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)

Novel antithrombotic and antiplatelet agents may help reduce the short-term risk of ischemic complications and the long-term risk of restenosis in patients undergoing coronary revascularization procedures. Recent clinical trials suggest that, compared with heparin, direct thrombin inhibitors (such as hirudin and hirulog) offer a predictable dose-response effect on the activated partial thromboplastin time without a concomitant increase in bleeding. Among the newer antiplatelet agents, the platelet integrin glycoprotein IIb/IIIa inhibitors (including c7E3 Fab and Integrelin) have generated the greatest interest. Clinical trial data have shown that c7E3 Fab (administered in conjunction with heparin) significantly reduces ischemic events and improves clinical outcomes. In phase II trials, Integrelin has also shown similar effects. The primary limitations have been an increase in heparin-associated bleeding, which suggests that the safety profile may be enhanced by careful adjustment of the heparin dose implementation of other patient management guidelines. The safety and efficacy data obtained in future trials should shed more light on the appropriate roles of these drugs in interventional cardiology.
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PMID:Enhancing safety and outcomes with the newer antithrombotic and antiplatelet agents. 766 16

We used flow cytometry to investigate surface membrane protein expression by platelets and platelet-derived microparticles from normal individuals and a patient with Glanzmann's thrombasthenia. Microparticles were detected by both forward scatter and side scatter using FACScan. The binding of coagulation factors on microparticles was investigated by using monoclonal anti-Factor IX (IXa) and anti-Factor X (Xa) antibodies. Furthermore, the procoagulant activity of microparticles was measured with a chromogenic substrate (S-2222) using a microtiter enzyme-linked immunosorbent assay. Both types of platelets showed similar release of microparticles. Microparticles released from platelets after activation with the calcium ionophore A23187 did not bind factors IXa and Xa, but when purified factors Va and Xa were added to the incubation buffer, factor Xa binding increased markedly in both normal and thrombasthenic platelets. Both normal and thrombasthenic platelets showed a similar time-dependent release of microparticles when activated with A23187. However, the binding of an antibody to granule membrane protein-140 also increased time-dependently in normal microparticles, but was little increased in thrombasthenic microparticles. These findings suggest that glycoprotein IIb/IIIa does not participate in the expression of prothrombinase activity on the surface of activated platelets and microparticles, whereas this glycoprotein appears to have an important role in the movement of granule membrane protein-140 from platelets to microparticles.
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PMID:Flow cytometric analysis of surface membrane proteins on activated platelets and platelet-derived microparticles from healthy and thrombasthenic individuals. 814 98

Hemorrhagic events remain the most worrisome complication in patients receiving drugs that alter hemostasis for treatment of acute coronary syndromes. The 7E3 Fab monoclonal antibody provides a dose-dependent inhibition of platelet aggregation via the glycoprotein IIb/IIIa receptor. This study examines the correlation of hemostatic parameters with bleeding events in patients receiving intravenous 7E3 while enrolled in acute myocardial infarction and high-risk percutaneous transluminal coronary angioplasty pilot studies. Patients with acute myocardial infarction received 100 mg of tissue-type plasminogen activator over 3 hours followed by an escalating intravenous bolus dose of murine 7E3 (0.1 mg/kg [n = 5], 0.2 mg/kg [n = 22], 0.15 mg/kg [n = 13], 0.25 mg/kg [n = 20]). Patients in the high-risk angioplasty trial received a chimeric 7E3 bolus (up to 0.25 mg/kg) with (n = 32) or without (n = 15) intravenous continuous infusion of 7E3 (10 micrograms/min for 6 to 24 hours) after elective angioplasty. Patients in both studies received aspirin therapy (325 mg/day) and partial thromboplastin time-guided (1.5 to 2 times normal) heparin infusion. Bleeding events occurred in 34 of 124 patients (27%). The median template bleeding times (minutes) for patients in the groups with bleeding versus no bleeding events in the trials was 13.5 versus 14 and 30 versus 30, respectively (p = NS). In patients with myocardial infarction, a substantial decline in platelet count at 24 hours was associated with bleeding (p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lack of usefulness of prolonged bleeding times in predicting hemorrhagic events in patients receiving the 7E3 glycoprotein IIb/IIIa platelet antibody. The TAMI Study Group. 823 99

The aim of the present study was to investigate the reactivity of immunoreagents developed for clinical applications in humans in different animal species (hen, mouse, rat, rabbit, guinea-pig, dog, pig, sheep, baboon). Prothrombin fragment 1 + 2, thrombin-antithrombin III complex and fibrinopeptide A were tested for coagulation, platelet factor 4 and beta-thromboglobulin for platelet activation, glycoprotein IIb-IIIa, glycoprotein Ib and P-selectin for platelet membrane glycoproteins, D-dimers for fibrinolysis, thrombomodulin for activation of endothelial cells and thrombospondin and von Willebrand factor for adhesive proteins. Prothrombin fragment 1 + 2, platelet factor 4, beta-thromboglobulin and D-dimers were revealed only in baboons. Fibrinopeptide A was well detected in baboons but weakly in mice, dogs, pigs and sheep. Whereas glycoprotein IIb-IIIa was revealed on guinea-pig, dog and sheep platelets and glycoprotein Ib on rabbit and dog platelets, P-selectin and thrombomodulin were never detected. Thrombospondin was revealed in hens, mice, rats, guinea-pigs, pigs, sheep and baboons and von Willebrand factor in mice, rats, guinea-pigs, dogs, pigs, sheep and baboons. Interestingly, thrombin-antithrombin III complex (TAT) was detected in all species tested except the hen. A time- and dose-dependent increase in TAT was observed when rats, dogs or pigs were infused with thromboplastin (4.5-450 microliters/kg/h), while administration of hirudin (1 mg/kg) abolished this TAT generation. Thus, the TAT immunoassay could provide a tool for the screening of antithrombotic drugs in a number of animal species. However, the possibility of using a wider panel of human immunoreagents would appear to be restricted to baboons which display good species cross-reactivity.
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PMID:Cross-reactivity of human molecular markers for detection of prethrombotic states in various animal species. 858 12

Microparticles are released during in vitro platelet activation and have been detected in vivo in several pathologies. Their characterization is of interest as they may play a potential role in hemostasis. Here, we report the formation of microparticles as the result of increases in intracellular Ca2+ brought about by inhibition of Ca(2+)-ATPases. They were isolated following centrifugation of the activated platelet suspension over a sucrose layer. Flow cytometric studies using annexin V-FITC as a probe for aminophospholipids, prothrombinase activity measurements and annexin V inhibition experiments enabled us to evaluate the procoagulant activity of microparticles prepared in this way. The efficiency of the annexin V inhibition (IC50 = 10-20 nM) of this activity confirmed significant anticoagulant properties for this protein. Microparticles also contained the glycoprotein IIb-IIIa complex, detected in flow cytometry at a density higher than on the remnant platelets. The activation of calpain, a Ca(2+)-dependent protease, in platelets was shown to be more efficient under conditions of a sudden Ca2+ influx. The microparticles contained only the active form of calpain detected by Western blotting using a monoclonal antibody able to recognize both the unactivated and the activated catalytic subunit of the enzyme. However, flow cytometry failed to find significant amounts of active calpain on the microparticle or on the platelet surface. Our results, while confirming the procoagulant activity of microparticles, also document for the first time the exclusive presence of the activated form of calpain, inferring a possible role for this protease in microparticle-mediated functions.
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PMID:Procoagulant activity and active calpain in platelet-derived microparticles. 879 23

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

After a standardized trauma to carotid arteries or femoral veins of hamsters, the antithrombotic effects of two antiplatelet agents (aspirin and the glycoprotein IIb/IIIa antagonist G4120) and two anticoagulants (heparin and the direct thrombin inhibitor r-hirudin) were studied in vivo. The thrombus area volume was assessed by image analysis of the transilluminated experimental vessels. Heparin, r-hirudin, and G-4120 demonstrated a dose-dependent complete inhibition of arterial and venous thrombosis. In contrast, the antithrombotic effect of aspirin was only partial in both vessel types. A significant correlation between activated partial thromboplastin time (aPTT) at the end of the experiments and the antithrombotic effect was observed with the anticoagulant agents. However, only r-hirudin inhibited thrombus formation at a therapeutical prolongation of aPTT, while heparin required supratherapeutical amounts to achieve the same inhibition. The data confirm that the inhibition of aspirin, heparin, r-hirudin, and G-4120 on the formation of platelet-rich thrombi is independent of the blood flow rate.
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PMID:A technique to investigate microvascular mural thrombus formation in arteries and veins: II. Effects of aspirin, heparin, r-hirudin, and G-4120. 901 42

An understanding of the coagulation process and the role of platelets is essential to recognizing the shortcomings of older anticoagulant therapies and appreciating the clinical potential of newer forms of antiplatelet and anticoagulant therapy for acute coronary syndromes. The anticoagulant actions of heparin are severely limited by dependence on antithrombin III, neutralization by platelet factor 4, and the resistance of clot-bound thrombin and platelet membrane-bound factor Xa to the heparin-antithrombin III complex. Unlike heparin, the direct thrombin inhibitors (such as hirudin) are active against both circulating and clot-bound thrombin. However, in recent clinical trials they have not resulted in major improvements in patient outcome. Another new class of drugs, the glycoprotein IIb/IIIa receptor antagonists, blocks the final common pathway of platelet aggregation and is capable of preventing platelet accumulation at sites of injury. The net effect is a dramatic reduction in the amount of platelet membrane available to support the process of coagulation. Clinical trials with the glycoprotein IIb/IIIa inhibitors have suggested that this class of agents may be particularly effective in reducing the thrombotic complications associated with coronary interventional procedures and may be useful in the treatment of acute coronary syndromes.
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PMID:Fundamentals of coagulation and glycoprotein IIb/IIIa receptor inhibition. 953 94

An understanding of the coagulation process and the role of platelets is essential to recognizing the shortcomings of older anticoagulant therapies and appreciating the clinical potential of newer forms of antiplatelet and anticoagulant therapy for acute coronary syndromes. The anticoagulant actions of heparin are severely limited by dependence on antithrombin III, neutralization by platelet factor 4, and the resistance of clot-bound thrombin and platelet membrane-bound factor Xa to the heparin-antithrombin III complex. Unlike heparin, the direct thrombin inhibitors (such as hirudin) are active against both circulating and clot-bound thrombin. However, in recent clinical trials they have not resulted in major improvements in patient outcome. Another new class of drugs, the glycoprotein IIb/IIIa receptor antagonists, blocks the final common pathway of platelet aggregation and is capable of preventing platelet accumulation at sites of injury. The net effect is a dramatic reduction in the amount of platelet membrane available to support the process of coagulation. Clinical trials with the glycoprotein IIb/IIIa inhibitors have suggested that this class of agents may be particularly effective in reducing the thrombotic complications associated with coronary interventional procedures and may be useful in the treatment of acute coronary syndromes.
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PMID:Fundamentals of coagulation and glycoprotein IIb/IIIa receptor inhibition. 959 17

We examined the effects of glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists c7E3 Fab and DMP728 on the development of platelet prothrombinase (PT) activity. c7E3 Fab dose-dependently inhibited the rate of thrombin-stimulated thrombin generation over a 1-minute reaction time. The IC50 was 11 nM with an IC90 of 1000 nM. DMP728 inhibited PT activity maximally by 60% at 100 nM. A similar profile was observed for the inhibition of platelet tenase activity. Inhibition was platelet specific up to approximately 200 nM c7E3 Fab. Above 200 nM, inhibition was platelet independent, as shown by the inhibition of activity assembled on PS/PC vesicles. c7E3 Fab and DMP728 did not inhibit calcium ionophore-induced activity. DMP728 potency diminished with reaction time (over 6 minutes) whereas c7E3 Fab potency did not. Inhibition by 2 microM DMP728 was not further increased by 20 nM c7E3 Fab. Heparin inhibition of platelet PT activity was additive to that of c7E3 Fab. Studies with added von Willebrand factor (vWf) indicate that in the context of thrombin activation vWf activates platelets through mechanisms independent of GPIIb/IIIa to promote PT activity. Thrombin activation induced binding of FITC-Annexin V to a subpopulation of platelets which was reduced by approximately 50% by pretreatment with either c7E3 Fab or DMP728. Together, these data indicate that c7E3 Fab and DMP728 inhibit the development of GPIIb/IIIa-mediated platelet PT activity at events during platelet activation. The inhibitory activities are not additive, suggesting these agents compete for the same site or inhibit via the same mechanism. Inhibition accompanies a reduction in the number of phosphatidylserine binding sites, implying that GPIIb/IIIa receptor antagonists reduce platelet membrane scrambling induced by thrombin. The additivity of inhibition with heparin by c7E3 Fab suggests a combination of these agents might have a greater bleeding liability than the use of either agent alone.
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PMID:Glycoprotein IIb/IIIa receptor antagonists inhibit the development of platelet procoagulant activity. 970 Aug 55


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