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

Thromboembolic disorders are the major cause of mortality and morbidity in Western societies. Coagulation enzymes, such as thrombin, factor Xa and a tissue factor/factor VIIa complex, together with platelet GPIIb/IIIa receptors, are the focal point of attention in pharmaceutical research aimed at finding new antithrombotic agents. However, finding orally active drugs for these particular molecular targets has proved to be anything but straightforward. Thrombin, factor Xa, tissue factor/factor VIIa and platelet GPIIb/IIIa receptors display a preference for molecules containing highly basic arginine and/or acidic aspartate moieties, which are, however, associated with poor bioavailability after oral application. Different approaches have been taken to achieve favourable absorption, metabolism, distribution and clearance, without compromising the antithrombotic activity of the compounds. This review highlights the use of the prodrug principle in optimising antithrombotic agents.
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PMID:Metabolism-directed optimisation of antithrombotics: the prodrug principle. 1645 27

The search for the optimal antithrombotic efficacy to bleeding risk ratio in interventional cardiology has promoted the development of new antithrombotics and to the elaboration of new association strategies. The relatively modest and inconstant antiaggregant effect of 300 mg of clopidogrel has led to the use of higher dosages of 600 mg or 900 mg. The improved biological effects justify clinical evaluation on a larger scale. While waiting for the results of the CHARISMA trial, several studies seem to demonstrate the benefits of long-term administration. New thienopyridines, the leader of which is prasugrel, have powerful biological effects and have already been assessed in larger clinical trials. The anti GPIIb/IIIa molecules, the indications of which have been recently redefined, feature in new administration strategies under evaluation. The use of direct or indirect thrombin antagonists during invasive procedures remains necessary and several molecules are candidates for replacing unfractionated heparin, with a more predictable activity. Low molecule weight heparins have been shown to be easier to use compared with unfractionated heparin. Synthetic factor Xa inhibitors are at an early stage of development. Of the direct thrombin antagonists, bivalirudine provides an improved benefit/risk ratio and is a new option in the catheter laboratory.
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PMID:[Present and future developments of antithrombotic agents]. 1655 39

Heparin-induced thrombocytopenia (HIT) is a serious, immune-related complication of heparin therapy. One of the most severe manifestations of HIT is the development of thromboembolic events, which is based on platelet activation and aggregation caused by HIT-associated antibodies. Therapeutic options for patients with HIT are limited despite advancement toward the development of alternative (nonheparin) anticoagulants, such as direct thrombin inhibitors and indirect anti-factor Xa agents. Platelet GPIIb/IIIa receptor antagonists have been shown to be the final common pathway for platelet aggregation regardless of the use of activator or anticoagulant. In this study, the ability of a novel platelet GPIIb/IIIa antagonist, a free acid form of roxifiban (XV459), to block platelet activation/aggregation in response to highly characterized heparin-PF4 antibody-positive plasma/heparin was examined using light transmittance aggregometry, serotonin release, and (125)I-fibrinogen binding assays to human platelets. XV459 at 20 nM maximally inhibited (P < 0.001) the platelet-activation/aggregation responses as mediated by the HIT antibody-positive plasma (in the presence of therapeutic heparin concentrations). Compared with controls, both HIT antibodies/heparin and TEAC (a mixture of thrombin [0.1 IU/ml], epinephrine [1 microg/ml], arachidonate [0.1 mM], and collagen [10 microml]) resulted in significantly higher levels of fibrinogen binding to human platelets (5-7-fold increase; P < 0.001). Concentration-dependent profiles of XV459 on the mean percent inhibition of (125)I-fibrinogen binding in the presence of HIT antibodies and TEAC were achieved ( approximately 50% inhibition at 10 nM XV459). The platelet GPIIb/IIIa receptor antagonist (XV459) might be of potential benefit in the management of thrombotic thrombocytopenia produced by heparin and/or related glycosaminoglycans.
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PMID:Platelet GPIIb/IIIa antagonist, XV459, in heparin-induced thrombocytopenia. 1703 13

An 18-month-old Oldenbourg filly was presented with a bleeding diathesis. Laboratory testing included platelet count, gingival bleeding time, prothrombin time (PT), activated partial thromboplastin time (aPTT), von Willebrand factor (vWf) antigen, clottable fibrinogen, clot retraction time, PFA-100 closure time, platelet aggregometry (on platelet-rich plasma), and thrombelastography (TEG). TEG was performed by using kaolin and tissue factor as coagulation activators. Expression of the platelet receptor for fibrinogen was assessed by flow cytometry by using anti CD41 (alpha(IIb) or glycoprotein IIb)/CD61 (beta(III) or glycoprotein IIIa) and anti-CD41 antibodies. Abnormal laboratory findings included prolonged oral mucosal bleeding time (>12 hours), prolonged closure time with collagen/ADP (>300 seconds), and absence of clot retraction after 60 minutes. TEG reaction times were similar with kaolin and tissue factor in the patient and a control horse. However, maximum amplitudes in the patient were decreased with both kaolin (43.7 mm; control, 63.9 mm) and tissue factor (37.7 mm; control, 57.8 mm). Platelet aggregation responses to ADP and collagen were profoundly reduced in the affected horse compared with a control. Flow cytometry showed an absence of CD41 and decreased expression of CD41/CD61-reacting antigen on the patient's platelets compared with those from a control horse. The laboratory findings supported a diagnosis of Glanzmann thrombasthenia, likely caused by a mutation in the gene encoding the GPIIb subunit.
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PMID:Glanzmann thrombasthenia in an Oldenbourg filly. 1752 98

The conventional management of thrombotic disorders is based on the use of heparin, oral anticoagulants, and aspirin. The development of low molecular weight heparins and the synthesis of heparinomimetics such as the chemically synthesized pentasaccharide represent a refined use of heparin. Aspirin still remains the lead drug in the management of thrombotic and cardiovascular disorders. The newer antiplatelet drugs such as the adenosine diphosphate receptor inhibitors, glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors and other specific inhibitors have limited effects and have been tested in patients who have already been treated with aspirin. The oral anticoagulants such as warfarin provide a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. The optimized use of these drugs still remains the approach of choice to manage thrombotic disorders. The new anticoagulant drugs target specific sites in the hemostatic network. There is a major thrust on the development of orally bioavailable anticoagulant drugs to replace oral anticoagulants. Heparin and low molecular weight heparins have been considered with various chemical enhancers for absorption. Both the factor Xa and antithrombin agents have been developed for oral use and some of these agents are in clinical development. Besides the limited bioavailability, the therapeutic indices of some of these drugs have been rather disappointing. Factor Xa inhibitors such as the pentasaccharides have undergone aggressive clinical development. The newer antiplatelet drugs have added a new dimension in the management of thrombotic disorders. The newer drugs are attractive for several reasons; however, none of these are expected to completely replace the conventional drugs in polytherapeutic approaches. It is conceivable that some of the newer drugs in combined modalities may mimic the broad therapeutic spectrum of heparins and warfarin. However, clinical validation is required for the therapeutic interchange for specific indications.
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PMID:The future of anticoagulation. 1830 91

The conventional management of thrombotic and cardiovascular disorders is based on the use of heparin, oral anticoagulants and aspirin. Despite progress in the sciences, these drugs still remain a challenge and mystery. The development of low molecular weight heparins (LMWHS) and the synthesis of heparinomimetics represent a refined use of heparin. Additional drugs will continue to develop. However, none of these drugs will ever match the polypharmacology of heparin. Aspirin still remains the leading drug in the management of thrombotic and cardiovascular disorders. The newer antiplatelet drugs such as adenosine diphosphate receptor inhibitors, GPIIb/IIIa inhibitors and other specific inhibitors have limited effects and have been tested in patients who have already been treated with aspirin. Warfarin provides a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. The optimized use of these drugs still remains the approach of choice to manage thrombotic disorders. The new anticoagulant targets, such as tissue factor, individual clotting factors, recombinant forms of serpins (antithrombin, heparin co-factor II and tissue factor pathway inhibitors), recombinant activated protein C, thrombomodulin and site specific serine proteases inhibitors complexes have also been developed. There is a major thrust on the development of orally bioavailable anti-Xa and IIa agents, which are slated to replace oral anticoagulants. Both the anti-factor Xa and anti-IIa agents have been developed for oral use and have provided impressive clinical results. However, safety concerns related to liver enzyme elevations and thrombosis rebound have been reported with their use. For these reasons, the US Food and Drug Administration did not approve the orally active antithrombin agent Ximelagatran for several indications. The synthetic pentasaccharide (Fondaparinux) has undergone clinical development. Unexpectedly, Fondaparinux also produced major bleeding problems at minimal dosages. Fondaparinux represents only one of the multiple pharmacologic effects of heparins. Thus, its therapeutic index will be proportionately narrower. The newer antiplatelet drugs have added a new dimension in the management of thrombotic disorders. The favorable clinical outcomes with aspirin and clopidogrel have validated COX-1 and P2Y12 receptors as targets for new drug development. Prasugrel, a novel thienopyridine, Cangrelor and AZD 6140 represent newer P2Y12 antagonists. Cangrelor and AZD 6140 are direct inhibitors, whereas Prasugrel requires metabolic activation. While clinically effective, recent results have prompted a closure of a clinical trial with Prasugrel due to bleeding. The newer anticoagulant and antiplatelet drugs are attractive, however, none of these are expected to replace the conventional drugs in polytherapeutic approaches. Heparins, warfarin and aspirin will continue to play a major role in the management of thrombotic and cardiovascular disorders for years to come.
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PMID:Changing trends in anti-coagulant therapies. Are heparins and oral anti-coagulants challenged? 1850 23

Activated platelets contribute to the arrest of bleeding by forming aggregates at sites of vascular injury and by providing a surface for assembling enzyme complexes involved in fibrin formation (platelet procoagulant activity; PCA). Impairment in the latter property of platelets has been observed in some disorders of hemostasis. In Scott syndrome, there is a defect in membrane vesiculation and in the surface expression of phosphatidylserine (PS), the phospholipid that is necessary for assembling the factor VIIIa/IXa (tenase) and factor Va/Xa (prothrombinase) complexes involved in thrombin formation. A family with an isolated defect in vesiculation, but normal prothrombinase activity, has also been reported. In the Quebec platelet disorder, overexpression of the fibrinolytic enzyme urokinase-type plasminogen activator results in the degradation of alpha-granule proteins, including factor V, and a specific abnormality in platelet factor V is the basis for the prothrombinase defect in platelet factor V-New York. The impaired prothrombinase activity in patients with delta-storage pool deficiency may be due to a failure to provide sufficient amounts of secreted adenine nucleotides which, when bound to P2 purinergic receptors, are necessary to maintain the intracellular Ca (2+) levels that are required for the surface expression of PS. Platelet prothrombinase activity and thrombin potential in patients with Glanzmann thrombasthenia (GPIIb-IIIa deficiency) may be decreased, normal, or increased, depending on the experimental conditions, for reasons that are not currently clear. The most consistent platelet PCA abnormality in the Bernard-Soulier syndrome (GPIb-complex deficiency) is an abnormally short serum prothrombin time, associated with a defect in the process by which an interaction between fibrin, von Willebrand factor, and GPIb promotes PCA.
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PMID:Impaired platelet procoagulant mechanisms in patients with bleeding disorders. 1940 96

Bernard-Soulier Syndrome (BSS) is an inherited recessive bleeding disorder. In some instances, diagnosis might be restricted to routine blood exams, including bleeding time, prothrombin time (PT), and partial thromboplastin time (APTT). Exams such as platelet aggregation, and testing for expression of ristocetin cofactor, or von Willebrand factor may not be commonly performed. This leads to misdiagnosis in a number of patients, which are subsequently treated erroneously. Flow cytometry has been used widely as a tool in the diagnosis of leukemias, lymphomas, and many other immuno-hematological diseases. The purpose of this study was to assess whether flow cytometry could be helpful in the diagnosis of Bernard-Soulier Syndrome in Brazilian patients. For this, we examined a selected group of 15 patients with suspected BSS based on classical diagnosis. We used a panel of antibodies to detect the expression of glycoproteins GPIbalpha, GPIIb, GPIIIa, GPIX, as well as CD9. Abnormalities of GPIb and GPIX were observed in nine of the 15 patients, which included severe reduction of both antigens, of one or the other, or normal levels but weak expression. Strikingly, this abnormality correlated with severely reduced expression of CD9 in all cases. We discuss the implications for flow cytometric diagnosis of BSS.
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PMID:Flow cytometry as a tool in the diagnosis of Bernard-Soulier syndrome in Brazilian patients. 1945 30

The standard assay for monitoring anticoagulation during extracorporeal life support (ECLS) is the activated clotting time (ACT) test, with celite, kaolin, and glass beads being the most commonly used activators to initiate contact activation. The point-of-care ACT test has been the preferred test in catheterization labs and cardiac theatres because it has a number of advantages over laboratory tests (Spinler et al., Ann Pharmacother 39(7-8):1275-1285, 2005): Shorter time between sampling and results. Smaller blood sample size. Availability to have test performed by non-lab personnel. Reduced errors associated with sample mislabeling/mishandling. Decreased risk of sample degradation with time. There are other coagulation monitoring tests available; however these are usually specific and do not take into account the global picture of the entire clotting system. The standard coagulation tests (prothrombin time (PT), activated partial thromboplastin time, thrombin time (TT), and fibrinogen level) are plasma tests measuring plasma haemostasis and not patient haemostasis. The ACT measurement uses whole blood, thereby incorporating the importance of platelets and phospholipids in the role of coagulation. Many of the problems with the haemostatic system during ECLS are caused by the activation of platelets, which are not detected by standard tests. Because an ACT test is nonspecific there are many variables such as hypothermia, platelets, aprotinin, GP IIb/IIIa antagonists, haemodilution, etc. that can alter its results. For this reason it is important to gain an understanding as to how these variables interact for meaningful interpretation of the ACT test result.
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PMID:Activated clotting time (ACT). 2354 12

Dual antithrombotic agents acting as anticoagulants and aggregation inhibitors could have substantial advantages over currently prescribed combinations of antithrombotic drugs. Herein, we report compounds with moderate inhibitory activity for factor Xa and fibrinogen GPIIb/IIIa binding (both in the micromolar range). These compounds resulted from our efforts to merge the pharmacophores of selective factor Xa inhibitor rivaroxaban with a mimic of the Arg-Gly-Asp (RGD) sequence of fibrinogen to obtain designed multiple ligands with potential antithrombotic activity. Resulting from this study, a structurally novel class of submicromolar fibrinogen GPIIb/IIIa binding inhibitor bearing 1,2,4-oxadiazol-5(4H)-one moiety is also described.
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PMID:Low molecular weight dual inhibitors of factor Xa and fibrinogen binding to GPIIb/IIIa with highly overlapped pharmacophores. 2364 13


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