Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelets participate in formation of thrombin through secretion of coagulation factors and by providing a catalytic surface on which prothrombinase complex is assembled. We studied the effects of four antiplatelet drugs on thrombin formation in healthy volunteers. Thrombin generation was monitored both in vitro--in recalcified plasma--and ex vivo--in blood emerging from a standardized skin microvasculature injury, which also served to determine bleeding time. A mathematical model has been developed to describe the latter reaction. It is based on estimation of the rate of increase in fibrinopeptide A (FPA), a specific marker of thrombin activity, in blood emerging from skin incisions. Two hours after the ingestion of 500 mg of aspirin, thrombin formation became significantly impaired both in vitro and ex vivo. In contrast, 2 hours after the oral administration of placebo, indomethacin 50 mg, or OKY-046 (a thromboxane synthase inhibitor) 400 mg, thrombinogenesis remained unaltered. Ticlopidine, studied either 3 hours after 500 mg oral administration, or after 5 days of intake at a daily dose of 500 mg, had no effect on thrombin generation. Thus, aspirin, contrary to other antiplatelet drugs, depresses thrombin formation in clotting blood, a phenomenon that might be of clinical relevance. It is suggested that aspirin exerts this effect by acetylating prothrombin and/or macromolecules of platelet membrane.
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PMID:Antiplatelet drugs and generation of thrombin in clotting blood. 139 58

A technically simple model of arterial thrombosis in the rat, induced by a crush injury to the dorsal aorta is described. The mechanical injury to the artery caused deep medial injury and the formation of a platelet-rich thrombus with associated fibrin formation which was assessed both radiometrically and morphometrically. No significant inclusion of erythrocytes was noted in the thrombus. Administration of the platelet inhibitors aspirin, BM 13505 (a thromboxane receptor antagonist) or CGS 12970 (a thromboxane synthase inhibitor) reduced the extent of platelet deposition on the injured vessel, but no decrease in fibrin(ogen) was observed. In contrast, infusion of prostacyclin resulted in reductions in both these components of the thrombus. In studies involving inhibition of thrombin activity, the direct thrombin inhibitor CGP 39393 (recombinant desulphatohirudin) inhibited both the platelet and fibrin(ogen) deposition. The indirect thrombin inhibitors were less effective; unfractionated heparin and low-molecular-weight heparin inhibited both platelet and fibrin(ogen) deposition but only at doses which rendered the blood uncoagulable, as evaluated by the activated partial thromboplastin time. Dermatan sulphate only inhibited platelet deposition. The results suggest that thrombin plays a key role in the initiation of thrombus formation in this experimental model. The agonist prostaglandins (PGG2, PGH2, and TXA2) would appear to have a supporting role in the platelet deposition onto the thrombotic surface but do not have a role to play with respect to fibrin(ogen) deposition.
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PMID:A non-occlusive model of arterial thrombus formation in the rat and its modification by inhibitors of platelet function, or thrombin activity. 160 87

Despite their widespread use in patients with acute myocardial infarction, all currently available thrombolytic agents suffer from a number of significant limitations, including resistance to reperfusion, the occurrence of acute coronary reocclusion, and bleeding complications. Several lines of research towards improvement of thrombolytic therapy are being explored, including strategies to enhance the fibrinolytic potency of plasminogen activators and to improve conjunctive antiplatelet or antithrombotic agents. Mutants and variants of plasminogen activators, chimeric plasminogen activators, and conjugates of plasminogen activators with monoclonal antibodies have been constructed, and plasminogen activators from animal or bacterial origin have been evaluated. Some of these new thrombolytic agents have shown promise in animal models of venous or arterial thrombosis and in pilot studies in patients with acute myocardial infarction. Such molecules include mutants of tissue-type plasminogen activator (t-PA) with prolonged half-life and/or resistance to protease inhibitors and staphylokinase. Antiplatelet strategies include the use of platelet glycoprotein IIb/IIIa receptor blocking agents, of thromboxane synthase inhibitors and endoperoxide receptor antagonists. Antithrombotic strategies include the use of selective inhibitors of thrombin, tissue factor or factor Xa. The efficiency and safety of these new agents in man will have to be carefully evaluated.
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PMID:New thrombolytic agents and strategies. 754 72

Platelet activation plays a critical role in thromboembolic disorders, and aspirin remains a keystone in preventive strategies. This remarkable efficacy is rather unexpected, as aspirin selectively inhibits platelet aggregation mediated through activation of the arachidonic-thromboxane pathway, but not platelet aggregation induced by adenosine diphosphate (ADP), collagen and low levels of thrombin. This apparent paradox has stimulated investigations on the effect of aspirin on eicosanoid-independent effects of aspirin on cellular signalling. It has also fostered the search for antiplatelet drugs inhibiting platelet aggregation at other levels than the acetylation of platelet cyclo-oxygenase, such as thromboxane synthase inhibitors and thromboxane receptor antagonists. The final step of all platelet agonists is the functional expression of glycoprotein (GP) IIb/IIIa on the platelet surface, which ligates fibrinogen to link platelets together as part of the aggregation process. Agents that interact between GPIIb/IIIa and fibrinogen have been developed, which block GPIIb/IIIa, such as monoclonal antibodies to GPIIb/IIIa, and natural and synthetic peptides (disintegrins) containing the Arg-Gly-Asp (RGD) recognition sequence in fibrinogen and other adhesion macromolecules. Also, some non-peptide RGD mimetics have been developed which are orally active prodrugs. Stable analogues of prostacyclin, some of which are orally active, are also available. Thrombin has a pivotal role in both platelet activation and fibrin generation. In addition to natural and recombinant human antithrombin III, direct antithrombin III-independent thrombin inhibitors have been developed as recombinant hirudin, hirulog, argatroban, boroarginine derivatives and single stranded DNA oligonucleotides (aptanes). Direct thrombin inhibitors do not affect thrombin generation and may leave some 'escaping' thrombin molecules unaffected. Inhibition of factor Xa can prevent thrombin generation and disrupt the thrombin feedback loop that amplifies thrombin production.
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PMID:Novel antithrombotic drugs in development. 764 2

After a 1-month placebo run-in phase, 27 patients with proven peripheral arterial obstructive disease participated in a double blind placebo controlled study and were divided in 3 groups, receiving either placebo, ridogrel 300 mg b.i.d. (a combined thromboxane synthase and receptor blocking agent) or a combination of ridogrel 300 mg b.i.d. and ketanserin 20 mg t.i.d. (a 5-HT2 serotonergic receptor antagonist) for a period of 1 month. In both active treatment groups, serum levels of thromboxane B2 decreased significantly to 3% of baseline. The levels of 6-keto-prostaglandin F1 alpha and prostaglandin F2 alpha increased two- to three-fold and levels of prostaglandin E2 6 times. Platelet aggregation induced by collagen and by U 46619, a thromboxane A2 mimetic, were significantly inhibited by both treatment regimen. Template bleeding times were significantly prolonged but plasma fibrinogen levels and the activated partial thromboplastin time were not affected with the active treatments. No such changes were seen with placebo. An inhibition of the serotonin-induced platelet aggregation was only seen in the ketanserin-treated group. In a 3-month open follow-up period during combined treatment with ridogrel and ketanserin in 22 patients, the effects on platelet function and prostanoids were maintained. The total duration of the walking distance on a treadmill improved significantly from 323 +/- 53 seconds to 399 +/- 48 seconds and the onset of claudication pain improved significantly from 121 +/- 29 seconds to 212 +/- 44 seconds, whereas the maximal drop of the post-exercise ankle/arm pressure gradient markedly and significantly improved from a control value of 0.38 +/- 0.05 to 0.51 +/- 0.05. These findings suggest that a combination of ridogrel and ketanserin may be of therapeutic value in the treatment of intermittent claudication.
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PMID:The effect of a combined administration of ridogrel and ketanserin in patients with intermittent claudication. 837 14

Several agents which inhibit platelet aggregation (aspirin, ticlopidine, dipyridamole), and anticoagulants (vitamin K antagonists, unfractionated heparin, low molecular weight heparins and heparinoids) are in clinical use. The search for more effective antiaggregating agents has resulted in the development of clopidogrel, a chemical analogue of ticlopidine with minimal bone-marrow suppressing effects, thromboxane synthase inhibitors and receptor blockers, and antagonists of platelet receptor glycoproteins Ib and IIb/IIIa. In addition there is increasing therapeutic experience with chimeric monoclonal antibodies against the platelet receptors, glycoprotein IIb/IIIa, and, to a minor extent, with synthetic peptides or non-peptide inhibitors against the same receptors. Although new anticoagulants have become available, their efficacy has only been tested in animal models of thrombosis: tissue factor pathway inhibitor, factor Xa inhibitors (recombinant tick anticoagulant peptide, antistasin, natural pentasaccharide and DX-9065), recombinant thrombomodulin and recombinant protein C have been tested in this manner. Considerable clinical progress has been made with direct thrombin inhibitors, such as recombinant hirudin and hirulog which appear to be effective antithrombotic agents in patients. There is also clinical experience with argatroban, an arginine derivative which is a competitive antagonist to thrombin. However, PPACK, a tripeptide synthetic compound which irreversibly blocks the active catalytic site of thrombin, has not been investigated in the clinical setting.
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PMID:New developments in antiplatelet and antithrombotic therapy. 886 14