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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ticlopidine has become an established therapy in patients with stroke, and during stenting in patients with coronary artery disease. Clopidogrel, another thienopyridine, is a safe and promising alternative, that irreversibly inhibits ADP-induced platelet aggregation, and reduces formation of both arterial and venous thrombi. In a recent, large, well-controlled trial (CAPRIE), clopidogrel has been shown to be superior to aspirin in terms of prevention of ischaemic stroke, myocardial infarction and death in patients with atherosclerotic vascular disease. Clopidogrel provides a safe opportunity to enhance reperfusion when administered during stent placement, by protecting platelets from excessive activation. However, the ability of clopidogrel to be superior to ticlopidine in terms of its antiplatelet properties in the clinical setting of coronary stenting, is unknown. The effects of clopidogrel versus ticlopidine on platelet and endothelial function are yet to be determined and may strongly affect the outcome, benefits, and complications following coronary stent placement. Further clinical trials, well-designed, and carefully conducted, should elucidate possible benefits of clopidogrel during coronary interventions, especially in conjunction with new and aggressive reperfusion techniques. The benefits of clopidogrel in an expanding array of clinical conditions, including myocardial infarction, may be directly related to platelet inhibition. Moreover, marginal clinical benefits, and recently reported severe bleeding events in some patients after oral platelet glycoprotein IIb/IIIa therapy, may advance clopidogrel as a safe, and efficient alternative during coronary interventions. This review summarises the latest, and often confusing data on the effects of thienopyridines on certain haemostatic characteristics in interventional cardiology. 1999 Academic Press.
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PMID:Clopidogrel: the future choice for preventing platelet activation during coronary stenting? 1043 68

Naftidrofuryl (Praxilene; NAF) significantly improves claudication distance in patients with peripheral vascular disease (PVD). Endothelin-1 (ET-1) is a powerful endogenous vasoconstrictor and the circulating levels of ET-1 are elevated in patients with vascular disease. Platelet rich plasma (PRP) was prepared from healthy volunteers. NAF at concentrations similar to therapeutic levels (3.5-14 micromol/l), inhibited (P < 0.02) platelet activation (as indicated by a fall in median platelet volume, MPV) induced by ET-1 (0.4 micromol/l) alone. NAF also inhibited (P <0.0001) shape change (PSC; an early phase of platelet activation, characterised by an increase in MPV) induced by ET-1 (0.4 micromol/l) in combination with ADP (0.05-0.15 micromol/l) or serotonin (0.03-0.13 micromol/ l). We assessed the effect of ET(A) (BQ123, 50 nmol/l) or ET(B) (BQ788, 50 nmol/l) receptor antagonists on PSC induced by ET-1 alone. Both antagonists significantly inhibited PSC. We conclude that ET-1 activates human platelets. Both ET(A) and ET(B) receptors probably contribute to this response by a complex mechanism that requires further elucidation. NAF antagonises the action of ET-1 on human platelets. These actions may contribute to the beneficial effects of NAF in PVD.
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PMID:Effect of endothelin-1 on human platelet shape change: reversal of activation by naftidrofuryl. 1103 Apr 61

Insulin resistance is associated with an increased risk of atherothrombotic vascular disease, but the mechanisms are poorly understood. We determined how insulin in vivo regulates platelet activation in nonobese and obese subjects by using methods mimicking thrombus formation. Twelve nonobese (aged 42+/-2 years, body mass index 24.0+/-0.4 kg/m(2)) and 14 obese (aged 43+/-1 years, body mass index 37.2+/-1.5 kg/m(2)) subjects were studied under euglycemic hyperinsulinemic (3-hour insulin infusion of 1 mU. kg(-1). min(-1)) conditions. Before and at the end of hyperinsulinemia, the following were determined: (1) platelet-related early hemostasis (shear rate of approximately 4000 s(-1)) by platelet function analysis; (2) platelet deposition to collagen during whole-blood perfusion (shear rate of 1600 s(-1)); (3) aggregation responses to collagen, thrombin receptor-activating peptide, ADP, and epinephrine; and (4) platelet cGMP concentrations. Insulin action on glucose metabolism was 69% lower in the obese subjects (1.6+/-0.2 mg. kg(-1). min(-1)) than in the nonobese subjects (5.4+/-0.4 mg. kg(-1). min(-1), P<0.0001). The in vivo insulin infusion inhibited platelet deposition to collagen from 4.3+/-0.6x10(6) to 3.5+/-0.4x10(6) per square centimeter in the nonobese subjects (P<0.05) but failed to do so in the obese subjects (5.2+/-0.8x10(6) versus 5.5+/-0.7x10(6) per square centimeter, P=NS; P<0.01 versus nonobese subjects). Epinephrine- and ADP-primed closure times by platelet function analysis were prolonged by insulin in the nonobese but not the obese subjects (P<0.05 for between-group difference). In the nonobese subjects, insulin decreased aggregation to all agonists and significantly increased platelet cGMP concentrations (2.5+/-0.3 versus 3.2+/-0.5 pmol/10(9) for before versus after insulin, respectively; P<0.01). In the obese subjects, insulin did not alter collagen-induced aggregation or cGMP concentrations (1.9+/-0.2 versus 1.8+/-0.1 pmol/10(9) for before versus the end of in vivo hyperinsulinemia, respectively; P=NS). These data demonstrate that normal in vivo insulin action inhibits platelet interaction with collagen under conditions mimicking thrombus formation and reduces aggregation to several agonists. These platelet-inhibitory actions of insulin are blunted or absent in obese subjects and could provide 1 mechanism linking insulin resistance to atherothrombotic disease.
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PMID:Inhibition of platelet-collagen interaction: an in vivo action of insulin abolished by insulin resistance in obesity. 1178 78

Acetylsalicylic acid inhibits thromboxane A2 production and reduces the risk of vascular occlusive events by 20% to 25%. Ticlopidine inhibits ADP-dependent platelet aggregation and reduces the same risk by 30% to 35%, but produces some adverse effects. Clopidogrel is a ticlopidin-related antiplatelet drug, with the same mechanism of action; it reduces the expression of the glycoprotein IIb/IIIa, the fibrinogen receptor on the platelet surface. Clopidogrel has the same clinical efficacy of ticlopidin and has a decreased incidence of adverse effects. The effect of one daily dose of 75 mg of clopidogrel on platelet function in 90 subjects was evaluated; 41 with coronary artery disease and 49 with cerebral vascular disease. Before treatment and after 6 and 12 weeks, bleeding time and fibrinogen plasma concentration were also evaluated. There was a reduction in 5-microM ADP-induced platelet aggregation of 38%+/-27% at 6 weeks and 44%+/-29% at 12 weeks in patients with coronary artery disease; 35%+/-41%, 29%+/-59% in the cerebral vascular disease group; and 36%+/-36% and 35%+/-49% in the total group. Reduction of 20 microg/mL collagen-induced platelet aggregation was not significant in any group. Plasma fibrinogen levels did not vary during treatment. Bleeding time was significantly prolonged in all studied groups. There were no hemorrhagic complications; only digestive discomfort in less than 3% of patients. Clopidogrel efficiently reduces ADP-induced platelet aggregation and prolongs bleeding time and is a safe and efficacious antiplatelet drug.
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PMID:Effect of clopidogrel on platelet aggregation and plasma concentration of fibrinogen in subjects with cerebral or coronary atherosclerotic disease. 1251 89

We report a case of a 76-year-old-man who developed spontaneous hemarthrosis of his right knee following clopidogrel-aspirin treatment. Clopidogrel is an ADP receptor antagonist and in combination with aspirin widely used in patients with atherosclerotic vascular disease to reduce the incidence of ischemic events. To date, no case of spontaneous hemarthrosis following clopidogrel-aspirin therapy has been reported. Prompt aspiration after discontinuing the ADP receptor antagonist-aspirin combination therapy can assist early diagnosis and may prevent further damage to the joint. In conclusion, spontaneous hemarthrosis is a possible complication following clopidogrel-aspirin therapy and is recommended to be evaluated when appropriate clinical symptoms (e.g., intraarticular effusion) present.
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PMID:Spontaneous hemarthrosis of the knee associated with clopidogrel and aspirin treatment. 1262 8

Platelets play a key role in the development of ischemic complications in the arterial circulation. Antiplatelet therapy has proven effective in the treatment and prevention of ischemic events. Numerous clinical studies have confirmed the therapeutic efficacy of aspirin to such a point that this antiplatelet agent has become the gold standard in clinical practice. Clopidogrel is a thienopyridine compound that inhibits platelet aggregation by selectively binding to adenylate cyclase-coupled ADP receptors. Results of a large, double-blind, randomized study (CAPRIE) confirm that administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction or vascular death. The present article highlights the importance of activation of platelets through ADP receptors and reviews the pharmacology and clinical studies of clopidogrel, a selective inhibitor of these mechanisms.
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PMID:Clopidogrel: a selective inhibitor of platelet ADP receptors. 1287 16

Antiplatelet therapy has been the focus of extensive clinical investigations over the last two decades. A variety of agents and regimens have been advanced for the prevention and treatment of vascular disease. Despite the proven life-saving clinical benefits of inhibiting platelets, this therapy is associated with an increased risk of bleeding. The objective of this study was to determine the risk of hemorrhage in the major classes of antiplatelet agents. Data from clinical trials published 1988-2002 in English were retrieved from MEDLINE, OVID, and CARDIOSOURCE. Only those studies in which patients had clinical follow-up for at least 1 month and in which a full description of hemorrhagic complications was reported were included. Information on sample size, study design, duration, agent, patient characteristics, and bleeding severity was independently and blindly reviewed. Data from 51 clinical trials with a total of 338,191 patients were analyzed. The antiplatelet agents were divided into 6 groups: aspirin (ASA) < 100 mg; ASA > or = 100 mg; dipyridamole, thienopyridines; intravenous and oral GP IIb/IIIa inhibitors. The variance estimate and confidence intervals were calculated for each treatment assignment. Low-dose aspirin and dipyridamole therapy were associated with the lowest risk of bleeding (3.6% and 6.7%, respectively). The highest rate of bleeding complications (44.6%) was associated with the GP IIa/IIIb inhibitors. Despite substantial differences in the reporting patterns of bleeding complications, low-dose ASA and dipyridamole therapy were associated with the lowest risk. Surprisingly, doses of ASA >/= 100 mg caused a relatively high hemorrhagic event rate, which was comparable to that of ADP-receptor blockers. These findings should be considered when using combination antiplatelet and/or anticoagulant therapy with conventional doses of ASA.
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PMID:Risk of bleeding complications with antiplatelet agents: meta-analysis of 338,191 patients enrolled in 50 randomized controlled trials. 1469 31

Aspirin (acetylsalicylic acid) reduces the odds of serious atherothrombotic vascular events and death in a broad category of high risk patients by about one-quarter. The mechanism is believed to be inhibition of thromboxane biosynthesis by inactivation of platelet cyclo-oxygenase-1 enzyme. However, aspirin is not that effective; it still fails to prevent the majority of serious vascular events. Mechanisms that may account for the failure of aspirin to prevent vascular events include non-atherothrombotic causes of vascular disease, non-adherence to aspirin therapy, an inadequate dosage, alternative "upstream" pathways of platelet activation (e.g. via stimulation of the ADP, collagen or thrombin receptors on platelets), aspirin-insensitive thromboxane biosynthesis (e.g. via monocyte cyclo-oxygenase-2), or drugs that interfere with the antiplatelet effects of aspirin. Genetic or acquired factors may further modify the inhibitory effects of aspirin on platelets (e.g. polymorphisms involving platelet-associated proteins, increased platelet turnover states). Identification and treatment of the potential causes of aspirin failure could prevent at least another 20% of serious vascular events (i.e. over and above those that are currently prevented by aspirin). There is currently no role for routine laboratory testing to measure the antiplatelet effects of aspirin. Clinicians should ensure that patients at high risk of atherothrombosis (>3% risk over 5 years) are compliant with aspirin therapy and are taking the correct dosage (75-150 mg/day). Patients who cannot tolerate aspirin, are allergic to aspirin, or have experienced recurrent serious atherothrombotic events whilst taking aspirin, should be treated with clopidogrel, and patients with acute coronary syndromes benefit from the combination of clopidogrel plus aspirin. Future research is required to standardize and validate laboratory testing of the antiplatelet effects of aspirin and to identify treatments that can both improve these laboratory measures and reduce the risk of future atherothrombotic events.
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PMID:Failure of aspirin to prevent atherothrombosis: potential mechanisms and implications for clinical practice. 1496 66

Valsartan selectively blocks angiotensin II binding to the AT1 receptor. ince platelet activation plays a key role in the pathogenesis of vascular disease, and because AT1 receptors are present on the platelet surface, we assessed the in vitro effects of valsartan and its metabolite, valeryl 4-hydroxy valsartan (V4HV), on platelets in 30 subjects with multiple risk factors for cardiovascular disease. Platelet characteristics in blood samples pretreated and incubated with 10 nmol to 100 micromol concentrations of valsartan and V4HV were assessed by aggregometry, rapid platelet analyzers, and by flow cytometry. Pretreatment of blood with valsartan and V4HV resulted in inhibition of conventional plasma (ADP, P = 0.0001, valsartan; epinephrine, P = 0.0001, V4HV) and whole blood collagen-induced (P = 0.01, valsartan; P =.0001, V4HV) platelet aggregation. Closure time was delayed (P = 0.02, valsartan; P = 0.03, 4VHV), indicating platelet inhibition in whole blood under high shear conditions. Expression of many surface platelet receptors, namely GP IIb/IIIa antigen, and activity, vitronectin, p-selectin, and LAMP-1 was significantly reduced compared with autologous baseline activity. Intensity of platelet-leukocyte formation and other platelet activation markers remained unchanged. Platelet inhibition was not dose dependent and was more potent for 4VHV than valsartan in the therapeutic range.Valsartan and 4VHV exhibited significant in vitro inhibition of human platelets. Their antiplatelet properties, especially more potent activity of the metabolite appear to be independent of those of other antiplatelet agents. Whether valsartan reduces vascular ischemic events via additional pathways of platelet inhibition in patients with myocardial infarction and ischemic stroke requires further clinical research.
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PMID:Effects of valsartan and valeryl 4-hydroxy valsartan on human platelets: a possible additional mechanism for clinical benefits. 1507 55

Lipoxygenases (LOX) contribute to vascular disease and inflammation through generation of bioactive lipids, including 12-hydro(pero)xyeicosatetraenoic acid (12-H(P)ETE). The physiological mechanisms that acutely control LOX product generation in mammalian cells are uncharacterized. Human platelets that contain a 12-LOX isoform (p12-LOX) were used to define pathways that activate H(P)ETE synthesis in the vasculature. Collagen and collagen-related peptide (CRP) (1 to 10 microg/mL) acutely induced platelet 12-H(P)ETE synthesis. This implicated the collagen receptor glycoprotein VI (GPVI), which signals via the immunoreceptor-based activatory motif (ITAM)-containing FcRgamma chain. Conversely, thrombin only activated at high concentrations (> 0.2 U/mL), whereas U46619 and ADP alone were ineffective. Collagen or CRP-stimulated 12-H(P)ETE generation was inhibited by staurosporine, PP2, wortmannin, BAPTA/AM, EGTA, and L-655238, implicating src-tyrosine kinases, PI3-kinase, Ca2+ mobilization, and p12-LOX translocation. In contrast, protein kinase C (PKC) inhibition potentiated 12-H(P)ETE generation. Finally, activation of the immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing platelet endothelial cell adhesion molecule (PECAM-1) inhibited p12-LOX product generation. This study characterizes a receptor-dependent pathway for 12-H(P)ETE synthesis via the collagen receptor GPVI, which is negatively regulated by PECAM-1 and PKC, and demonstrates a novel link between immune receptor signaling and lipid mediator generation in the vasculature.
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PMID:Platelet 12-lipoxygenase activation via glycoprotein VI: involvement of multiple signaling pathways in agonist control of H(P)ETE synthesis. 1521 16


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