Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149871 (deep vein thrombosis)
 12,364 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue factor pathway inhibitor (TFPI) controls activation of blood coagulation while antithrombin (AT) regulates the final stage. Both inhibitors inhibit the intermediate stage of activation. Subnormal levels of TFPI increase the risk of disseminated intravascular coagulation (DIC) in septic conditions, and the risk of occlusive thrombi over damaged vascular intima or fissured arteriosclerotic plaques. The risk of venous thrombosis is increased by subnormal AT or subnormal activity of the protein C system. In contrast, TFPI may be little involved in the control of deep venous thrombosis. Heparin strongly accelerates AT and releases TFPI to the blood. Both these effects may contribute to the antithrombotic effect of heparin. In septic DIC, heparin may contribute little to quench activation of coagulation. Once hereditary deficiency of TFPI is described, its biological role will be better understood.
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PMID:Relative roles of tissue factor pathway inhibitor and antithrombin in the control of thrombogenesis. 764 20

Reviparin is a low-molecular-weight heparin (LMWH) prepared by controlled nitrous acid digestion of porcine mucosal heparin. The trade name designation for this agent is Clivarin. This agent has been released in Germany and France for the prophylaxis of deep venous thrombosis (DVT) in surgical patients. This agent is developed utilizing optimized procedures and exhibits a uniform, narrow-molecular-weight distribution in comparison to the other commercially available LMWHs. The specific activity in the anticoagulant assays is approximated to be 32 U/mg whereas the specific activity in terms of anti-Xa units is designated 120 aXa U/mg. Reviparin is capable of producing a dose- and time-dependent antithrombotic effect in animal models of thrombosis. While the ex vivo effects are initially presented at antithrombotically active dosages, this agent has been found to produce antithrombotic effects without any detectable ex vivo actions. This agent is also known to release tissue factor pathway inhibitor (TFPI) after both intravenous (IV) and subcutaneous (SC) administration. Repeated administration of Reviparin produces progressively stronger antithrombotic effects. Similarly, the bleeding as measured by rabbit ear blood loss is also progressively increased. However, the ratio between the dosage producing these effects is quite large. The current studies are designed to provide additional data on the molecular profile using new calibration methods and additional results on the pharmacologic studies in a dose-dependent manner. In particular, the release of TFPI following IV and SC administration in a primate model is described. The effect of repeated administration mimicking the post-surgical prophylaxis of DVT is also reported in terms of any augmentation of the antithrombotic or hemorrhagic effects of these agents.
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PMID:Pharmacologic validation of the clinical effects of an optimized low-molecular-weight heparin-reviparin. 766 Jan 44

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

Low molecular weight heparin (LMWH) is currently prescribed for the treatment of deep vein thrombosis at the dose of 100 IU antiXa/kg twice daily or at a dose of 175 IU antiXa/kg once daily with a similar efficacy. We decided to study the chrono-pharmacology of curative dose of LMWH once daily administrated according to the one previously described with unfractionated heparin (UFH). Ten healthy volunteers participated in an open three-period crossover study according to three 24 h cycles, separated by a wash-out interval lasting 7 days: one control cycle without injection, two cycles with subcutaneous injection of 200 IU antiXa/kg of Dalteparin (Fragmin) at 8 a.m. or at 8 p.m. Parameters of heparin activity were analysed as maximal values and area under the curve. Activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT) and tissue factor pathway inhibitor (TFPI) were higher after 8 p.m. injection than after 8 a.m. injection (p < 0.05) while no chrono-pharmacological variation of anti factor Xa (AXa) activity was observed. Thus the biological anticoagulant effect of 200 IU antiXa/kg of Dalteparin seems to be higher after an evening injection than after a morning injection. A chrono-therapeutic approach with LMWH, as prescribed once daily, deserves further investigation since our results suggest that a preferential injection time may optimise the clinical efficacy of these LMWH.
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PMID:Chrono-pharmacological study of once daily curative dose of a low molecular weight heparin (200 IU antiXa/kg of Dalteparin) in ten healthy volunteers. 858 3

Previous studies have reported that pre-operative plasmas of patients over the age of 40 years who developed post-operative deep vein thrombosis (DVT) had approximately twice the amount of proteolysed factor VII found in plasmas of patients in whom prophylaxis with heparin or low M(r) heparin was successful. These and other studies also reported higher concentrations of thrombin-antithrombin III in pre- and post-operative plasmas of patients who developed post-operative thrombosis than in plasmas of patients in whom prophylaxis was successful. Whether the extent of factor VII proteolysis seen in the patients who developed post-operative DVT is related to the severity of their disease or age is not known. This report investigated age-related changes in the concentrations of total factor VII protein, factor VII zymogen, factor VIIa, tissue factor pathway inhibitor, thrombin-antithrombin III, and prothrombin fragment 1 + 2 in normal plasmas and the relationships between these parameters. With the exception of thrombin-antithrombin III, statistically significant increases in the concentrations of these parameters with age were found. Additionally, the differences between the concentrations of total factor VII protein and factor VII zymogen, an index factor VII proteolysis in vivo, were statistically significant only for individuals over age 40. Using linear regression analysis, a significant correlation was found to exist between the concentrations of plasma factor VIIa and prothrombin fragment 1 + 2. Since factor VIIa-tissue factor probably initiates coagulation in vivo, we hypothesize that the elevated plasma factor VIIa (reflecting a less tightly regulated tissue factor activity and therefore increased thrombin production in vivo) accounts for the high risk for post-operative thrombosis seen in individuals over the age of 40.
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PMID:Age-related changes in factor VII proteolysis in vivo. 875 6

Low molecular weight heparins (LMWHs) are now universally accepted as drugs of choice for post-surgical prophylaxis of DVT. Currently these agents are also being developed for therapeutic and cardiovascular indications. Because of manufacturing differences, each of the LMWHs exhibit distinct pharmacologic and biochemical profiles. The specific activity of these agents in the anticoagulant assays ranges from 35 to 45 anti-IIa U/mg whereas the specific activity in terms of anti-Xa units is designated as 80 to 120 anti-Xa U/mg. These LMWHs are capable of producing product specific dose and time dependent antithrombotic effects in animal models of thrombosis. While the ex vivo effects are initially present at dosages that are antithrombotic, these agents have been found to produce sustained antithrombotic effects without any detectable ex vivo anticoagulant actions. In the experimental animal models and in various clinical trials, these agents have also been found to release tissue factor pathway inhibitor (TFPI) after both intravenous (i.v.) and subcutaneous (s.c.) administration. Repeated administration of LMWHs produces progressively stronger antithrombotic effects; however, the hemorrhagic responses vary and are largely dependent on products. The release of TFPI following i.v. and s.c. administration in a primate model also demonstrated the product individuality and the relevance of this inhibitor to the actions of LMWHs. The effect of repeated administration mimicking the post-surgical prophylaxis of DVT also exhibited product based augmentation of the antithrombotic or hemorrhagic effects. Antithrombotic and hemorrhagic studies are reported that compare the pharmacologic profile of some of the available LMWHs. Product individuality in terms of relative potency in different assays and the failure of standardization protocols to provide any guidelines for product substitution and prediction of the clinical effects is also addressed.
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PMID:Are the available low-molecular-weight heparin preparations the same? 880 34

Some major developments in the area of antithrombotic therapy have occurred during the past decade. Of these, the concept of fractionation of heparin has resulted in the development of several products from this agent. The introduction of low molecular weight heparins (LMWHs) has added a new chapter to the prophylactic and therapeutic management of thromboembolic disorders. These agents are now globally accepted as drugs of choice for post-surgical prophylaxis of deep vein thrombosis (DVT). Currently, the LMWHs are being developed for various therapeutic and cardiovascular indications. Reviparin is an optimized LMWH prepared by controlled nitrous acid digestion of porcine mucosal heparin. This drug has been developed using validated procedures and exhibits a relatively narrow molecular weight distribution in contrast to most other commercially available LMWHs. The specific activity in anticoagulant assays is approximately 32 U/mg whereas the specific activity in terms of anti-Xa units is 120 anti-Xa U/mg. Reviparin is capable of producing a dose- and time-dependent antithrombotic effect in animal models of thrombosis. While the ex vivo effects initially occur at dosages that are antithrombotic, this agent has been found to produce sustained antithrombotic effects without any detectable ex vivo anticoagulant actions. This agent has also been found to release tissue factor pathway inhibitor (TFPI) after both intravenous and subcutaneous administration. Repeated administration of reviparin produces progressively stronger antithrombotic effects. The current studies are designed to provide additional data on its molecular profile using new calibration methods and additional results on the pharmacological studies in a dose-dependent manner. In particular, the release of TFPI following i.v. and s.c. administration in a primate model is described. The effect of repeated administration mimicking the post-surgical prophylaxis of DVT is also reported in terms of any increase in the antithrombotic or haemorrhagic effects of this agent. Comparative antithrombotic and pharmacological studies are also reported to compare the pharmacological profiles of reviparin, nadroparin and enoxaparin.
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PMID:Preclinical studies on a low molecular weight heparin. 882 24

Heparin, a negatively charged sulphated glycosaminoglycan, is clinically the most important antithrombotic drug. Heparin augments the inhibitory activity of antithrombin (AT) towards thrombin, factor Xa (FXa) and other activated clotting enzymes. Tissue factor pathway inhibitor (TFPI) is an endogenous heparin releasable three domain Kunitz-type coagulation inhibitor which inhibits the crucial tissue factor-factor VIIa (TF-FVIIa) dependent coagulation pathway in the presence of FXa. The importance of the TF-FVIIa pathway and TFPI has recently been reviewed (1). TFPI is located to different vascular pools, the largest being the vascular endothelium from where TFPI can be released dose-dependently to the blood by heparins (2). TFPI is speculated to contribute to the anticoagulant properties of heparins, but to which degree is not yet fully understood. In recent years low molecular weight heparins (LMWH) have proven to be effective and safe both for prophylactic (3) and therapeutic treatment (4) of deep vein thrombosis (DVT). Protamine is the least toxic and clinically most commonly used antidote to heparin. However, in vitro and in vivo LMW heparinized blood is not fully neutralized by protamine, as substantial anti-Xa activity remains following neutralization (5). This post-protamine effect has been shown to be partly TFPI dependent when measured in a dilute TF-dependent assay (6,7). We undertook this in vivo study on healthy volunteers in order to investigate whether TFPI released by UH or LMWH (intravenous (iv) or subcutaneous (sc)) remains in the circulation following neutralization of the heparin activity with protamine sulphate (PS). We measured TFPI by three different methods-chromogenic activity, anticlotting activity and a new antigen assay specific for full-length and three-domain TFPI.
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PMID:The effect of protamine sulphate on plasma tissue factor pathway inhibitor released by intravenous and subcutaneous unfractionated and low molecular weight heparin in man. 918 23

The introduction of low-molecular-mass heparins (LMMHs) has added a new dimension to the prophylactic and therapeutic management of thromboembolic disorders. These agents are now globally accepted as drugs of choice for postsurgical prophylaxis of deep vein thrombosis (DVT). Currently, the LMMHs are being developed for various therapeutic and cardiovascular indications. Reviparin is an optimized LMMH prepared by controlled nitrous acid digestion of porcine mucosal heparin. This drug has been developed utilizing validated procedures and exhibits a relatively narrow molecular mass distribution in contrast to most other commercially available LMMHs. The specific activity in the anticoagulant assays is approximately 40 U/mg whereas the specific activity in amidolytic anti-Xa assays is approximately 100 anti-Xa U/mg. Reviparin is capable of producing dose- and time-dependent antithrombotic effects in animal models of thrombosis. Although ex vivo anticoagulant effects are initially observed at dosages that are antithrombotic, this agent has been found to produce sustained antithrombotic effects when ex vivo anticoagulant actions are not measurable. Repeated administration of this LMMH induces progressively stronger antithrombotic effects. This drug has also been found to release tissue factor pathway inhibitor (TFPI) following both intravenous (IV) and subcutaneous (SC) administration. The studies included in this article are designed to provide additional data on the molecular profile using new calibration methods and additional results on pharmacologic studies. In particular, the release of TFPI following IV and SC administration to nonhuman primates is described. The effect of repeated administration of Reviparin mimicking the postsurgical prophylaxis of DVT is also reported in terms of any augmentation of the antithrombotic or hemorrhagic effects of this agent.
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PMID:Biochemical and pharmacologic characteristics of Reviparin, a low-molecular-mass heparin. 920 Mar 35

Thrombin generation is a key event in the pathophysiology of coronary syndromes and provides the rationale for treatment with anticoagulants. Unlike standard heparin, low-molecular-weight heparin (LMWH) has little effect on activated partial thromboplastin time. LMWH treatment has been monitored by measurement of anti-Factor Xa activity, but this may not accurately reflect the anticoagulant action because LMWHs also inhibit Factor II. The Heptest is a clotting assay that is sensitive to both anti-Xa and anti-IIa activity, as well as inhibition of the extrinsic pathway by LMWH-stimulated release of tissue factor pathway inhibitor. The plasma thrombin neutralization assay has also been used to measure LMWH and to detect low concentrations to which chromogenic assays are insensitive. In the clinical setting, monitoring the anti-Xa activity in patients treated with LMWH after acute deep vein thrombosis offered no advantages over a standard weight-adjusted dose. Moreover, in acute coronary syndromes there is no increase in major hemorrhage rates with weight-adjusted LMWH. Monitoring of LMWH concentrations may be advisable in the presence of comorbid conditions carrying an increased risk of hemorrhage, such as renal disease, advanced age, severe over- or underweight, or a history of previous bleeding episodes.
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PMID:Monitoring of low-molecular-weight heparins in cardiovascular disease. 973 79


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