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:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Quiescent platelets readily adhere to surface-immobilized fibrinogen. In contrast, platelets exposed to soluble fibrinogen do not demonstrate such activity. As part of an effort to characterize this phenomenon, a solid-phase reagent was prepared by adsorbing human fibrinogen to polystyrene-divinylbenzene microparticles. Using a suspension of human platelets, phase-contrast microscopy was used to quantitate directly platelets bound to fibrinogen-coated beads. This method is fast, straightforward, and requires minimal amounts of reagents and sample. An existing turbidimetric assay was modified to monitor optically the rate and extent of platelet-fibrinogen binding. When platelet-rich plasma was added to a stirred suspension of fibrinogen-coated beads, the rate of aggregation was related directly to the concentration of fibrinogen on the bead surface. This response could not be mitigated by the thrombin inhibitor, hirudin, indicating that any thrombin generated in the reaction has no role in bead aggregation. Conversely, the alpha(IIb)beta(3) antagonist, abciximab (ReoPro), completely prevented aggregation, implicating specific fibrinogen-alpha(IIb)beta(3) interactions as responsible for the observed effect. Beads coated with either albumin or a densely packed, pure film of the neutral phospholipid, phosphatidylcholine (lecithin), do not aggregate under identical conditions, nor do fibrinogen-coated beads aggregate when platelet-depleted plasma is added. When fibrinogen was coated to beads as a mixed film with lecithin, a striking increase in reactivity toward platelets was demonstrated, compared to unmodified beads. These studies indicate that the observed adhesion of platelets to beads is a direct result of platelet-fibrinogen interactions and platelets respond differently to fibrinogen when presented as a mixed film with lipid, compared to the protein alone at an interface.
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PMID:Reactivity of human platelets with immobilized fibrinogen is dictated by the chemical character of the surface. 1158 37

Acute coronary syndromes (ACS), including those associated with or without ST-segment elevation, share a common pathophysiology mediated by activated platelets and thrombin. It is becoming increasingly appreciated that reperfusion therapies using primary mechanical or pharmacologic strategies result in suboptimal reperfusion at the myocardial tissue level. Complete reperfusion of the coronary microvasculature has recently been shown to be an important predictor for survival following myocardial infarction. Abciximab has well-established clinical benefits in numerous interventional trials. Through its anti-platelet and anti-thrombotic activities, abciximab reduces thrombus formation and hence minimizes risk of thrombotic microvascular embolization and improves tissue-level reperfusion. Several recent landmark trials have evaluated the clinical efficacy of adjunctive abciximab during mechanical or pharmacologic reperfusion therapy in the setting of ACS. This article provides an update of the role of abciximab in the treatment for ACS based on the results of these clinical trials.
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PMID:Defining the role of abciximab for acute coronary syndromes: lessons from CADILLAC, ADMIRAL, GUSTO IV, GUSTO V, and TARGET. 1170 9

The interaction between platelet glycoprotein Ib and von Willebrand factor (vWF) plays a crucial role in platelet-mediated thrombus formation under high-shear-stress conditions. The aim of this study was to investigate the antiplatelet profile of a humanized anti-vWF monoclonal antibody, AJW200. In vitro studies were performed with a modified cone-and-plate viscometer and human platelets. AJW200 inhibited high-shear-stress-induced platelet adhesion, aggregation, and thrombin generation, but it did not have such effects under low-shear-stress conditions. Although abciximab inhibited platelet aggregation under both shear stress conditions, it did not inhibit platelet adhesion and thrombin generation. In addition, the pharmacokinetics and pharmacodynamics of AJW200 were evaluated in cynomolgus monkeys. Sustained inhibition of ristocetin-induced platelet aggregation was observed over 24 hours, 6 days, and 2 weeks after a single bolus injection of 0.3, 1, and 3 mg/kg, respectively. Moderate prolongation of the bleeding time was observed at the doses of 1 and 3 mg/kg. Abciximab markedly prolonged the bleeding time at 0.4 mg/kg, at which concentration complete inhibition of ADP-induced platelet aggregation was observed. These results suggest that glycoprotein Ib-vWF blockade with AJW200 results in a sustained antiplatelet effect without extensive prolongation of the bleeding time, probably due to a shear-stress-dependent inhibitory action.
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PMID:Pharmacokinetics and pharmacodynamics of AJW200, a humanized monoclonal antibody to von Willebrand factor, in monkeys. 1178 81

Platelets play an important role in the pathophysiology of acute myocardial infarction, unstable angina, and ischemic stroke. The expression of the glycoprotein IIb/IIIa (alphaIIb/beta3 integrin) receptor on the surface of activated platelets constitutes the common pathway for platelet aggregation. Glycoprotein IIb/IIIa has low affinity for its soluble ligands (fibrinogen and von Willebrand factor) in resting platelets. In the setting of vascular injury, platelet activation occurs after binding of the glycoprotein Ib-IX-V receptor to von Willebrand factor in the extracellular matrix (at high shear rate) and binding of soluble agonists to specific platelet membrane receptors. The ensuing inside-out signaling increases several-fold the affinity and avidity of alphaIIb/beta3 for its ligands. High affinity ligand binding to alphaIIb/beta3 triggers outside-in signaling, causing microskeletal contraction and platelet retraction. The signaling pathways for inside-out and outside-in signaling are incompletely understood. Glycoprotein IIb/IIIa antagonists were developed under the premise that these agents would abrogate platelet aggregation while preserving platelet monolayer deposition at sites of injury. A number of parenteral and oral agents have been developed and evaluated in clinical trials. Three of them are approved in the United States and other countries: abciximab (ReoPro; the Fab fragment of a chimeric human-mouse antibody), eptifibatide (Integrelin; a cyclic heptapeptide), and tirofiban (Aggrastat; a tyrosine-derived nonpeptide molecule). The greatest clinical impact of these parenteral agents (used in conjunction with aspirin and heparin) has been in the prevention of ischemic complications after percutaneous coronary intervention. In contrast, oral agents have yielded disappointing results in the secondary prevention of acute coronary syndromes, and none of them are approved at present. Eptifibatide and tirofiban are specific for alphaIIb/beta3, whereas abciximab also exhibits cross-reactivity with the alphavbeta3 and alphaMbeta2 integrins. Although alphaIIb/beta3 is unique to platelets and megakaryocytes, alphavbeta3 is more widely distributed and mediates several functions, including endothelial cell migration, monocyte adhesion, angiogenesis, and inhibition of apoptosis. alphaMbeta2 mediates leukocyte-platelet interactions. In the percutaneous coronary intervention trials, abciximab has been more efficacious than the other parenteral agents, perhaps because of cross-reactivity with these other integrins, the pharmacodynamic profile of abciximab, or other effects. Other documented effects of abciximab include acute dethrombosis, reduction of thrombin generation, and improved flow in the coronary microcirculation after percutaneous coronary intervention. Abciximab is presently under evaluation in the treatment of acute ischemic stroke. Promising data have been obtained in experimental models of tumor angiogenesis and sickle cell anemia.
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PMID:Platelet glycoprotein IIb/IIIa antagonists: lessons learned from clinical trials and future directions. 1200 56

The acute coronary syndromes (ACS), with or without ST-segment elevation, share a common pathophysiology of activated platelets and thrombin generation stimulated by plaque erosion and rupture. Both mechanical and pharmacologic treatment strategies have evolved in an attempt to improve reperfusion at the myocardial tissue level. Intracoronary stents have lowered the incidence of abrupt vessel closure and restenosis, while potent platelet inhibition from intravenous glycoprotein IIb/IIIa antagonists has reduced the rate of periprocedural myocardial infarction and late mortality. Abciximab has well-established clinical benefits in percutaneous revascularization trials, and several recent landmark studies have evaluated the efficacy of concomitant abciximab during mechanical reperfusion therapy in the setting of ACS. These trials are reviewed, and an overall perspective is provided.
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PMID:Glycoprotein IIb/IIIa inhibition in early intent-to-stent treatment of acute coronary syndromes: EPISTENT, ADMIRAL, CADILLAC, and TARGET. 1264 41

The involvement of glycoprotein (GP) IIb-IIIa (alphaIIbbeta3-integrin) in the stimulation of secretion from platelet dense and alpha-granules was investigated. Fibrinogen binding with GP IIb-IIIa and platelet aggregation were inhibited by fragments of anti-GP IIb-IIIa monoclonal antibodies (monAB)--Fab fragment of antibody c7E3 (preparation ReoPro) and F(abacute;)(2) fragment of antibody FraMon (preparation FRAMON). Suppression of GP IIb-IIIa receptor activity by both preparations led to 100% inhibition of [(14)C]serotonin secretion from dense granules upon platelet activation with ADP, to partial inhibition upon activation with thromboxane A(2) analog U46619 (by 60-70%) and thrombin at 0.1 U/ml (by 40-50%), but did not decrease serotonin secretion induced by thrombin at 1 U/ml. ReoPro and FRAMON completely inhibited ADP-induced release of soluble P-selectin from platelet alpha-granules, but did not influence P-selectin secretion stimulated by U46619 and by both thrombin concentrations. MonAB CRC54 against GP IIb-IIIa, which induced its interaction with fibrinogen and platelet aggregation, also stimulated serotonin and P-selectin secretion. Both types of release reactions were completely suppressed by ReoPro and FRAMON. Aspirin, the cyclooxygenase inhibitor, also prevented CRC54-induced secretion, proving the dependence of this process on thromboxane A(2) synthesis. Upon platelet activation by concanavalin A (Con A), caused by clusterization of membrane glycoproteins, GP IIb-IIIa blockade only slightly (by 15-20%) decreased serotonin secretion. High level of Con A-induced secretion was also detected in a patient with hereditary deficiency of GP IIb-IIIa. Thus, neither clusterization nor occupation of GP IIb-IIIa are essential for the stimulation of Con A-induced release reaction. The data indicate that GP IIb-IIIa binding with fibrinogen leads to the stimulation of secretion from platelet granules. When the level of secretion does not depend on GP IIb-IIIa interaction with the ligands or its presence on platelets full-scale release reaction is presumably stimulated by activating signals formed without GP IIb-IIIa involvement.
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PMID:Role of glycoprotein IIb-IIIa (alpha IIb beta 3-integrin) in stimulation of secretion from platelet granules. 1269 68

Under conditions of arterial-wall shear rates, platelets bind to von Willebrand factor (vWf) by way of the glycoprotein Ib (GP Ib) complex and integrin alpha(IIb)beta(3). Both adhesive receptors may also play roles in the development of procoagulant activity of platelets. Here, we investigated the effect of shear stress, as provided by a rotating cylinder, on GP Ib- and integrin alpha(IIb)beta(3)-dependent thrombin generation in coagulating platelet-rich plasma (PRP). We measured thrombin continuously with the use of fluorometry from the cleavage rate of a fluorescent low-affinity substrate. The integrin alpha(IIb)beta(3) antagonist abciximab progressively reduced the peak of thrombin formation up to 43% when rate of stirring and shear stress were increased (estimated shear rates of 105-420 s(-1)). Abciximab did not lower the peak of thrombin formation in stirred PRP from patients with Glanzmann's thrombasthenia lacking alpha(IIb)beta(3) but, surprisingly, shortened the time until onset. In PRP from control subjects, antibodies specifically directed against vWf-binding epitopes on GP Ibalpha reduced thrombin formation, with 25% to 30% at the high but not at the low stirring rate. In combination with the anti-GP Ib antibody, abciximab retained its strong inhibitory effect only at the high stirring rate. We conclude that thrombin formation and coagulation in stirred PRP depend, to a large extent, on platelet adhesion to integrin alpha(IIb)beta(3) and, in a shear-dependent way, on GP Ib.
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PMID:Integrin alphaIIbbeta3 and shear-dependent action of glycoprotein Ibalpha stimulate platelet-dependent thrombin formation in stirred plasma. 1276 79

In addition to inhibiting platelet (plt) aggregation abciximab, a glycoprotein (GP) IIb/IIIa antagonist, reduces coagulation in blood or platelet-rich plasma. We assessed the effects of abciximab (10 micro g mL(-1)) on adhesion-dependent procoagulant activity (PCA) of plt upon: (i) collagen to model initial adhesion; or (ii) plasma clot or fibrin to model a preformed thrombus with retained thrombin activity. In a two-stage assay gel-filtered plt (GFP) first adhered on collagen, plasma clot, or fibrin, and plt activation was traced with platelet factor 4 (PF 4) release. Second, PCA was measured on adherent plt (i) by soluble prothrombin fragments (F1 + 2); and (ii) chromogenically by adding defibrinated plasma and thromboplastin. Abciximab inhibited aggregation upon collagen-adherent plt both in the absence and presence of plasma. In contrast, without plasma abciximab enhanced plt deposition to fibrin surfaces depending on thrombin generation and fibrin polymerization. However, abciximab reduced PCA and generation of F1 + 2 on adherent plt surface-independently by 35%, whereas PF 4 release persisted. Also, a GP Ib inhibitor, mAb SZ2, attenuated PCA by 40% alone, and by 65% together with abciximab, leaving 35% of PCA unaltered. Abciximab decreased generation of new thrombin on both collagen- and clot-adherent plt. However, abciximab did not inhibit alpha-granule release, suggesting distinct pathways for PCA and release reaction. Deposition of isolated plt on clots in the presence of abciximab was dependent on thrombin and polymerizing plt-derived fibrin(ogen). Due to local consumption of natural anticoagulants adjacent to a preformed thrombus the antithrombotic effect of abciximab benefits from additional inhibition of thrombin.
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PMID:Abciximab inhibits procoagulant activity but not the release reaction upon collagen- or clot-adherent platelets. 1287 19

Irrespective of their mechanism of action, anticoagulants reduce the formation and action of thrombin. Thus they interfere with a final step in coagulation. Among platelet inhibitors only the GPIIb/IIIa antagonists inhibit the common pathway of aggregation, namely the formation of platelet-to-platelet bridges which are mediated by fibrinogen or von Willebrand factor. In contrast, acetylsalicylic acid (ASA), NSAIDs, clopidogrel (Plavix) or ticlopidine (Tyklid) inhibit platelet activation by abrogating the formation or action of a secondary platelet agonist, namely of thromboxane A(2) or ADP. They do not block platelet aggregation which is directly induced by thrombin. Therefore, ASA, clopidogrel, or ticlopidine are not associated with a significant risk of bleeding as long as other factors such as an extensive thrombocytopenia or anticoagulation are not involved. Therefore, in contrast to anticoagulants, therapeutic drug monitoring is not necessary with ASA, clopidogrel, nor ticlopidine. On the other hand, ASA has even to be applied at a dosage that almost completely inhibits thromboxane synthesis in order to act on platelet aggregation at all. Among the GPIIb/IIIa-antagonists only parenteral drugs have been approved for therapeutic use, e. g. abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat). Clinical studies revealed an increased risk of bleeding without a sufficient therapeutic benefit of oral GPIIb/IIIa antagonists. GPIIb/IIIa antagonists may induce thrombocytopenia that is attributed to an out-side-in signalling or immunological phenomena. A test system (Ultegra, Accumetrics) is available for a therapeutic drug monitoring of GPIIb/IIIa antagonists. However, estimation of the bleeding risk always requires an evaluation of all factors influencing the haemostatic system, especially when heparin or other inhibitors are applied additionally.
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PMID:[Platelet aggregation disorders]. 1460 82

First Russian glycoprotein (GP) IIb-IIIa antagonist, preparation Monafram, is the F(ab')2 fragment of anti-GP IIb-IIIa monoclonal antibody FRaMon. In in vitro experiments it was shown that Monafram blocked platelet aggregation induced by ADP and thrombin; reduced secretion from platelet granules; and due to simultaneous interaction with two GP IIb-IIIa molecules almost irreversibly bound to platelet surface. Monafram clinical trials were performed in healthy volunteers (n = 10) and in patients with ischemic heart disease undergoing high risk coronary angioplasty (n = 153). Monafram intravenous bolus administration at 0.25 mg/kg decreased ADP-induced platelet aggregation by more than 90, 80, 60 and 30% at 1, 12, 24 and 72 h after injection, respectively. No significant differences were detected between antiaggregatory effects of Monafram and ReoPro introduced at 0.25 mg/kg bolus + 12 h infusion at 0.125 microg/kg per min. Durable inhibition of aggregation after Monafram administration was mediated by platelet-bound preparation--free Monafram was cleared from plasma within 12 h, while platelet-bound preparation occupied more than 90, 70-80 and 40-50% of GP IIb-IIIa at 1, 12-24 and 72 h after injection, respectively. Major bleedings and allergic reactions were detected in none of patients, deep thrombocytopenia--in one patient and antibodies against Monafram--in 5% of patients. Within one month after coronary angioplasty Monafram decreased the number of end points (fatal and nonfatal myocardial infarction and angina recurrence) from 11.4 to 3.3%.
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PMID:[Antiplatelet effects of glycoproteins IIb-IIIa antagonist monafram]. 1534 Oct 84


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