, and 7-fold respectively. At these dosages, cuticle and ear bleeding times were prolonged for all inhibitors and showed increases of 177%-389% (cuticle) and 45%-129% (ear). Our results demonstrate that direct inhibition of prothrombinase complex assembly is effective in arresting venous thrombosis.
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PMID:A comparative study of prothrombinase and thrombin inhibitors in a novel rabbit model of non-occlusive deep vein thrombosis. 802 1

Low molecular weight heparins (LMWHs) are now considered to be the drugs of choice for prophylaxis against deep venous thrombosis (DVT) in post operative patients undergoing both general and orthopaedic surgical procedures. Despite extensive research, the exact mechanism of the antithrombotic activity of LMWHs remains unclear. These agents have been shown to activate the fibrinolytic system and to directly inhibit both the activity and the generation of factor Xa and thrombin. New evidence suggests that LMWHs also stimulate the release of endogenous tissue factor pathway inhibitor (TFPI) from the vascular endothelium. This study was designed to investigate the role of TFPI in mediating the antithrombotic activity of LMWHs. We measured the plasma levels of TFPI in a group of post orthopaedic surgery patients treated with daily subcutaneous injections of LMWH and a group of patients treated with placebo. In the placebo group (n = 25), the plasma TFPI levels were slightly elevated immediately after surgery but returned to their baseline value by the fifth post operative day. In contrast, in the group of patients treated with LMWH (n = 34), the plasma levels of TFPI increased significantly and remained elevated for up to 7 days following surgery. However, the TFPI levels in both groups showed wide patient to patient variability. These results indicate that LMWHs stimulate the release of TFPI into the bloodstream of post surgical patients. This suggests the importance of TFPI in mediating the antithrombotic activity of LMWHs.
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PMID:Role of tissue factor pathway inhibitor in post surgical deep venous thrombosis (DVT) prophylaxis in patients treated with low molecular weight heparin. 802 8

Cemented total hip replacement surgery is associated with intraoperative cardiorespiratory depression and postoperative proximal deep vein thrombosis which may be linked to an extreme intraoperative thrombin generation and local and systemic effects of monomethylmethacrylate (MMA) released into circulation from curing cement. This in vitro study demonstrates that MMA alone or in combination with thrombin have effects on monocytes and human umbilical vein endothelial cells (HUVEC) which modulate their procoagulant activities. Moderate doses of MMA had a slight tissue factor (TF) inducing effect on monocytes. Small doses of MMA (0.1-1 mg/ml) [corrected] markedly potentiated the TF inducing effect of thrombin or lipopolysaccharide (LPS) which was included as a reference stimulant. These TF modulating effects of MMA were not seen with HUVEC. However, the generation of fibrinopeptide A (FPA) in cell overlay plasma indicated enhanced procoagulant activity of HUVEC treated with moderate doses of MMA, probably reflecting MMA cytotoxicity leading to cell retraction and exposure of extracellular matrix. Furthermore, small doses of MMA had a slight enhancing effect on FPA generation when coincubated with thrombin. These findings indicate that MMA in concentrations found in central venous blood in vivo, alone or together with thrombin, directly or indirectly exert effects that contribute to activation of coagulation.
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PMID:Effect of monomethylmethacrylate on procoagulant activities of human monocytes and umbilical vein endothelial cells in vitro. 808 39

Two groups of 23 and 84 patients with hip fracture received intramuscularly 100 and 300 mg dermatan sulfate (MF701) b.i.d., respectively, for the prophylaxis of deep vein thrombosis. Median duration of treatment was 17 and 16 days, respectively. Four blood samples were collected from each patient while under treatment. Plasma levels of dermatan sulfate were determined by a chromogenic substrate assay. A one-compartment model for multiple doses was employed to estimate the pharmacokinetic parameters. Fitting was applied to mean plasma concentrations calculated for each sampling time and weighted according to the number of samples available at each time. Thrombin clotting time was measured on the same plasma samples. Antithrombotic efficacy was assessed by bilateral venography. Plasma levels of dermatan sulfate increased gradually throughout the treatment, indicating a marked accumulation process. Time to reach steady-state was 14 or 9 days with 100 or 300 mg b.i.d., respectively. This was due to an apparent prolonged terminal half-life (68 or 43 h), which actually reflected slow absorption from the injection sites. The clinical efficacy of MF701 in preventing DVT was found to be dependent on the plasma concentration of the drug and also, but less significantly, on the prolongation of thrombin clotting time. Dermatan sulfate plasma levels greater than 9 micrograms/ml are advisable to optimize efficacy in hip fracture patients.
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PMID:Intramuscular dermatan sulfate MF701 in patients with hip fracture: relationship between pharmacokinetics and antithrombotic efficacy. 809 79

The important roles of thrombin in the development and propagation of thrombosis are well recognized. In addition to being the enzyme for clotting fibrinogen (the major protein component of blood clots), thrombin accelerates its own generation by activating factor V, factor VIII, factor XI and platelets. It accelerates the stabilization of clots by activating factor XIII to factor XIIIa, the enzyme which crosslinks fibrin. There are probably two major pathways for regulating the availability of thrombin in vivo: inactivation of thrombin (by antithrombin III/vessel wall heparan sulfate and perhaps by other endogenous antithrombins) and the inactivation of factor Va and factor VIIIa by activated protein C. Factor Va and factor VIIIa accelerate the production of thrombin. However, when thrombin becomes bound to fibrin (in clots or possibly on cell surfaces), the ability of antithrombin III/heparin to inactivate thrombin is then reduced significantly. Impairment by fibrin of thrombin inhibition by antithrombin III may account in part for the inability of unfractionated heparin to prevent post-operative deep vein thrombosis in up to 20% of patients who undergo major elective orthopaedic surgery, and may also explain the need for oral anticoagulants after unfractionated and low molecular weight heparins are used to initiate the treatment of established deep vein thrombi. The ineffectiveness of the antithrombin III/heparin pathway for inhibiting thrombin under some circumstances has been a contributory factor for the development, evaluation and identification of other inhibitors of thrombin which are more able than antithrombin III/heparin to inactivate thrombin when the enzyme is bound to fibrin. The focus of this review is to detail how these synthetic agents, by directly or indirectly inactivating thrombin, can also effectively inhibit prothrombin activation in vitro.
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PMID:Mechanisms for the anticoagulant effects of synthetic antithrombins. 815 38

Fibrin D-Dimer (D-Di), prothrombin activation fragment (F 1+2) and thrombin-antithrombin III complexes (TAT) were measured using ELISA procedures in the plasma of patients with an acute deep venous thrombosis (DVT), at presentation and on days 2, 6 and 10 after initiation of heparin treatment. Patients were randomly allocated into two treatment groups: 44 patients received adapted doses of continuous intravenous unfractionated heparin (UH) whereas 47 received 1 mg/kg every twelve hours of a low molecular weight heparin (enoxaparin) subcutaneously. A phlebography and a perfusion lung scan were performed before inclusion and on day 10. Failure of therapy (n = 9) was defined by venogram worsening or confirmed pulmonary embolism. Improvement (n = 44) or stationary state (n = 38) were defined by venogram evolution in the absence of new leg scan defects. At presentation, D-Di, F 1+2 and TAT were above cut-off values in 97, 66 and 89% of patients respectively. D-Di levels correlated with the extent of venous thrombosis whereas TAT and F 1+2 did not. Mean levels of D-Di decreased sharply during the first days of treatment but were still abnormal on day 10. A secondary increase of D-Di on days 6 or 10 by more than 3 micrograms/ml occurred in 4 of the 9 patients who developed a thromboembolic recurrence but in none of the 72 patients who had a more favorable outcome. F 1+2 and TAT time-courses were not related to clinical evolution. In the Enoxaparin group, there was no relationship between antifactor Xa activities and any biological markers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Markers of hemostatic system activation in acute deep venous thrombosis-evolution during the first days of heparin treatment. The DVTENOX Study Group. 816 10

The prevalence of antithrombin (AT) deficiency in the general population has been variously estimated to be between 0.05 and 5 per 1,000 in the population; 2,491 blood donors were screened in an attempt to clarify this issue using plasma samples taken from the blood donor units. From this initial population, 122 individuals were identified as having plasma AT levels lower than 2 standard deviations below the normal mean. Twenty-two samples had evidence that thrombin had been generated during blood collection and the remaining cohort of 100 blood donors were asked to return but only 59 complied. The data obtained from these 59 were compared with that from 51 age- and sex-matched control blood donors. Both groups of subjects were assessed for previous evidence, or family history, of thrombotic events, as well as exposure to risk factors associated with the development of deep vein thrombosis (DVT). All had venous blood samples taken from which the supernatant plasma was immediately removed and quick frozen for later assaying. Only 6 of the 59 subjects with initial low AT levels had repeat AT-Xa levels below 0.80 units/ml (normal range 0.94 +/- 0.14). Upon repeating the AT-Xa determinations on new samples from these six individuals, only three were found again to be low. One was found to have a type 3 AT deficiency (an Arg47Cys substitution). The other two with a low AT level had mean functional AT-Xa levels of 0.61 and 0.71 units/ml, respectively, with correspondingly low AT:Ag levels consistent with a type 1 AT deficiency. Two of these three subjects has been in high risk situations without evidence of having developed DVT and none had evidence of venous reflux on Doppler venography. In addition, none had personal or family histories of previous thrombotic events. These present data indicate that the prevalence of AT deficiency in our blood donor population is 2 per 1,000 (95% confidence intervals: 0.7-6/1,000).
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PMID:Prevalence of antithrombin deficiency in healthy blood donors: a cross-sectional study. 817 2

Low molecular weight heparins are well established in the prophylaxis of deep vein thrombosis in patients with general surgery, in high risk patients undergoing elective hip surgery or emergency surgery and also in patients with an enhanced risk of thrombosis who are treated in medical wards. There are, however, many possibilities for improving prophylaxis and treatment with LMWH. The mechanisms by which low molecular weight heparins and also unfractionated heparin inhibit thrombus formation are not fully understood. The inhibition of thrombin formation and local effects at the endothelial level may be more important than antithrombin-III mediated effects on factor IIa and on factor Xa. For most low molecular weight heparins the most effective dose regimens to be used in patients at high risk have not yet been established. Low molecular weight heparins may be more effective in the treatment of deep venous thrombosis than unfractionated heparin. In the therapeutic studies published so far the major intention was to show that low molecular weight heparins can prevent the progression of deep venous thrombosis and pulmonary embolism to the same extent as unfractionated heparin. Extended treatment regimens, however, may lead to a relevant thrombus reduction. Outpatient treatment for a longer period of time with results not far from those obtained with thrombolysis seem possible especially in elderly patients. Low molecular weight heparins in their present form or modified low molecular weight heparins may be useful for long-term treatment of patients with atherosclerosis with the aim of regression of atherosclerotic lesions. New forms of application, e.g. inhalation, may render long-term treatment more feasible.
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PMID:Low molecular weight heparins--state-of-the-art and unsolved issues. 818 Mar 24


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