Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet aggregates, stabilized by fibrin, rapidly form hemostatic plugs when blood vessels are severed or arterial thrombi at sites of vessel injury, such as ruptured atherosclerotic plaques, or regions where blood flow is disturbed, such as at stenoses. These thrombi cause the thromboembolic complications of atherosclerosis: heart attacks, strokes, and peripheral vascular disease. Platelet adhesion to subendothelial components such as collagen activates signalling pathways that lead to thromboxane A2 formation and secretion of platelet granule contents, including ADP. Both these substances cause platelet aggregation, a process in which the integrin, glycoprotein IIb/IIIa, becomes a receptor for fibrinogen, which forms bridges between adjacent platelets. On the surface of stimulated platelets, coagulation is accelerated and thrombin is generated; it is a potent inducer of platelet aggregation and secretion and also causes fibrin to form around the aggregates, stabilizing them. There are receptors on the platelet surface for thrombin, thromboxane A2, collagen, ADP, platelet-activating factor, fibrinogen, von Willebrand factor, and other ligands. Agents that inhibit platelet aggregation and the signalling pathways that are activated by the various aggregating agents are under intensive investigation in many laboratories.
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PMID:Role of platelets in thrombosis and hemostasis. 806 74

The binding of fibrinogen to its receptor on mammalian platelets and avian thrombocytes has been extensively studied; and the receptors, composed of glycoproteins IIb and IIIa, have been characterized in both systems. Recently, monocytes have been implicated in the thrombotic complications of atherosclerosis, and in both the avian and human systems this appears to be through a procoagulant activity which leads to fibrinogen polymerization. Although fibrin polymerization by avian monocytes has been reported, the receptor for fibrinogen on these cells has not been reported previously. The present study describes the presence of glycoprotein IIb- and IIIa-like proteins in avian macrophages and correlates the localization of these glycoproteins with regions to which fibrinogen binds. Through the use of immunofluorescence light microscopy and immunogold electron microscopy in conjunction with monospecific, polyclonal antibodies, GPIIb and GPIIIa cross-reacting antigens were identified on membranes of monocyte/macrophages cultured from White Carneau pigeons. A specific concentration of the antigens was found on membrane ruffles and microvilli, sites to which FITC-labeled fibrinogen also bound. Interaction of the antibodies with pigeon macrophages was confirmed by enzyme-linked immunosorbent assays with cultured cells. Immunoblotting of membranes isolated from pigeon monocyte/macrophages identified a protein of 132,000 M(r) that was recognized by anti-GPIIb and a protein of 114,000 M(r) that was recognized by anti-GPIIIa. These pigeon monocyte glycoproteins comigrated with glycoproteins IIb and IIIa isolated from human platelets.
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PMID:Glycoprotein IIb/IIIa cross-reacting antigen in monocyte-derived macrophages from the pigeon. 822 17

Platelets contain a vast number of biologically active molecules within cytoplasmic granules which are classified according to their respective distinct ultrastructures, densities and content. The alpha-granule is a unique secretory organelle in that it exhibits further compartmentalization and acquires its protein content via two distinct mechanisms: (1) biosynthesis predominantly at the megakaryocyte (MK) level (with some vestigial platelet synthesis) (e.g. platelet factor 4) and (2) endocytosis and pinocytosis at both the MK and circulating platelet levels (e.g. fibrinogen (Fg) and IgG). The currently known list of alpha-granular proteins continues to enlarge and includes many adhesive proteins (e.g. Fg, von Willebrand factor (vWf) and thrombospodin (TSP)), plasma proteins (e.g. IgG and albumin), cellular mitogens (e.g. platelet derived growth factor and TGF beta), coagulation factors (e.g. factor V) and protease inhibitors (e.g. alpha 2-macroglobulin and alpha 2-antiplasmin). More recently the inner lining of the alpha-granule unit membrane has been demonstrated to contain a number of physiologically important receptors including glycoprotein IIb/IIIa (alpha IIb beta 3) and P-selectin. The alpha-granules originate from small precursor granules which can be observed budding from the trans-Golgi network within the platelet precursor cell the MK. During MK maturation the alpha-granules become very prominent and are ultimately packaged into platelets during thrombopoiesis. The alpha-granular contents are destined for release during platelet activation at sites of vessel wall injury and thus play an important role in haemostasis, inflammation, ultimate wound repair and in the pathogenesis of atherosclerosis.
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PMID:Platelet alpha-granules. 846 33

In the primary prevention of arterial disease, there may be a role for anti-oxidant vitamins and for oestrogen replacement therapy in postmenopausal women. For the secondary prevention of thrombotic complications of atherosclerosis, aspirin has proven efficacious in reducing both mortality and morbidity. Patients with ischaemic heart disease and moderately elevated serum cholesterol benefit from simvastatin administration. Heparin and oral anticoagulants are the mainstay in the primary and secondary prevention of venous thrombosis. More potent antithrombotic compounds, the direct thrombin inhibitors and the glycoprotein IIb-IIIa antagonists, are mainly being evaluated in emergency coronary medicine. Preliminary results are encouraging but haemorrhagic problems need to be solved. The trend toward a decrease in late restenosis following coronary angioplasty using a IIb-IIIa antagonizing Fab fragment may prove to be a major therapeutic breakthrough.
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PMID:Clinical trials of primary and secondary prevention of thrombosis and restenosis. 857 89

The inhibitors of platelet membrane integrin receptor glycoprotein IIb/IIIa occupy the receptor, preventing fibrinogen binding and platelet aggregation. The inhibition is direct and may be advantageous over the partial inhibition induced by agents interfering at individual pathways to platelet aggregation. The inhibitors, and more specifically abciximab, the monoclonal antibody against the receptor, are effective to prevent the acute complications associated with percutaneous intervention procedures. Based on the positive results of these trials, which have enrolled a large proportion of patients with unstable angina, and on a few pilot studies in unstable angina, large trials have been completed and are ongoing in patients with an acute coronary syndrome. It is hoped that these drugs will prevent the acute complications associated with thrombus formation, and also, past the acute phase, prevent the recurrence of the disease and rapid progression of atherosclerosis.
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PMID:Glycoprotein IIb/IIIa inhibitors in unstable angina. 935 71

Platelet glycoprotein IIb/IIIa may be involved in the pathogenesis of myocardial infarction as the key element in platelet aggregation and as the binding site of lipoprotein(a) to platelets, inhibiting plasminogen binding and activation. Recently, a strong association between the P1A2 polymorphism of the glycoprotein IIIa gene and acute coronary thrombosis has been reported. although this has not been confirmed. In an associated study, we determined plasma lipoprotein levels, the apo E genotype and the P1A genotype in 250 males under 55 years with myocardial infarction and they were compared with 250 age- and sex-matched controls. Patients showed an over-representation of the epsilon3/4 genotype with respect to the control group. We found that there were no differences in the allelic frequency of P1A2 between case patients and age-matched controls (chi2 = 0.05, P = 0.92) and that subjects bearing the P1A2 allele showed higher plasma lipoprotein(a) concentration than p1A1/P1A1 individuals. Therefore, in this population there is no association between carriage of p1A2 allele and increased risk of myocardial infarction but the carriage of P1A2 is associated with higher plasma Lp(a) concentration.
Atherosclerosis 1998 Sep
PMID:Lipoprotein(a) and the significance of the association between platelet glycoprotein IIIa polymorphisms and the risk of premature myocardial infarction. 1057 85

The role of the platelet and the endothelium in the pathogenesis of atherosclerosis and subsequent ischemic events has been the subject of extensive investigation. Arterial sites where endothelial function is severely impaired are often the sites of atheroma development. Lesion evolution impairs endothelial function, leading to a self-perpetuating cycle of growth. During early lesion development, overt thrombotic events are rare. However, rupture of an advanced, necrotic plaque or intimal ulceration triggers arterial thrombosis, at which point the importance of platelet function may be seen clearly. The Antiplatelet Trialists' Collaboration meta-analysis demonstrated the benefit of antiplatelet therapy to patients with atherosclerotic disease. Aspirin is the most widely studied agent and is considered the standard of antiplatelet therapy. Newer agents that intervene at different stages of the platelet activation pathway have been developed. Clopidogrel, a new adenosine diphosphate receptor antagonist, is more effective than aspirin in reducing vascular events in patients with prior myocardial infarction, stroke, or established peripheral arterial disease. The glycoprotein IIb-IIIa antagonists such as abciximab have proven effective in the setting of active arterial thrombosis and percutaneous revascularization, but their value in secondary prevention remains unknown. All patients with atherosclerosis should be treated with an antiplatelet drug. Current evidence suggests that either aspirin or clopidogrel are appropriate first-line agents. There is urgent need for an analysis of the risk/benefit ratio in various populations and clinical settings to determine the most appropriate type and intensity of therapy for a given patient.
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PMID:Platelet-endothelial interactions in atherothrombotic disease: therapeutic implications. 1055 82

The diagnosis coronary artery disease is classically based on patient's symptoms and morphology, as analyzed by angiography. The importance of risk factors for the development of coronary atherosclerosis and disturbance of coronary vasomotion is clearly established. However, microembolization of the coronary circulation has also to be taken into account. Microembolization may occur as a single or as multiple, repetitive events, and it may induce inflammatory responses. Spontaneous microembolization may occur, when the fibrous cap of an atheroma or fibroatheroma (Stary i.v. and Va) ruptures and the lipid pool with or without additional thrombus formation is washed out of the atheroma into the microcirculation. Such events with progressive thrombus formation are known as cyclic flow variations. Plaque rupture occurs more frequently than previously assumed, i.e. in 9% of patients without known heart disease suffering a traffic accident and in 22% of patients with hypertension and diabetes. Also, in patients dying from sudden death microembolization is frequently found. Patients with stable and unstable angina show not only signs of coronary plaque rupture and thrombus formation, but also microemboli and microinfarcts, the only difference between those with stable and unstable angina being the number of events. Appreciation of microembolization may help to better understand the pathogenesis of ischemic cardiomyopathy, diabetic cardiomyopathy and acute coronary syndromes, in particular in patients with normal coronary angiograms, but plaque rupture detected by intravascular ultrasound. Also, the benefit from glycoprotein IIb/IIIa receptor antagonist is better understood, when not only the prevention of thrombus formation in the epicardial atherosclerotic plaque, but also that of microemboli is taken into account. Microembolization also occurs during PTCA, inducing elevations of troponin T and I and elevations of the ST segment in the EKG. Elevated baseline coronary blood flow velocity, as a potential consequence of reactive hyperemia in myocardium surrounding areas of microembolization, is more frequent in patients with high frequency rotablation than in patients with stenting and in patients with PTCA. The hypothesis of iafrogenic microembolization during coronary interventions is now supported by the use of aspiration and filtration devices, where particles with a size of up to 700 microns have been retrieved. In the experiment, microembolization is characterized by perfusion-contraction mismatch, as the proportionate reduction of flow and function seen with an epicardial stenosis is lost and replaced by contractile dysfunction in the absence of reduced flow. The analysis of the coronary microcirculation, in addition to that of the morphology and function of epicardial coronary arteries, and in particular appreciation of the concept of microembolization will further improve the understanding of the pathophysiology and clinical symptoms of coronary artery disease.
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PMID:Coronary microembolization--its role in acute coronary syndromes and interventions. 1060 63

Modern diagnostic modalities as well as ongoing improvement of vascular prosthetic material and surgical techniques have stimulated progress in vascular surgery. New discoveries concerning the mechanism of endothelial function, atherosclerosis, developments in gene therapy and endovascular techniques will expand the future therapeutic spectrum of vascular surgery. Endoluminal implantation of stent grafts for the treatment of aortic aneurysm may be a reasonable alternative to conventional surgery, especially in high-risk patients. Long-term results of this procedure, however, are not yet available. Stenting of internal carotid artery stenosis may be considered as an experimental method of treatment. Its feasibility, efficacy, safety and long-term results must be analyzed before the application of the method may be restricted or recommended. Endoluminal irradiation (brachytherapy) reduces intimal hyperplasia/restenosis and can improve the long-term results of percutaneous transluminal angioplasty. Anti-atherosclerotic and anti-aggregatory therapy (with statins, estrogens, antibiotics, nitric oxide precursor/donors, glycoprotein IIb/IIIa receptor inhibitors) will play an important role in the prevention of ischemic diseases and improve the results of surgical/interventional treatment by reducing intimal hyperplasia and restenosis. Gene therapy opens new vistas in vascular medicine. Angiogenetic factors can be used for the treatment of patients with distal occlusion of the peripheral arteries. Gene transfer may be useful in the conservative treatment of progressive aortic aneurysms. A more unified vision toward vascular medicine might be the key for research and development in the future.
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PMID:Vascular surgery between the millenniums. 1073 84

Thrombin plays a central role in thrombogenesis: it activates platelets, converts fibrinogen to fibrin, and activates factor XIII, which then crosslinks and stabilizes the fibrin clot. In addition, thrombin amplifies coagulation by activating factors VIII and V, key cofactors in the generation of activated factor X and thrombin, respectively. Even platelet function is influenced by thrombin. Hence, thrombin generation is most important both in the chronic progression of coronary atherosclerotic disease and in its conversion to acute events. To date, various therapeutic approaches capitalize on this knowledge by targeting specific thrombin-related pathways. Among the successful and carefully documented pharmacologic strategies in acute or chronic coronary heart disease are the use of unfractioned heparin, low-molecular-weight heparin, thrombolysis, hirudin, and/or inhibition of thrombin generation by glycoprotein IIb/IIIa antagonists, most often utilized on top of antiplatelet therapy (e.g., with acetylsalicylic acid) and/or vitamin K antagonism. The present review provides insights into the pathophysiology of thrombin generation in coronary atherosclerosis and gives an overview over the above mentioned therapeutic thrombin modifications.
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PMID:Pathophysiology and therapeutic modification of thrombin generation in patients with coronary artery disease. 1094 Mar 51


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