Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adhesion of both leukocytes and platelets to microvascular endothelial cells has been implicated in the pathogenesis of ischemia/reperfusion (I/R) injury in several vascular beds. The objectives of this study were to (1) assess the platelet-leukocyte-endothelial cell interactions induced in the cerebral microvasculature by middle cerebral artery occlusion (MCAO)/reperfusion, and (2) define the molecular determinants of the prothrombogenic and inflammatory responses in this model of focal I/R. MCAO was induced for 1 hour in wild-type (WT) mice, WT mice treated with a monoclonal antibody (mAb) to either P-selectin or GPIIb/IIIa, and in P-selectin-/-(P-sel-/-) chimeras. Isolated platelets labeled with carboxyfluorescein diacetate succinimidyl ester (CFDASE) were administered intravenously and observed with intravital fluorescence microscopy. Leukocytes were observed after intravenous injection of rhodamine 6G. One hour of MCAO followed by 1 hour of reperfusion resulted in the rolling and adhesion of leukocytes in venules, and after 4 hours of reperfusion, the adhesion of both leukocytes and platelets was detected. Although both the P-selectin and GPIIb/IIIa mAbs significantly reduced the adhesion of leukocytes and platelets at 4 hours of reperfusion, the antiadhesive effects of the P-selectin mAb were much greater. The leukocyte and platelet adhesion responses were significantly attenuated in both P-sel-/- --> WT and WT --> P-sel-/- bone marrow chimeras, compared with WT --> WT chimeras. Neutropenia, induced by antineutrophil serum treatment, also reduced the recruitment of leukocytes and platelets after cerebral I/R. These findings implicate a major role for both platelet-associated and endothelial cell-associated P-selectin, as well as neutrophils in the inflammatory and prothrombogenic responses in the microcirculation after focal cerebral I/R.
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PMID:Platelet-leukocyte-endothelial cell interactions after middle cerebral artery occlusion and reperfusion. 1536 21

Suppression of platelet activation improves the efficacy of thrombolytic therapy for stroke. Thus, combination treatment with recombinant tissue plasminogen activator (r-tPA) and 7E3 F(ab')2, a GPIIb/IIIa inhibitor that binds the platelet to fibrin, may improve the efficacy of thrombolytic therapy in embolic stroke. Magnetic resonance imaging (MRI) was used to monitor treatment response in rats subjected to embolic middle cerebral artery (MCA) occlusion (MCAo). Animals were randomized into treated (n=12) and control (n=10) groups and received intravenous combination therapy or saline, respectively, 4 hours after MCAo. Magnetic resonance imaging (MRI) measurements performed 1 hour after MCAo showed no difference between groups. However, an increased incidence (50%) of MCA recanalization was found in the treated group at 24 hours compared with 20% in the control group. The area of low cerebral blood flow at 24 and 48 hours was significantly smaller in the combination treatment group, and the lesion size, as indicated from the T2 and T1 maps, differed significantly between groups. Fluorescence microscopy measurements of cerebral microvessels perfused with fluorescein isothiocyanate-dextran and measurements of infarct volume revealed that the combination treatment significantly increased microvascular patency and reduced infarct volume, respectively, compared with the control rats. The efficacy of combination treatment 4 hours after ischemia is reflected by MRI indices of tissue perfusion, MCA recanalization, and reduction of lesion volume. The treatment also reduced secondary microvascular perfusion deficits.
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PMID:Analysis of combined treatment of embolic stroke in rat with r-tPA and a GPIIb/IIIa inhibitor. 1567 15

Current options for reperfusion therapy in patients admitted to a community hospital without cardiac catheterization facilities include administration of fibrinolytic drugs followed by observation, with referral to angiography driven by symptoms and signs of ischemia; transfer to a tertiary care center for primary percutaneous coronary intervention (PCI); or a strategy of facilitated PCI in which administration of fibrinolytics and platelet glycoprotein IIb/IIIa inhibitors (alone or in combination) is followed by transfer for immediate angiography and PCI if appropriate. We systematically analyzed multiple randomized and nonrandomized trials to review the pathophysiology of reperfusion therapy in acute myocardial infarction to derive insights about the likelihood of success of a strategy of facilitated PCI compared with transfer only or fibrinolysis only. The basis for the recommendations made herein is a hypothetical curve relating the duration of symptoms before reperfusion to reduction in mortality and extent of myocardial salvage. During the first 2 to 3 hours after symptom onset, a striking benefit of reperfusion is present; within this period, time to treatment is critical. Subsequently, a mortality benefit is still present but of decreasing magnitude over time. In this situation, the priority is to open the artery, and time to treatment is less critical. Results of facilitated PCI may depend largely on timing of presentation. If presentation is late after symptom onset (ie, on the "flat" part of the curve), there will be little mortality benefit from earlier patency and patients will be subject to the bleeding risks of fibrinolytic drugs. In contrast, among patients presenting very early (60-90 minutes after symptom onset), outcomes with fibrinolytic therapy alone are excellent, and it will be difficult for any other strategy to result in a significant improvement. But in patients presenting 2 to 3 hours after onset of symptoms, a strategy of facilitated PCI may move patients from the plateau to the descending limb of the curve, with a substantial improvement in myocardial salvage and mortality. Two large ongoing trials may provide definitive answers to these issues.
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PMID:Pharmacological facilitation of primary percutaneous coronary intervention for acute myocardial infarction: is the slope of the curve the shape of the future? 1572 69

Ischemic stroke and reperfusion (ISR) is associated with an inflammatory response characterized, in part, by the formation of leukocyte-platelet aggregates (LPA). Aggregate formation may amplify the immunologic and hemostatic functions of both cell types and thus exacerbate reperfusion injury after ischemic stroke. LPA formation in peripheral blood may also serve as a biomarker of the severity of injury. However, it is not fully known whether ISR causes LPA formation that can be detected in the peripheral blood. Therefore, the purpose of this study was to measure LPA in the peripheral blood after ISR using a rat model. The filament method was used to perform ISR. Blood was collected from the jugular vein before ischemia, after 4 hours of ischemia, and after 1 hour of reperfusion. Flow cytometry was used to quantify LPA in peripheral blood. Separate ISR groups were treated with tirofiban, a platelet GPIIb/IIIa inhibitor, and fucoidan, a selectin adhesion molecule inhibitor, and analyzed for LPA. Leukocyte CD11b expression and reactive oxygen species production were also analyzed to note the role of polymorphonuclear neutrophilic (PMN) activation on LPA formation. After ISR, LPA levels in peripheral blood were twice as large as preischemic levels. Both GPIIb/IIIa and selectin adhesion molecule inhibition (p < .05) decreased LPA to preischemic values. PMN CD11b expression was increased above baseline but did not differ between groups. Reactive oxygen species production did not differ between groups during reperfusion. These data suggest that ischemic stroke and reperfusion results in an increase in LPA that can be consistently measured in peripheral blood. LPA formation may be a useful biomarker and potential therapeutic target after ischemic stroke and reperfusion.
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PMID:Leukocyte-platelet aggregates in rat peripheral blood after ischemic stroke and reperfusion. 1578 37

Inflammation and platelet activation are critical phenomena in the setting of acute coronary syndromes. Platelets may contribute to increase ischemic injury by enhancing the inflammatory response of leukocytes and endothelial myocardial cells. Pharmacological inhibition of platelet activation prevents ischemic complications in patients with coronary diseases. Agents directed against the integrin glycoprotein IIb/IIIa (GP IIb/IIIa) receptor not only inhibit platelet aggregation but also have been demonstrated to limit the inflammatory response in acute coronary syndromes. The question then raised is if the inhibition of platelet activation by other mechanisms than the blockade of GP IIb/IIIa may also exert anti-inflammatory effects. The aim of the present study was to analyze if clopidogrel may exert anti-inflammatory effects during the acute phase of myocardial infarction. A ligature was placed around the left anterior descending coronary artery of New Zealand White rabbits. After 15 min of ischemia, the myocardium was reperfused and the ischemic coronary artery was isolated 24 h after the ischemia. A group of ischemic rabbits was given a single oral dose of clopidogrel (20 mg kg(-1)) just after the arterial occlusion and the animal was recovered. Sham-operated animals served as control. P-selectin expression was significantly increased in infarcted rabbits with respect to control rabbits. Clopidogrel administration reduced P-selectin expression with respect to untreated infarcted rabbits. CD40 ligand and tissue factor expression was increased in the ischemic coronary artery and reduced after clopidogrel administration. Clopidogrel also protected endothelial nitric oxide synthase protein expression in the ischemic coronary artery, a protein that has been found downregulated under inflammatory conditions. In conclusion, inhibition of platelet activation by clopidogrel exerted anti-inflammatory effects on the ischemic coronary artery.
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PMID:Effect of clopidogrel on the expression of inflammatory markers in rabbit ischemic coronary artery. 1604 1

As a result of vascular injury, activated platelets will rapidly interact with circulating platelets, via membrane glycoprotein complex alphaIIbbeta3 (GPIIb-IIIa) and fibrinogen, to form a thrombus or a plug preventing fatal bleeding. In addition, platelets interacting with ruptured atherosclerotic plaques or with the surface of diseased vessels can aggregate and induce ischemia that prevents blood flow. However, increasing evidence has also shown that circulating platelets interact with leukocytes and endothelial cells, via specific adhesion molecules, in inflammation, vascular remodelling and thrombosis. The aim of this chapter is to present the importance of cell-cell interactions involving platelets and leukocytes in events related to inflammation, coagulation, vascular remodelling and thrombosis. A key adhesion molecule implicated in platelet interaction with leukocytes is P-selectin, also known as CD62P. It is present on activated platelets and endothelial cells, and its counterpart on leukocytes is known as P-selectin glycoprotein ligand-1 (PSGL-1). A critical co-factor leading to leukocyte activation in platelet-monocyte aggregate formation is the presence of a chemokine known as RANTES. It acts in concert with platelet P-selectin and PSGL-1 in monocyte stimulation.
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PMID:Platelet-leukocyte aggregates and derived microparticles in inflammation, vascular remodelling and thrombosis. 1614 74

The benefits of glycoprotein (GP) IIb-IIIa inhibitors in percutaneous coronary intervention are well established, but the experience with these agents in the setting of peripheral interventions is limited. In this single-center pilot trial, the safety and feasibility of adjunctive treatment with the GP IIb-IIIa inhibitor eptifibatide (INTEGRILIN, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, and Schering-Plough Corporation, Kenilworth, New Jersey) was evaluated in 85 patients undergoing percutaneous transluminal angioplasty or stenting for severe claudication or critical limb ischemia. Eptifibatide treatment was safe, with low rates of major bleeding (3.5%) and thrombocytopenia (1.2%); one patient developed a post-procedure compartment syndrome requiring fasciotomy. The procedure was technically successful (defined as <30% residual stenosis or >50% increase in vessel diameter) in 84 of 85 (98.8%) patients. None of the patients required target vessel revascularization (TVR) during hospitalization, and only 1 patient (1.2%) required TVR within 30 days. These results demonstrate that adjunctive use of eptifibatide during percutaneous peripheral intervention is safe and supports further studies to establish the potential efficacy of GP IIb-IIIa inhibitors in this setting.
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PMID:Glycoprotein IIb-IIIa receptor inhibition with eptifibatide in percutaneous intervention for symptomatic peripheral vascular disease: the circulate pilot trial. 1628 82

Coronary ischemia augments inhomogeneity in ventricular repolarization. Decrease in the QT dispersion (QTd) following restoration of coronary blood flow to the ischemic myocardium by successful percutaneous coronary intervention (PCI) is an expected outcome. The purpose of the study was to seek whether glycoprotein IIb/IIIa (GP IIb/IIIa) inhibition has additional beneficial effects on QT dispersion after angiographically successful PCI. The study involved 111 consecutive patients scheduled for elective coronary balloon angioplasty with or without stent implantation. Sixty patients (mean age 58 +/-9) were randomized to receive standard therapy including preprocedural aspirin, ticlopidine, and IV heparin, and 51 patients (mean age 54 +/-10) were randomized to receive additional IV tirofiban infusion before the lesion was crossed with the guidewire. Standard 12-lead simultaneous ECG recordings for the measurement of QTd and corrected QTd (QTcd) (calculated by using Bazett's formula) were obtained before and immediately after the procedure, and at the 6th, and 24th hours. Blood samples for detection of postprocedural myocardial damage (CK-MB and cTn-I) were taken before and immediately after the procedure, at the 6th, 12th, and 24th hours. In total, 128 stenoses were treated with PCI. Seventy of these lesions were in the standard therapy group and 58 in the tirofiban group. QTd and QTcd were not statistically different between the 2 groups before and immediately after the procedure and at the 6th hours, but at the 24th hour QTd and QTcd were significantly longer in the standard therapy group (p=0.047 and p=0.001, respectively). Postprocedural troponin-I elevation (B=0.692, p=0.037), maximum inflation pressure (B=0.182, p=0.001), and previous myocardial infarction (MI) (B=0.885, p=0.004) were defined as the predictors of the final QT dispersion at the 24th hour. QT dispersion significantly decreased after successful percutaneous coronary intervention. GP IIb/IIIa inhibition therapy was not superior by means of recovery of increased QT dispersion during the early hours of the intervention, but it prevented minor myocardial necrosis and provided more long-lasting recovery in QT dispersion as compared with heparin therapy. This impact of GP IIb/IIIa receptor inhibition on QTd may be a possible mechanism by which these drugs reduce cardiovascular events after PCI.
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PMID:Impacts of glycoprotein IIb/IIIa inhibition on QT dispersion after successful percutaneous coronary intervention. 1670 87

Cooling of the patient is routinely applied in cardiac surgery to protect organs against ischemia. Hypothermia induces activation of platelets, but the effects of temperatures such as used during cardiac surgery are not well described. To investigate this in an in-vitro study heparinized whole blood was incubated at different temperatures (37 degrees C, 34.5 degrees C, 32 degrees C, 29.5 degrees C, 27 degrees C, 24.5 degrees C, 22 degrees C, 19.5 degrees C and 17 degrees C). The effect of these temperatures on aggregation, P-selectin expression, GP IIb/IIIa activation and platelet microparticle (PMP) formation of unstimulated and ADP-stimulated platelets of 36 subjects was evaluated in flow cytometry. A four-parametric logistic model was fitted to depict the temperature effect on platelet parameters. Lower temperatures increased aggregates, P-selectin expression, and GP IIb/IIIa activation. The number of PMPs decreases with hypothermia. Additional experiments revealed a slight influence of heparin on platelet P-selectin expression but excluded an effect of this anticoagulant on the other evaluated parameters. Threshold temperatures, which mark 5% changes of platelet parameters compared to values at 37 degrees C, were calculated. On ADP-stimulated platelets the thresholds for P-selectin expression and GP IIb/IIa activation are 34.0 degrees C and 36.4 degrees C, respectively, and lie in the temperature range routinely applied in cardiac surgery. Hypothermia-induced platelet activation may develop in most patients undergoing cardiac surgery, possibly resulting in thromboembolic events, coagulation defects, and proinflammatory leukocyte bridging by P-selectin bearing platelets and PMPs. These findings suggest that pharmacological protection of platelets against hypothermia-induced damage may be beneficial during cardiac surgery.
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PMID:Critical temperature ranges of hypothermia-induced platelet activation: possible implications for cooling patients in cardiac surgery. 1739 24

Platelet microparticles (PMP) are released from activated platelets and play an important role in hemostasis, thrombosis and inflammation. Since platelets were recently found to demonstrate an intrinsic capacity for activating both classical and alternative pathways of the complement system, the present study extended these observations to PMP. PMP were generated by treating platelets with 10 microM A23187 (37 degrees C, 5 min). PMP were identified by flow cytometry, based on size, Annexin V binding, and expression of P-selectin and GPIIb (CD41). PMP expressed gC1qR/p33, a multifunctional cellular protein that was recently described to activate the classical complement cascade. PMP also expressed the classical pathway and contact system regulator, C1 inhibitor (C1-INH), as well as CD55 and CD59. Despite C1-INH expression, PMP supported classical pathway C4 activation in the presence of purified C1 and C4. Moreover, statistically significant deposition of C3b and C5b-9 was detected on PMP exposed to plasma, concurrently with expression of CD55 and CD59. These data provide the first evidence for the ability of PMP to support in situ complement activation. Complement activation contributes to a variety of vascular and inflammatory disease states including atherosclerosis and ischemia/reperfusion injury.
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PMID:Expression of complement components and inhibitors on platelet microparticles. 1843 23


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