UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microglia, brain resident macrophages, become activated in brains injured due to trauma, ischemia, or neurodegenerative diseases. In this study, we found that thrombin treatment of microglia induced NO release/inducible nitric-oxide synthase expression, a prominent marker of activation. The effect of thrombin on NO release increased dose-dependently within the range of 5-20 units/ml. In immunoblot analyses, inducible nitric-oxide synthase expression was detected within 9 h after thrombin treatment. This effect of thrombin was significantly reduced by protein kinase C inhibitors, such as Go6976, bisindolylmaleimide, and Ro31-8220. Within 15 min, thrombin activated three subtypes of mitogen-activated protein kinases: extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase/stress-activated protein kinase. Inhibition of the extracellular signal-regulated kinase pathway and p38 reduced the NO release of thrombin-treated microglia. Thrombin also activated nuclear factor kappaB (NF-kappaB) within 5 min, and N-acetyl cysteine, an inhibitor of NF-kappaB, reduced NO release. However, thrombin receptor agonist peptide (an agonist of protease activated receptor-1 (PAR-1)), could not mimic the effect of thrombin, and cathepsin G, a PAR-1 inhibitor, did not reduce the effect of thrombin. These results suggest that thrombin can activate microglia via protein kinase C, mitogen-activated protein kinases, and NF-kappaB but that this occurs independently of PAR-1.
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PMID:Thrombin induces NO release from cultured rat microglia via protein kinase C, mitogen-activated protein kinase, and NF-kappa B. 1089 7

Lower extremity ischemia is one aspect of atherosclerosis, a disease associated with both inflammation and hypercoagulability. Many recent studies have focused on a diversity of mechanisms by which inflammation can promote blood clotting. However, it has not been proven that inflammation can actually trigger clinically relevant thrombus formation in vivo. The purpose of the study was to determine the plasma levels of markers of inflammation and their possible association with markers for coagulability with special emphasis on the difference between patients with and without diabetes. Forty-six patients, 20 diabetics and 26 without diabetes scheduled for lower extremity revascularisation were examined by preoperative blood sampling. A strong positive correlation between C-reactive protein (CRP) and fibrinogen was found, particularly in diabetics. A high fibrinogen level was not associated with other markers of hypercoagulability, Thrombin-Antithrombin (TAT), Prothrombin Fragment 1+2 (F 1+2) and D-dimer although the latter three correlated with each other. There was also a correlation between von Willebrand antigen (vWF) and CRP, also in this case the relationship was dependent on the findings in patients with diabetes. It is concluded that there is a difference between diabetic and nondiabetic patients with lower limb ischemia with the former showing stronger signs of inflammation.
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PMID:Markers of inflammation and hypercoagulability in diabetic and nondiabetic patients with lower extremity ischemia. 1206 38

Acute coronary syndromes encompass a spectrum of conditions, including myocardial infarction and unstable angina. These syndromes are related to the formation and disruption of atherosclerotic plaque. Rupture of plaque leads to thrombin generation, fibrin deposition, and platelet aggregation, ultimately resulting in restriction of blood flow and ischemia of cardiac tissue. Percutaneous coronary intervention (PCI), including angioplasty and coronary stent placement, has been developed to open occluded arteries. The frequency with which these procedures are performed speaks to their largely successful outcomes. However, the mechanical manipulations of PCI result in additional plaque rupture and damage to the vessel wall, exposing subendothelial components to blood and resulting in the initiation of the clotting cascade and in platelet activation. Left unchecked, these intertwined processes lead to formation of arterial thrombi at the site of endothelial damage, and potentially to abrupt vessel closure or embolization of thrombi into the distal microcirculation. Thrombin plays a central role in thrombus formation and platelet activation, and its inhibition significantly reduces thrombus-related sequelae. Current antithrombotic strategies during PCI are based on the traditional indirect thrombin inhibitor heparin. Heparin has several limitations in efficacy and safety, due in part to its indirect mechanism of action. Bivalirudin, a direct thrombin inhibitor, offers significant improvement over heparin in the clinical outcomes and risks associated with PCI.
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PMID:The role of thrombin inhibition during percutaneous coronary intervention. 1206 71

Degeneration or survival of cerebral tissue after ischemic injury depends on the source, intensity, and duration of the insult. In the model of focal ischemia, reduced blood flow results in a cascade of pathophysiologic events, including inflammation, excitotoxicity, and platelet activation at the site of injury. One serine protease that is associated closely with and produced in response to central nervous system (CNS) injury is thrombin. Thrombin enters the injury cascade in brain either via a compromised blood-brain barrier or possibly from endogenous prothrombin. Thrombin mediates its action through the protease-activated receptor family (PAR-1, -3, and -4). PARs belong to the superfamily of G protein-coupled receptors with a 7-transmembrane domain structure and are activated by proteolytic cleavage of their N-terminus. We showed that thrombin can be neuroprotective or deleterious when present at different concentrations before and during oxygen-glucose deprivation, an in vitro model of ischemia. We examined the change in mRNA expression levels of PAR-1 to 4 as a result of transient focal ischemia in rat brain, induced by microinjection of endothelin near the middle cerebral artery. Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis, after ischemic insult on the ipsilesional side, PAR-1 was found to be downregulated significantly, whereas PAR-2 mRNA levels decreased only moderately. PAR-3 was upregulated transiently and then downregulated, and PAR-4 mRNA levels showed the most striking (2.5-fold) increase 12 hr after ischemia, in the injured side. In the contralateral hemisphere, mRNA expression was also affected, where decreased mRNA levels were observed for PAR-1, -2, and -3, whereas PAR-4 levels were reduced only after 7 days. Taken together, these data suggest involvement of the thrombin receptors PAR-1, PAR-3, and PAR-4 in the pathophysiology of brain ischemia.
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PMID:Transient focal ischemia in rat brain differentially regulates mRNA expression of protease-activated receptors 1 to 4. 1470 48

The last few years have clarified the tight link between inflammation and coagulation. In addition to the identification of new regulatory mechanisms of the coagulation system and of an explosive number of mediators of inflammation, it is now clear that the existence of a positive feed-back between inflammation and coagulation leads to reciprocal activation of both pathways. Plasma levels of acute phase proteins involved in coagulation and fibrinolysis are elevated during inflammation, while natural anticoagulant mechanisms are depressed. Pro-inflammatory cytokines "activate" cell membranes exposed to flowing blood (endothelium, platelets, monocytes, neutrophils) which from physiologically inert or anticoagulant become procoagulant. Increased tissue factor expression results in increased thrombin formation within the microcirculation. Thrombin is central to fibrin deposition but it also plays a key role in cell-mediated mechanisms involving inflammation, cell proliferation and activation of the natural anticoagulant protein C. Depression of natural anticoagulant mechanisms, occurring in severe sepsis, results in uncontrolled thrombin formation, with pro-inflammatory activity prevailing, and the feed-back loop of inflammation and coagulation ultimately leading to multi-organ failure. However, both in the clinical setting and in animal experiments, heparin or direct anticoagulants have shown no effect on survival even if blocking fibrin deposition. Organ failure is only partially due to the thrombotic occlusion of the microcirculation, while other mechanisms of endothelial damage are probably more relevant in the development of ischemia. The endothelium is central to the maintenance of the natural anticoagulant mechanisms (TFPI, antithrombin, protein C). The protein C system, in addition to dumping thrombin formation, specifically modulates inflammation by cell signaling. This system is markedly depressed in severe sepsis. The infusion of activated protein C, or restoring normal levels of protein C within the circulation - depending on the individual bleeding risk are powerful tools to treat the endothelitis responsible for the clinical sequelae of severe sepsis.
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PMID:[Protein C and coagulation in sepsis]. 1518 14

The incidence of iatrogenic femoral false aneurysms has risen dramatically in recent years and is estimated at 0,5% for diagnostic procedures and may rise to 9% or more for therapeutic procedures. This increased incidence is related to the increased number of arterial punctures performed for diagnostic or therapeutic purposes and their major complexity and duration. Risk factors for the development of iatrogenic false aneurysms include operator inexperience, age greater than 60, female gender, catheter size greater than 8F and concurrent anticoagulation. Prevention of false aneurysms is based upon an atraumatic arterial puncture, good compression therapy after sheath removal and use of percutaneous arterial closure devices. Contrarily to the arterial lesions following severe injuries, the natural course of false aneurysms is quite benign with spontaneous occlusion in the majority of cases. Therefore, a mandatory surgical approach is no longer advocated and alternative therapeutic options have been proposed. These include sonographic surveillance, compression ultrasonography, percutaneous thrombin or coil embolization. Surgery is still clearly indicated in presence of local nervous or venous compression, associated homolateral lower limb ischemia, great size of the aneurysm, and unsuccessful non-invasive treatment. Sonographic surveillance has shown to be safe in hospitalized or ambulatory patients. However, fear of aneurysm rupture and cost of repeated ultrasonographic exams preclude widespread utilisation. Compression ultrasonography is safe and effectiveness varies between 70 and 100%, according to studies. Compression ultrasonography may be painful, has often to be associated with mild analgesia, is time consuming and less effective in presence of concurrent anticoagulation. Thrombin injection seems particularly effective, is painless and has a limited rate of complications in expert hands. Severe anaphylactic reactions and severe coagulopathy in reexposed patients have been described and represent clear contra-indications to thrombin injection. Coil embolization of the false aneurysm is as effective as thrombin injection and is reported in a limited number of patients. There is no formal consensus about treatment of the vast majority of non-surgical false aneurysms. In an absence of stringent indication to surgical approach, compression ultrasonography may be used first as it is widely available, and does not require highly specialized skills. Compression therapy should be done after a transient interruption of anticoagulant treatment, if allowed by clinical context. If compression therapy fails, percutaneous injection of thrombin or coil embolization are effective and associated with a low complication rate. However, these techniques are less widely available and necessitate an experienced operator. As recurrences have been described with each of these techniques, every non-surgically-treated false aneurysm should be monitored for 24 hour with ultrasonography control to ensure effective thrombosis.
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PMID:[Treatment of postcatheterization femoral false aneurysms]. 1522 1

Thrombin exerts multiple actions on cardiomyocytes leading to increased intracellular Na+ and Ca2+ concentrations, and to activation of a Ca2+-independent PLA2, and has been proposed to favor the genesis of arrhythmias and ischemic injury in acute coronary syndromes. However, the influence of thrombin on cardiomyocyte cell death during ischemia-reperfusion has not been studied. A beneficial influence of low thrombin concentrations has been described in other cell types. HL-1 cardiomyocytes were subjected to simulated ischemia (SI) and reperfusion (SR) and cell death was assessed by means of LDH release to the incubation media. Thrombin dose-dependently increased cell death in normoxic cells, in cells subjected to SI, and in cells subjected to SR (by 20+/-8%, 95+/-32% and 35+/-9%, respectively, at 100 U/ml). The effects of thrombin were associated to increased cytosolic Ca2+ overload, mimicked by 100 microM PAR-1 agonist peptide SFLLRNPNDKYEPF, and reversed by the direct thrombin inhibitor lepirudin (IC50=1.3+/-0.2 microg/ml). The presence of thrombin during simulated ischemia-reperfusion increases cardiomyocyte cell death by a mechanism that involves activation of PAR-1 receptors and can be prevented by the direct thrombin inhibitor lepirudin.
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PMID:Thrombin increases cardiomyocyte acute cell death after ischemia and reperfusion. 1603 7

The ability of subnanomolar concentrations of thrombin to protect both neurons and glia from ischemia and other metabolic insults has recently been reported. In this study, we demonstrate an additional neuroprotective property of thrombin; its ability to promote the release of the organic osmolyte, taurine, in response to hypoosmotic stress. Incubation of human 1321N1 astrocytoma cells with hypo-osmolar buffers (320-227 mOsM) resulted in a time-dependent release of taurine. Inclusion of thrombin (EC(50) = 60 pM) resulted in a marked increase in taurine efflux that, although evident under isotonic conditions (340 mOsM), was maximal at an osmolarity of 270 mOsM (3-4-fold stimulation). Thrombin-stimulated taurine efflux was dependent upon its protease activity and could be mimicked by addition of the peptide SFLLRN, a proteinase activated receptor-1 (PAR-1) subtype-specific ligand. Inclusion of anion channel blockers known to inhibit the volume-sensitive organic osmolyte anion channel attenuated thrombin-stimulated taurine release. Depletion of intracellular Ca(2+) with either 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) or thapsigargin, or alternatively, inhibition of protein kinase C (PKC) with bisindolylmaleimide or chelerythrine resulted in a 30 to 50% inhibition of thrombin-stimulated taurine efflux. Under conditions in which intracellular Ca(2+) was depleted and PKC activity inhibited, thrombin-stimulated taurine efflux was reduced by >85%. The results indicate that activation of PAR-1 receptors by thrombin facilitates the ability of 1321N1 astrocytoma cells to release osmolytes in response to a reduction in osmolarity via a mechanism that is dependent on intracellular Ca(2+) and PKC activity.
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PMID:Subnanomolar concentrations of thrombin enhance the volume-sensitive efflux of taurine from human 1321N1 astrocytoma cells. 1605 96

Given the pivotal role of thrombin in the pathogenesis of acute coronary syndromes (ACS) and its persistent activation at the site of arterial lesions, antithrombin agents are essential for the prevention of coronary events. Antiplatelet agents are used routinely in the prevention of ACS, but their inability to prevent thrombin generation might contribute to the remaining high rates of recurrent ischemic events after intense antithrombotic treatment in the acute phase. Combination treatment with antiplatelet agents and anticoagulants, such as low-molecular-weight heparins (LMWH) and vitamin K antagonists, provides improved efficacy in the secondary prevention of ACS but these agents have limitations that prevent widespread adoption of their use for long-term treatment. Ximelagatran is the first oral agent in the new class of direct thrombin inhibitors (DTIs) and has considerable therapeutic potential in ACS. The DTIs are able to inhibit free and fibrin-bound thrombin by directly binding to the thrombin catalytic site. Furthermore, the oral administration and predictable pharmacokinetics of ximelagatran mean that it can be used at a fixed dose without coagulation monitoring and is convenient for long-term therapy. The efficacy of ximelagatran in the prevention of coronary events has been investigated in patients with recent myocardial infarction (MI) in the phase II Efficacy and Safety of the Oral Direct Thrombin inhibitor Ximelagatran in Patients with Recent Myocardial Damage (ESTEEM) trial. Ximelagatran (24 to 60 mg twice daily) added to aspirin (160 mg once daily) reduced the risk of the composite end point of death, MI, and severe recurrent ischemia by 24% versus aspirin alone, with no significant increase in major bleeding. Elevated serum transaminase enzymes developed during the first 1 to 6 months of treatment in a proportion of patients given ximelagatran. These elevations usually abated without clinical sequelae whether or not treatment was continued. The ESTEEM results highlight the potential for ximelagatran as an efficacious and well-tolerated long-term treatment for the prevention of arterial thrombotic events.
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PMID:Prevention of cardiovascular events after acute coronary syndrome. 1612 17

The serine protease thrombin has shown direct neuroprotective and neurotoxic effects on brain tissue in cerebral ischemia. Previous data suggested that thrombin-induced protection in vivo can be achieved by preconditioning rather than by acute treatment. In the current work, we used a model of mild ischemia to investigate the effects of preischemic intracerebral thrombin injection on neural damage. By intracerebral injection of endothelin-1 in freely moving animals, we achieved middle cerebral artery occlusion (MCAO), and 7 days postischemia we performed histological quantification of the infarct areas. Thrombin was injected as a preconditioning stimulus intracerebrally 7 days or 2 and 3 days before ischemia. For acute treatment, thrombin was injected 20 min before MCAO. Thrombin induced significant neuroprotection when given 7 days before endothelin-1-induced MCAO but was deleterious when given 2 and 3 days before the insult. The deleterious effect was not seen when thrombin was given acutely before ischemia. Our data demonstrate that preconditioning with thrombin can protect against damage or worsen ischemic damage. Its effect depended on the time interval between thrombin injection and insult. A low dose of thrombin did not induce a major deleterious effect in the acute phase of the infarct development after mild transient ischemia.
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PMID:Preconditioning with thrombin can be protective or worsen damage after endothelin-1-induced focal ischemia in rats. 1639 2

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