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)

Glycoprotein IIb-IIIa (GPIIb-IIIa) is the fibrinogen receptor on activated platelets. GPIIIa is phosphorylated in resting platelets and the incorporation of 32Pi increases with platelet activation. To address the functional significance of this modification, the stoichiometry of GPIIIa phosphorylation was determined in resting and activated platelets by estimating the specific activity of metabolic [gamma-32P]ATP from the specific activity of phosphatidic acid. Approximately 0.01 mol of P/mol of GPIIIa was phosphorylated in resting platelets and 0.03 mol of P/mol of GPIIIa was phosphorylated in thrombin-, phorbol ester-, or U46619-treated platelets. Myosin light chain (MLC) phosphorylation served as a positive control for this method (1.2 mol of P/mol of MLC). Phosphorylation of purified GPIIb-IIIa by human platelet protein kinase C (PKC) resulted in levels of GPIIIa phosphorylation similar to that in platelets (0.05 mol of P/mol of GPIIIa). However, while GPIIIa in platelets was phosphorylated primarily on threonine, purified GPIIIa treated with PKC was phosphorylated primarily on serine. These results suggest that PKC may not directly phosphorylate GPIIIa in intact platelets. Ca2+/calmodulin-dependent kinase II phosphorylated purified GPIIIa to higher levels (0.5 mol of P/mol of GPIIIa) with phosphorylation on both threonine and serine. The limited phosphorylation of GPIIIa in intact platelets suggests that this event is unlikely to affect functions involving large populations of GPIIb-IIIa, such as its conversion to a fibrinogen receptor. However, these results may suggest the existence of a more readily phosphorylated subpopulation of GPIIb-IIIa with potentially distinct structural or functional properties.
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PMID:Phosphorylation of human platelet glycoprotein IIIa (GPIIIa). Dissociation from fibrinogen receptor activation and phosphorylation of GPIIIa in vitro. 165 Mar 65

Glycoprotein IIb (GPIIb) is a major glycoprotein of the human platelet plasma membrane, which together with glycoprotein IIIa (GPIIIa) forms a Ca2(+)-dependent heterodimer, GPIIb/IIIa, which serves as the major fibrinogen receptor in activated platelets. The precise localization of the epitopes for six anti-GPIIb monoclonal antibodies (M1-M6) has been determined by a combination of enzymic and chemical cleavage procedures, peptide isolation, N-terminal sequence analysis, peptide synthesis and enzyme immunoassay. The following localizations were found: M1, beta 1-16-36, beta 2-4-24; M2, alpha 747-755; M alpha 2, alpha 837-843; M3, alpha 849-857; M4, alpha 143-151; M5, alpha 550-558; M6, alpha 657-665. Besides considerations of the degree of exposure of these epitopes, several remarkable features are readily apparent. The earliest and main chymotryptic cleavage site of GPIIb in whole platelets is between alpha cysteine-545 and alpha phenylalanine-551. The epitope for M3 was located within the same sequence (alpha 842-857) as is the epitope for PMI-1 [Loftus, Plow, Frelinger, D'Souza, Dixon, Lacy, Sorge & Ginsberg (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 7114-7118] in spite of the fact that the exposure of the latter in whole platelets is EDTA-dependent whereas that in the former is not. The epitope for M5 shares full homology with the 540-548 peptide stretch of the alpha-subunit of the vitronectin receptor, and this antibody cross-reacts with endothelial cells. The M6 epitope is located in the 25 kDa membrane-bound fragment of GPIIb, which is most epitope is destroyed at an early stage of chymotrypic digestion. This suggests that this region of GPIIb, somewhere between the epitope for M5 (alpha 550-558) and the epitope for M2 (alpha 747-755), may carry the surface of interaction of GPIIb with GPIIIa in the GPIIb/IIIa heterodimer. Finally, the sequence where the epitope for M6 has been located (alpha 657-667) was the only one found to be hydropathically complementary to the gamma 402-411 peptide of fibrinogen within the amino acid sequence of both GPIIb and GPIIIa. This complementariness, the EDTA- or thrombin-dependence of the exposure of the alpha 657-665 stretch in whole platelets to M6 and the ability of this antibody to inhibit platelet aggregation led us to postulate that this peptide stretch is a putative binding site for fibrinogen in the platelet receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Further studies on the topography of human platelet glycoprotein IIb. Localization of monoclonal antibody epitopes and the putative glycoprotein IIa- and fibrinogen-binding regions. 170 15

Glycoprotein IIb-IIIa (alpha IIb beta 3) and the vitronectin receptor (alpha v beta 3), two integrins that share the common beta 3 subunit, have been reported to function as promiscuous receptors for the RGD-containing adhesive proteins fibrinogen, vitronectin, fibronectin, von Willebrand factor, and thrombospondin. The present study was designed to establish a cell system for the expression of either GP IIb-IIIa or the vitronectin receptor in an otherwise identical cellular environment and to compare the adhesive properties of these two integrins with those of native GP IIb-IIIa and the vitronectin receptor constitutively expressed in HEL cells or platelets. M21 human melanoma cells lack GP IIb-IIIa and use the vitronectin receptor to attach to vitronectin, fibrinogen, fibronectin, and von Willebrand factor. To study the functional properties of GP IIb-IIIa in these cells, we transfected GP IIb into M21-L cells, a variant of M21 cells (Cheresh, D.A., and R.C. Spiro. 1987. J. Biol. Chem. 262:17703-17711), which lack the expression of functional alpha v and are therefore unable to attach to vitronectin, fibrinogen, and von Willebrand factor. Transfectants expressing GP IIb were isolated by immunomagnetic beads and surface expression of the GP IIb-IIIa complex was documented by FACS analysis and immunoprecipitation experiments performed with 125I-labeled M21-L/GP IIb cells. Comparative functional studies demonstrated that GP IIb-IIIa expressed in M21-L/GPIIb cells as well as native GP IIb-IIIa constitutively expressed in HEL-5J20 cells (an HEL variant lacking alpha v beta 3) mediated cell attachment to immobilized fibrinogen, but not to vitronectin or von Willebrand factor, whereas the vitronectin receptor expressed in M21 cells and HEL-AD1 cells (an HEL variant expressing alpha v beta 3) mediated cell attachment to fibrinogen, vitronectin, and von Willebrand factor. Similarly, PGl2-treated resting platelets attached to immobilized fibrinogen but not to vitronectin or von Willebrand factor, and this attachment could be inhibited by mAb A2A9 (directed against a functional site on the GP IIb-IIIa complex). However, in contrast to platelets, which adhered to vitronectin and von Willebrand factor after stimulation by thrombin or PMA, activation of the protein kinase C pathway in M21-L/GP IIb or HEL cells did not induce cell adhesion to vitronectin or von Willebrand factor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Adhesive properties of the beta 3 integrins: comparison of GP IIb-IIIa and the vitronectin receptor individually expressed in human melanoma cells. 170 57

Platelets are blood cells that participate in the human primary hemostatic mechanism. Platelets need to be activated to perform all their functions and this activation can be initially produced after an endothelial injury that exposes subendothelial structures to the blood flow. Platelet adhesiveness can also occur by the intervention of high shear forces of the blood stream leading to the attachment of platelets to the subendothelium, forming a monolayer with platelet shape changes and pseudopod emission, that covers all the exposed subendothelial surface. Adhesiveness results from the participation of three components: Glycoprotein Ib, von Willebrand factor and collagen. Fibronectin and vitronectin can also participate in this process. Aggregation (platelet-platelet interaction) has as the final purpose to produce a platelet thrombi that constitutes the primary hemostatic plug. Aggregation involves a sequence of biochemical reactions that are initiated by the contact of an agonist agent (ADP, collagen, thrombin) with receptors on the platelet membrane, this is followed by the fibrinogen binding to Glycoprotein IIb/IIIa complex serving as a link with other surrounding platelets, the aggregation process is then amplified and becomes irreversible with the secretion of the platelet intragranular substances through the release reaction. These series of reactions have their own mechanisms of control that regulate or modulate platelet activation as the Ca2+/cAMP relationship, the balance between PGI2 and TxA2 and the enzymatic system of kinases and phosphatases. The relationship between platelets and other blood cells such as erythrocytes and leukocytes probably modulate the platelet aggregatory response during a vascular injury promoting mechanisms of thrombogenesis and wound healing. On the other hand, the multiple compounds released by the endothelial cell that inhibit platelet function, specially prostacyclin (PGI2) and recently the endothelial derived relaxing factor (EDRF) or nitric oxide have focused new understanding on the physiologic role of platelets in the control of hemostatic and thrombotic processes.
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PMID:[Platelet physiology. Advances in platelet reactivity. Review]. 805 81

A major component of thrombus formation is the activation of blood platelets and binding of soluble fibrinogen. Glycoprotein IIb-IIIa (GPIIb-IIIa) is the dominant receptor on platelets mediating this activity. This study describes how GPIIb-IIIa is differentially displayed on resting and activated human platelets and how this display is alternatively masked and enhanced by arginine-glycine-aspartic acid (RGD) containing or mimicking compounds. Results indicate that thrombin strongly increases GPIIb-IIIa display on platelet membrane surfaces while other platelet activators enhance GPIIb-IIIa display to lesser degrees. This upregulated display was masked by compounds RGDS, GPenGRGDSPCA and L-367,073. Conversely, membrane GPIIb-IIIa display was markedly enhanced on otherwise resting platelets by incubation with these same compounds. This study indicates that small ligands that bind to RGD recognition sites can modulate GPIIb-IIIa membrane surface display differentially, depending on the nature of their cellular targets.
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PMID:Ligand interactions with the RGD recognition site alter binding of GPIIb-IIIa reactive monoclonal antibody to human platelets. 837 15

Multiple clinical trials have been undertaken to understand better the events leading to unstable angina and non-Q wave myocardial infarction. Some of these studies focused on evaluating the role of antithrombotic therapy; others evaluated the role of more aggressive invasive treatment versus medical therapy. In the 1980s and 1990s, studies revealed that antithrombotic therapy with either acetylsalicyclic acid alone or heparin alone was more effective than placebo. The Thrombosis in Myocardial Infarction (TIMI) IIIB study attempted to compare medical therapy with early surgical intervention, reporting that early intervention did not result in any significant improvement in patient outcome over medical therapy. In the mid- to late 1990s, the thrombin hypothesis was introduced, suggesting that thrombin antagonists would arrest the coagulation and thrombotic cascade. The Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO) IIb study put the thrombin hypothesis to the test, and it found that there was no significant difference between hirudin and unfractionated heparin treatments after 30 days. Glycoprotein IIb/IIIa receptor antagonists were then researched in the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC), the c7E3 Fab Antiplatelet Therapy in Unstable Refractory angina (CAPTURE), the Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON) and the Platelet Receptor Inhibition of Ischemic Syndrome Management in Patients Limited to Unstable Angina Signs and Symptoms (PRISM-PLUS) studies, shifting the attention to the platelet. These studies gave contrasting results, bringing to the foreground the issues of optimal use of antithrombotic agents and proper timing of surgical intervention. Medical therapy for unstable angina and non-Q wave myocardial infarction was addressed in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) study, which compared a low molecular weight heparin, enoxaparin, with unfractionated heparin. A significant difference in outcomes was found in favour of enoxaparin.
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PMID:Approaches to the treatment of unstable angina and non-Q wave myocardial infarction. 977 27

The goals of therapy for unstable angina and non-Q-wave myocardial infarction (MI) are to maintain myocardial perfusion by inhibiting platelet aggregation and fibrin deposition at sites of plaque rupture, thereby preventing ongoing or new myocardial ischemia and cardiac death. Although aspirin and heparin sodium are cornerstones in the management of unstable angina and non-Q-wave MI, both have significant limitations that have prompted the development of new agents. The thienopyridines, ticlopidine hydrochloride and clopidogrel, appear to be at least as effective as aspirin in the management of unstable angina. Glycoprotein IIb/IIIa receptor antagonists are a new class of platelet inhibitors that are more potent than aspirin, because they target the final common pathway of platelet aggregation. Low-molecular-weight heparins provide a more stable pharmacodynamic response and are more convenient to use than unfractionated heparin. Direct thrombin inhibitors show promise for inhibiting thrombin-mediated platelet aggregation and fibrin deposition. We focus on the opportunities presented by these agents, detailing mechanisms of action, advantages over aspirin and heparin, and performance in recent clinical trials.
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PMID:Beyond heparin and aspirin: new treatments for unstable angina and non-Q-wave myocardial infarction. 1107 53

Prevention and management of acute coronary syndromes (ACS) are focal points of interest among health care providers. Acute coronary syndromes is an all-encompassing term that refers to unstable angina, non-Q wave myocardial infarction, and Q wave myocardial infarction. These syndromes are usually the result of atherosclerotic plaque rupture leading to thrombus formation in a coronary artery. Heparin and aspirin are traditional antithrombotic treatments. They typically are administered with antiischemic therapies and often with fibrinolytic agents for patients with ST segment elevation associated with acute myocardial infarction. Although aspirin and heparin are important, they have significant limitations that have prompted development of newer antithrombotic approaches. Adenosine diphosphate inhibitors have been evaluated as either alternatives or adjunctive treatment to aspirin. Glycoprotein IIb-IIIa receptor inhibitors, low-molecular-weight heparins, and direct thrombin inhibitors have been studied as concurrent therapy with, or as alternatives to, heparin.
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PMID:Clinical use of new antithrombotic therapies for medical management of acute coronary syndromes. 1125 56

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

In treating peripheral arterial disease, a profound knowledge of antiplatelet and anticoagulative drug therapy is helpful to assure a positive clinical outcome and to anticipate and avoid complications. Side effects and drug interactions may have fatal consequences for the patient, so interventionalists should be aware of these risks and able to control them. Aspirin remains the first-line agent for antiplatelet monotherapy, with clopidogrel added where dual antiplatelet therapy is required. In case of suspected antiplatelet drug resistance, the dose of clopidogrel may be doubled; prasugrel or ticagrelor may be used alternatively. Glycoprotein IIb/IIIa inhibitors (abciximab or eptifibatide) may help in cases of hypercoagulability or acute embolic complications. Desmopressin, tranexamic acid, or platelet infusions may be used to decrease antiplatelet drug effects in case of bleeding. Intraprocedurally, anticoagulant therapy treatment with unfractionated heparin (UFH) still is the means of choice, although low molecular-weight heparins (LMWH) are suitable, particularly for postinterventional treatment. Adaption of LMWH dose is often required in renal insufficiency, which is frequently found in elderly patients. Protamine sulphate is an effective antagonist for UFH; however, this effect is less for LMWH. Newer antithrombotic drugs, such as direct thrombin inhibitors or factor X inhibitors, have limited importance in periprocedural treatment, with the exception of treating patients with heparin-induced thrombocytopenia (HIT). Nevertheless, knowing pharmacologic properties of the newer drugs facilitate correct bridging of patients treated with such drugs. This article provides a comprehensive overview of antiplatelet and anticoagulant drugs for use before, during, and after interventional radiological procedures.
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PMID:Antiplatelet and anticoagulant drugs in interventional radiology. 2169 5


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