Anaphylaxis after thrombin injection of a femoral pseudoaneurysm: recommendations for prevention.
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After the injection treatment of a femoral pseudoaneurysm, an anaphylactic reaction occurred in a patient undergoing hemodialysis who previously had repeated exposure to thrombin. Before injecting bovine thrombin in patients with a history of prior exposure, we recommend that they undergo skin prick testing to detect possible allergy. (+info)
Involvement of aldose reductase in vascular smooth muscle cell growth and lesion formation after arterial injury.
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Abnormal proliferation of vascular smooth muscle cells (VSMCs) is an important feature of atherosclerosis, restenosis, and hypertension. Although multiple mediators of VSMC growth have been identified, few effective pharmacological tools have been developed to limit such growth. Recent evidence indicating an important role for oxidative stress in cell growth led us to investigate the potential role of aldose reductase (AR) in the proliferation of VSMCs. Because AR catalyzes the reduction of mitogenic aldehydes derived from lipid peroxidation, we hypothesized that it might be a potential regulator of redox changes that accompany VSMC growth. Herein we report several lines of evidence suggesting that AR facilitates/mediates VSMC growth. Stimulation of human aortic SMCs in culture with mitogenic concentrations of serum, thrombin, basic fibroblast growth factor, and the lipid peroxidation product 4-hydroxy-trans-2-nonenal (HNE) led to a 2- to 4-fold increase in the steady-state levels of AR mRNA, a 4- to 7-fold increase in AR protein, and a 2- to 3-fold increase in its catalytic activity. Inhibition of the enzyme by sorbinil or tolrestat diminished mitogen-induced DNA synthesis and cell proliferation. In parallel experiments, the extent of reduction of the glutathione conjugate of HNE to glutathionyl-1,4-dihydroxynonene in HNE-exposed VSMCs was decreased by serum starvation or sorbinil. Immunohistochemical staining of cross sections from balloon-injured rat carotid arteries showed increased expression of AR protein associated with the neointima. The media of injured or uninjured arteries demonstrated no significant staining. Compared with untreated animals, rats fed sorbinil (40 mg. kg(-1). d(-1)) displayed a 51% and a 58% reduction in the ratio of neointima to the media at 10 and 21 days, respectively, after balloon injury. Taken together, these findings suggest that AR is upregulated during growth and that this upregulation facilitates growth by enhancing the metabolism of secondary products of reactive oxygen species. (+info)
Annexin V relocates to the platelet cytoskeleton upon activation and binds to a specific isoform of actin.
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We have previously reported that stimulation of platelets causes a relocation of annexin V to the cytoplasmic side of the plasma membrane where it associates with actin. This study examined the association of annexin V with the platelet cytoskeleton and its binding to actin, following both physiological activation with thrombin and Ca2+ -ionophore activation. The time-dependence of annexin V incorporation into the detergent-extracted cytoskeleton following activation with thrombin was also measured. Although calcium from the intracellular stores was enough to relocate intracellular annexin V to the cytoskeleton, this relocation was further enhanced by influx of extracellular calcium. The association of annexin V with the cytoskeleton was found to be unaffected by the action of cytochalasin E, however, annexin V was solubilized when DNase I was used to depolymerize the membrane cytoskeleton, and spontaneously re-associated with the actin filaments when re-polymerization was induced in vitro. Using a bifunctional crosslinking reagent we have identified an 85-kDa complex in both membrane and cytoskeleton fractions containing annexin V and actin. Direct binding to actin filaments was only observed in high [Ca2+], however, inclusion of an extract from thrombin-stimulated platelets lowered the [Ca2+] requirement for the binding of annexin V to F-actin to physiological levels. We also show that GST-annexin V mimics the physiological binding of annexin V to membranes, and that this GST-annexin V binds directly to a specific isoform of actin. Immunoprecipitation using antibodies against annexin V copurify annexin V and gamma- but not beta-actin from activated platelets. This is the first report of a possible preferential binding of annexin V to a specific isoform of actin, namely gamma-actin. The results of this study suggest a model in which annexin V that relocates to the plasma membrane and binds to gamma-actin in an activation-dependent manner forms a strong association with the platelet cytoskeleton. (+info)
Activation of RhoA by thrombin in endothelial hyperpermeability: role of Rho kinase and protein tyrosine kinases.
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Endothelial cells (ECs) actively regulate the extravasation of blood constituents. On stimulation by vasoactive agents and thrombin, ECs change their cytoskeletal architecture and small gaps are formed between neighboring cells. These changes partly depend on a rise in [Ca(2+)](i) and activation of the Ca(2+)/calmodulin-dependent myosin light chain kinase. In this study, mechanisms that contribute to the thrombin-enhanced endothelial permeability were further investigated. We provide direct evidence that thrombin induces a rapid and transient activation of RhoA in human umbilical vein ECs. Under the same conditions, the activity of the related protein Rac was not affected. This was accompanied by an increase in myosin light chain phosphorylation, the generation of F-actin stress fibers, and a prolonged increase in endothelial permeability. Inhibition of the RhoA target Rho kinase with the specific inhibitor Y-27632 reduced all of these effects markedly. In the presence of Y-27632, the thrombin-enhanced permeability was additionally reduced by chelation of [Ca(2+)](i) by BAPTA. These data indicate that RhoA/Rho kinase and Ca(2+) represent 2 pathways that act on endothelial permeability. In addition, the protein tyrosine kinase inhibitor genistein reduced thrombin-induced endothelial permeability without affecting activation of RhoA by thrombin. Our data support a model of thrombin-induced endothelial permeability that is regulated by 3 cellular signal transduction pathways. (+info)
Cytokines and hemostasis.
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BACKGROUND AND OBJECTIVES: Cytokines are low molecular weight polypeptides that act as pleiotropic mediators of inflammation and may contribute significantly to regulation of hemostatic balance in both physiologic and pathologic conditions. The purpose of this review is to underline the most significant progresses recently achieved in this rapidly growing area. DESIGN AND METHODS: The authors have been involved both at home and abroad in experimental and clinical research in this field for years and have contributed original papers in peer-reviewed journals. In addition, the material examined in the present review includes articles published in journals covered by the Science Citation Index and Medline. RESULTS: Tissue factor, a transmembrane glycoprotein that serves as a surface receptor for coagulation factor VIIa, plays a key role in the initiation of coagulation processes. Very little, if any, tissue factor activity is detectable in normal conditions on the cell surface of monocytes and endothelial cells. However, upon proper stimulation by a number of agents such activity may be expressed in these cells, which can then contribute significantly to clotting activation. Pro-inflammatory cytokines (IL-1, IL-6 and TNF) are effective inducers of tissue factor upregulation and may trigger endothelial cells to change their antithrombotic properties into a procoagulant, clot-promoting state. Indeed, much experimental and clinical evidence has been accumulated to suggest that cytokines play a key role in the pathophysiology of hemostatic abnormalities in different disease states. These include, inter alia, the coagulopathy observed during septicemia, the veno-occlusive disease of the liver after bone marrow transplantation, the prothrombotic state associated with atherosclerotic vessels, the occurrence of deep venous thrombosis after major abdominal surgery and the thrombotic tendency of patients with cancer. Several new antithrombotic strategies based on these new concepts have been attempted in experimental models of thrombosis and also in man. Examples of new possible antithrombotic agents are the tissue factor pathway inhibitor, Fab fragments of monoclonal antibodies directed against factor VII or factor VIIa, mutant forms of biologically inactive tissue factor and inhibition of cytokines involved in the regulation of tissue factor expression. Many of these studies have produced positive or interesting results, although more must be learned before the appropriate drug and the adequate dose are defined in the different clinical situations. CONCLUSIONS: Pro-inflammatory cytokines (IL-1, IL-6 and TNF) play a key role in tissue factor expression on monocytes and on endothelial cells and contribute significantly to regulation of hemostatic balance in physiologic and pathologic conditions. This effect is of great interest from both speculative and practical viewpoints. (+info)
CD39 modulates endothelial cell activation and apoptosis.
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BACKGROUND: CD39 is the dominant vascular nucleoside triphosphate diphosphohydrolase (NTPDase) that exerts major effects on platelet reactivity by the regulated hydrolysis of extracellular adenine nucleotides. The effects of NTPDases on endothelial cell (EC) activation and apoptosis remain unexplored. MATERIAL AND METHODS: Recombinant replication-deficient adenoviruses were constructed with human CD39 cDNA (rAdCD39) or the bacterial beta-galactosidase (rAdbetagal). RESULTS: Intact human umbilical vein EC cultures infected with rAdCD39 had substantial and stable increases in NTPDase biochemical activity (14.50 +/- 3.50 Pi nmole/well/min), when contrasted with noninfected cells (0.95 +/- 0.002) and rAdbetagal infected cells (1.01 +/- 0.02; p<0.005). Increased NTPDase activity efficiently inhibited immediate type 2Y purinergic receptor (P2Y)-mediated EC activation responses viz. von Willebrand factor secretion in response to extracellular ATP. In addition, CD39 up-regulation blocked ATP-induced translocation of the transcription nuclear factor (NF)-kappaB to the cell nucleus, and abrogated transcription of mRNA encoding E-selectin, and consequent protein synthesis. CD39 also decreased the extent of apoptosis triggered by putative type-2X purinergic (P2X7) receptors in response to high concentrations of extracellular ATP in vitro. CONCLUSION: These properties of CD39 indicate primary vascular protective effects with potential therapeutic applications. (+info)
Laparoscopic splenectomy in a patient with acquired angioneurotic edema.
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BACKGROUND: We report the case of a 77-year-old female with acquired angioneurotic edema, C1 esterase inhibitor level = 4mg/dL, who was scheduled to undergo laparoscopic splenectomy. METHODS: In the operating room, we administered on call 500 units (UI) of C1 esterase inhibitor concentrate intravenously. Intraoperative hemodynamic instability and generalized blood oozing improved following the administration of aprotinin 250000 UI intravenous (IV) drip. CONCLUSION: We recommend the administration of an antifibrinolytic agent in addition to C1 esterase inhibitor concentrate in patients with acquired angioneurotic edema. (+info)
Effect of repeated exposure to methanol and toluene vapor on the metabolism of rats.
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Wistar male rats were repeatedly exposed to methanol and toluene vapors individually and simultaneously by inhalation 6 hours a day, five days a week for 4 weeks. Blood was obtained from the tail of the rats up to 23 hours after the end of 4-week exposure and the methanol and toluene concentrations were measured. Major metabolites of methanol and toluene, that is, formic acid and hippuric acid in urine were measured up to 6 days after the end of 4-week exposure. The biological half time of toluene in blood in the simultaneous exposure group was shorter than that in the toluene exposure group. This tendency was almost the same as that for one-day exposure, although the biological half time of solvents in the rat blood was prolonged. The half times of methanol were also longer than those for one-day exposure. (+info)