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)

Erythromelalgia is the main, pathognomonic and presenting symptom in patients with essential thrombocythemia and thrombocythemia associated with polycythemia vera. Complete relief from erythromelalgic and acrocyanotic pain is obtained with the cyclooxygenase inhibitors aspirin and indomethacin, but not with sodiumsalicylate, dipyridamol, sulfinpyrozone and ticlopedine. Thus, cyclooxygenase metabolites are necessary for erythromelalgia to develop. Local platelet consumption in erythromelalgic areas became evident by the demonstration of arteriolar fibromuscular intimal proliferation and occlusions by platelet-rich thrombi in skin biopsies, by the findings of shortened platelet survival times, significant higher levels of platelet activation markers beta-thromboglobulin, thrombomoduline and increased urinary thromboxane B2 excretion in thrombocythemia patients suffering from erythromelalgia. Aspirin treatment of erythromelalgia in thrombocythemia patients resulted in the disappearance of the erythromelalgic, thrombotic signs and symptoms, correction of the shortened platelet survival times, and a significant reduction of the increased levels of beta-TG, PF4, TM and urinary TxB2 excretion to normal. Erythromelalgia is frequently preceded or followed by atypical transient neurologic, ocular or coronary ischemic symptoms, which specifically respond to low-dose aspirin or reduction of platelet counts to normal. The broad spectrum of acropareshesias, erythromelalgia and acrocyanotic ischemia together with the episodic and transient atypical TIAs and ocular or coronary ischemic symptoms are caused by spontaneous activation and aggregation of hypersensitive platelets in the end-arterial microvasculature involving the peripheral, cerebral and coronary circulation of thrombocythemia patients. These microvascular circulation ischemic disturbances in thrombocythemia vera already occur at platelet counts in excess of 400 x 10(9) l(-1). Low-dose aspirin is highly effective and safe in the cure and prevention of thrombotic and ischemic events and does not elicit bleedings at platelet counts below 1000 x 10(9) l(-1). Spontaneous hemorrhages usually occur at very high platelet counts far in excess of 1000 x 10(9) l(-1) (HT) due to an acquired von Willebrand factor deficiency at increasing platelet counts. At platelet counts between 1000 and 2000 x 10(9) l(-1), thrombosis and bleeding (ETT and HT) frequently occur in sequence or paradoxically and low-dose aspirin does prevent thrombotic complications but aggravates or may elicit bleeding symptoms. Reduction of the platelet count to below 1000 x 10(9) l(-1) by platelet lowering agents usually results in the disappearance of the bleeding tendency and improvement of the von Willebrand syndrome, but the thrombotic tendency persists as long as platelet counts are above the upper limit of normal.
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PMID:Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia vera: a distinct aspirin-responsive arterial thrombophilia, which transforms into a bleeding diathesis at increasing platelet counts. 1278 99

The pathogenesis of acute coronary syndrome (ACS) and transient myocardial ischemia (TMI) is not completely understood. Therefore, the authors studied the biological indicators of thrombogenesis and sympathetic activity. The study was conducted on 50 patients with acute coronary syndrome and 30 patients with stable angina pectoris. Treatment was standardized with low-molecular-weight heparin and 300 mg aspirin/day but with no IIb/IIIa inhibitors, an oral beta-blocker, diltiazem 60 mg tid, glyceryl trinitrate i.v. in patients with ACS but with mononitrates orally and low-molecular-weight heparin in patients with stable angina. Twenty-four-hour continuous ECG monitoring and ST segment analysis were performed on day 2 of admission and heart rate analysis was performed 10, 5, and 1 minute before and during the myocardial ischemia periods. Blood sampling for von Willebrand factor (vWf) determination was performed through a peripheral vein at 8 AM, noon, 6 PM and 10 PM and half an hour after the description of angina. The patients with ACS were grouped as transient myocardial ischemia positive (n = 20) and negative (n = 30). The patients with stable angina were designated as the control group (n = 30). The detected vWf levels at 4 different daytime periods in patients with ACS were significantly higher than those in patients with stable angina. At the 6 PM to 10 PM period, the vWf level increase was significantly higher in patients with TMI than in the patients without TMI. At the 8 AM to noon period, the detected vWf levels decreased significantly in both TMI groups. During the nocturnal ischemia periods, the increase in vWf levels immediately after angina was significantly more apparent than the detected changes during daytime ischemia. Analysis showed that heart rates before the ischemia during stable angina episodes were significantly higher than those in TMI (-) (silent) angina. The heart rate difference between 10 minutes before and during the ischemia in the angina group was significantly different from that during TMI (-) (silent) ischemia. The heart rates at the times related to ischemia in the nocturnal period were significantly lower than those in the daytime period. The heart rate differences between the ischemia-related times and during the ischemia were significantly higher in daytime ischemic attacks than in nocturnal ischemic attacks. The study confirms that the vWf level, which is an indicator of thrombogenesis, was significantly increased in patients with ACS. Nocturnal ischemia is associated with thrombogenesis. Daytime ischemia is associated with increased sympathetic activity, and symptomatic ischemia is usually associated with increased sympathetic activity.
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PMID:The importance of von Willebrand factor level and heart rate changes in acute coronary syndromes: a comparison with chronic ischemic conditions. 1278 21

Sickle red cells express adhesion molecules including integrin alpha4beta1, CD36, band 3 protein, sulfated glycolipid, Lutheran protein, phosphatidylserine and integrin-associated protein. The proadhesive sickle cells may bind to endothelial cell P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), CD36 and integrins leading to its activation. Monocytes also activate endothelium by releasing proinflammatory cytokines like tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). Sickle monocytes also express increased surface CD11b and cytoplasmic cytokines TNFalpha and IL-1beta indicating activated state. Polymorphonuclear leukocytes (PMNs) are also activated with reduced L-selectin expression, enhanced CD64 expression and elevated levels of sL-selectin, sCD16 and elastase resulting in increased adhesiveness to the endothelium. Platelets are also activated and secrete thrombospondin (TSP) and cytokine IL-1. They also form platelet- monocytes aggregates causing endothelial cell P-selectin expression. Endothelial cell activation by these multiple mechanisms leads to a loss of vascular integrity, expression of leukocyte adhesion molecules, change in the surface phenotype from antithrombotic to prothrombotic, excessive cytokine production and upregulation of HLA molecules. Furthermore, contraction of these activated endothelial cells leads to exposure of extracellular matrix proteins, such as TSP, laminin, and fibronectin and their participation in adhesive interactions with bridging molecules from the plasma such as von Willebrand factor (vWf) released from endothelial cells, ultimately culminating in vasoocclusion and local tissue ischemia, the pathognomonic basis of vasoocclusive crisis.
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PMID:Cytokines in sickle cell disease. 1453 Jan 75

Thrombotic thrombocytopenic purpura (TTP) is a severe, occlusive, microvascular "thrombotic microangiopathy" characterized by systemic platelet aggregation, organ ischemia, profound thrombocytopenia, and erythrocyte fragmentation. Failure to degrade "unusually large" (UL) von Willebrand factor (VWF) multimers as they are secreted from endothelial cells probably causes most cases of familial TTP, acquired idiopathic TTP, thienopyridine-related TTP, and pregnancy-associated TTP. The emphasis in this review is the pathophysiology of familial and acquired idiopathic TTP. In each of these entities, there is a severe defect in the function of a plasma enzyme, VWF-cleaving metalloprotease (ADAMTS-13), that normally cleaves hyper-reactive ULVWF multimers into smaller and less adhesive VWF forms. In familial TTP, mutations in the ADAMTS13 gene cause absent or severely reduced plasma VWF-cleaving metalloprotease activity. Acquired idiopathic TTP, in contrast, is the result in many patients of the production of autoantibodies that inhibit the function of ADAMTS-13. Established, evolving, and some of the unresolved issues in TTP pathophysiology will be summarized.
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PMID:von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura. 1472 54

Ischemic damage results in irreversible ganglion cell loss in the retina. While the mechanisms underlying ischemia-induced ganglion cell loss are not clearly understood, we have recently reported that ischemia, induced by optic nerve ligation, results in increased nerve fiber layer-associated matrix metalloproteinase-9 (MMP-9) induction and loss of ganglion cells from the retina. This study was conducted to determine the cellular source of MMP-9 using antibodies against MMP-9 and various cell types in the inner retina. The results presented in this study show that optic nerve ligation leads to induction of MMP-9 and activation of astrocytes. Double labeling studies using antibodies against MMP-9 and GFAP showed a greater overlap of MMP-9 with GFAP, compared to antibodies against glutamine synthetase and MMP-9 which showed no overlapping, suggesting that activated astrocytes contribute to MMP-9 expression in the retina. Further, double labeling studies using antibodies against von Willebrand factor and MMP-9 or Mac-1 and MMP-9 showed no overlapping of MMP-9 with any antibodies indicating that endothelial cells and microglial cells are not the principal source of MMP-9 in the retina following optic nerve ligation.
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PMID:Optic nerve ligation leads to astrocyte-associated matrix metalloproteinase-9 induction in the mouse retina. 1474 83

Ozonated autohemotherapy (O3-AHT) is used in the treatment of atherosclerotic ischemia of lower limbs (AILL). The impact of ozone on serum lipids and endothelium injury is of particular interest since these factors are important in the development of atherosclerotic lesions. To evaluate this issue, a prospective, placebo-controlled study was designed. Twelve hemodialyzed subjects with AILL received autohemotherapy with oxygen as a control followed by O3-AHT with ozone concentration of 50 micro g/ml. Serum lipids and plasma activity of von Willebrand factor (vWF) were measured. After O3-AHT, total cholesterol significantly decreased compared to the baseline (-8.34%) [P < 0.01]. LDL cholesterol was also significantly lower than the initial value (-17.71%) [P < 0.001]. No significant changes in the activity of vWF were found after the first session of O3-AHT and after all nine sessions of O3-AHT. The study demonstrated that O3-AHT did not affect deleteriously the endothelium in patients with chronic renal failure on maintenance hemodialysis. It may stimulate beneficial changes in serum lipid profile manifesting as a decrease in the total- and LDL-cholesterol levels.
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PMID:Ozonated autohemotherapy in patients on maintenance hemodialysis: influence on lipid profile and endothelium. 1496 66

An angiogenesis assay based on gene transfer would be extremely useful for angiogenic gene therapy. A simple, reproducible, and quantitative assay to test angiogenic genes would provide more accurate predictions than conventional peptide-based assays. Here, we have developed a semiquantitative angiogenesis assay utilizing gene transfer into skeletal muscle, which is a target tissue for ischemic limb diseases. To facilitate quick and clean analysis, a naked plasmid DNA vector combined with an electroporation procedure was used for gene transfer. When the plasmid vector encoding vascular endothelial growth factor cDNA (pJDK-VEGF165) was injected into the tibialis anterior muscle of BALB/c mice, followed by in vivo electroporation and explant culture in growth factor-reduced Matrigel, the outward migration of sprouting cells was observed as early as day 2. The cells soon formed capillary networks, which peaked at day 7 and persisted until day 14. The capillary-like structures were positive for von Willebrand factor, platelet endothelial cell adhesion molecule, and vimentin, suggesting they were endothelial cells. There was little, if any, sprouting or formation of capillaries from the control vector (pJDK)-injected group. Consistent with the region of sprouting and network formation, the amount of secreted VEGF increased in the conditioned medium of explant cultures. The angiogenic potential of connective tissue growth factor (CTGF) was examined using the new assay. Whereas the CTGF gene alone induced weak sprouting activity, it appeared to inhibit the angiogenic activity of the VEGF165 gene during cotreatment. This attenuating activity of CTGF on VEGF was reproduced in vivo in a murine model of hindlimb ischemia. In a group of mice treated with both pJDK-CTGF and pJDK-VEGF165, the blood flow measured by laser Doppler imaging was significantly lower than that of the pJDK-VEGF165-treated group 10 days after femoral artery excision. These results are consistent with recent reports that suggest that CTGF inhibits VEGF. This confirms the usefulness of this novel ex vivo assay in assessing the angiogenic capacity of genes of interest. In summary, this new gene-based angiogenesis assay should be widely applicable in the study of angiogenic or antiangiogenic genes because it can readily predict the angiogenic potential of specific genes and their combinations.
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PMID:A novel ex vivo angiogenesis assay based on electroporation-mediated delivery of naked plasmid DNA to skeletal muscle. 1500 15

Prolonged cardiopulmonary bypass such as venoarterial bypass with extracorporeal membrane oxygenation (VA-ECMO) is becoming a potent therapeutic option in treating patients with severe respiratory and circulatory failure. However the chronic effects of this bypass modality have not yet been fully clarified. Recently, we developed an extremely durable thrombo-resistant ECMO system, and were successful with more than 5 months of continuous heparinless VA-ECMO in an animal experiment. This article presents the pathological findings on the lungs of the animal.A goat underwent VA-ECMO for a scheduled period of 151 days. This animal demonstrated a good general condition during the course of the experiment. On autopsy, however, the lungs of the animal showed severe alveolar fibrosis with topical atelectasis. von Willebrand factor levels on the endothelial cells in the alveolar capillaries were increased compared with those of normal goats. The ultrastructure of these cells showed ischemia-induced endothelial swelling. The pathological findings indicated that the vascular endothelial phenotypes had changed from respiratory type to nutrient type. The results of this study indicated that prolonged VA-ECMO may cause pulmonary alveolar fibrosis as a result of ischemia of the lungs accompanying reduced pulmonary blood flow.
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PMID:Observation of alveolar fibrosis in a goat following venoarterial bypass for up to 5 months using extracorporeal membrane oxygenation. 1530 78

Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia and thrombocytopenia, accompanied by microvascular thrombosis that causes variable degrees of tissue ischemia and infarction. Intravascular coagulation is not a prominent feature of the disorder. Plasma exchange can induce remissions in approximately 80% of patients with idiopathic TTP, but patients have a much worse prognosis when thrombotic microangiopathy is associated with cancer, certain drugs, infections, or tissue transplantation. Recently, acquired autoimmune deficiency of a plasma metalloprotease named ADAMTS13 was shown to cause many cases of idiopathic TTP. This review describes our current understanding of how to use this knowledge clinically. In Section I, Dr. Joel Moake describes the presentation of thrombotic microangiopathy, emphasizing the pathophysiology of idiopathic TTP. Platelets adhere to ultra-large (or "unusually large") von Willebrand factor (ULVWF) multimers that are immobilized in exposed subendothelial connective tissue and secreted into the circulation in long "strings" from stimulated endothelial cells. ADAMTS13 cleaves ULVWF multimers within growing platelet aggregates under flowing conditions, and this normally limits platelet thrombus formation. If ADAMTS13 is absent, either congenitally or due to acquired autoantibodies, platelet-rich microvascular thrombosis proceeds unchecked and TTP ensues. Plasma exchange is effective therapy for idiopathic TTP, probably because it replenishes the deficient ADAMTS13 and removes some of the pathogenic autoantibodies and endothelial-stimulating cytokines. Some patients have a type of thrombotic microangiopathy after transplantation/chemotherapy but do not have severe ADAMTS13 deficiency. The pathogenesis of their disease must differ but remains poorly understood. In Section II, Dr. Toshiyuki Miyata describes recent advances in assay methods that should facilitate routine laboratory testing of ADAMTS13 for patients with thrombotic microangiopathy. ADAMTS13 cleaves a single Tyr-Met bond in domain A2 of the VWF subunit. ADAMTS13 assays based on the cleavage of plasma VWF multimers have been used extensively but require considerable time and expertise to perform. A recombinant substrate containing 73 amino acid residues of VWF domain A2 has been devised that allows short incubation times and rapid product detection by gel electrophoresis or immunoassay. These results should encourage the development of even simpler assays that can be performed in most clinical laboratories. In Section III, Dr. James George provides an update on the long-term prospective study of thrombotic microangiopathy in the Oklahoma TTP-HUS Registry. At presentation, the clinical distinction between idiopathic TTP, various forms of secondary thrombotic microangiopathy, and even Shiga toxin-associated hemolytic uremic syndrome (HUS) can be problematic because the symptoms and laboratory findings often overlap. Consequently, plasma exchange usually is administered to any patient with thrombotic microangiopathy if there is doubt about the cause. The role of ADAMTS13 testing in choosing therapy remains uncertain, but the results do appear to have prognostic significance. Severe ADAMTS13 deficiency is specific for idiopathic TTP and identifies a subgroup with a high likelihood of response to plasma exchange, and high-titer ADAMTS13 inhibitors correlate strongly with a high risk of relapsing disease. Patients with normal ADAMTS13 activity have a much worse prognosis, although many factors probably contribute to this difference. Longitudinal study of these patients will continue to clarify the relationship of ADAMTS13 deficiency to the clinical course of thrombotic microangiopathy.
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PMID:Recent advances in thrombotic thrombocytopenic purpura. 1556 95

Increased activated circulating endothelial cells, enhanced von Willebrand factor (vWF:Ag) and adhesion molecules (sVCAM-1) are observed in patients with beta-thalassemia/hemoglobin E. Such evidences of endothelial cell injury are associated with altered intrarenal hemodynamics with a significant reduction in renal plasma flow. Altered renal functions (namely depleted creatinine clearance) and abnormal tubular function test, which is reflected by abnormally increased fractional excretion of magnesium (FE Mg), are also delineated. The increased FE Mg implies tubulointerstitial injury which may relate to the microvascular endothelial injury and chronic ischemia.
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PMID:Endothelial injury and altered hemodynamics in thalassemia. 1556 99


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