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 serum lipoprotein(a) [Lp(a)] level is a known risk factor for arteriosclerotic coronary artery disease. However, its association with restenosis after percutaneous transluminal coronary angioplasty (PTCA) is controversial. We hypothesized that the Lp(a) level is a significant risk factor for restenosis after angioplasty through a pathophysiological mechanism leading to excess thrombin generation or inhibition of fibrinolysis. We designed a prospective study of the relation of Lp(a) to outcome after PTCA, in which we measured selected laboratory variables at entry and collected clinical, procedural, lesion-related, and outcome data pertaining to restenosis. Restenosis was defined as >50% stenosis of the target lesion by angiography or as ischemia in the target vessel distribution by radionuclide-perfusion scan. Before the patients underwent PTCA, blood was obtained by venipuncture for measurement of Lp(a), total cholesterol, thrombin-antithrombin (TAT) complex, alpha2-antiplasmin-plasmin (APP) complex, and plasminogen activator inhibitor-1 (PAI-1). Evaluable outcome data were obtained on 162 subjects, who form the basis of this report. Restenosis occurred in 61 subjects (38%). The Lp(a) level was not correlated significantly with TAT, APP, PAI-1, or the TAT-APP ratio. Levels of TAT, APP, and PAI-1 were not statistically different in the patients with versus those without restenosis. The median ratio of TAT to APP was 2-fold higher in the restenosis group, and this difference approached statistical significance (P=0.07). Univariate analysis was performed for the association of clinical, lesion-related, and procedural risk factors with restenosis. Lp(a) levels did not differ significantly in the restenosis versus no-restenosis group, whether assessed categorically (>25 mg/dL versus <25 mg/dL) or as a continuous variable by Mann-Whitney U test. The number of lesions dilated and the lack of family history of premature heart disease were significantly associated with restenosis (P=0.002 and P=0.008, respectively). A history of diabetes mellitus was of borderline significance (P=0.055). By multiple logistic regression analysis, the number of lesions dilated was the only variable significantly associated with restenosis (P=0.03). We conclude that the number of lesions dilated during PTCA is a significant risk factor for restenosis, whereas the serum Lp(a) level was not a significant risk factor for restenosis in our patient population. The TAT to APP ratio merits further study as a possible risk factor for restenosis.
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PMID:Lipoprotein(a) level does not predict restenosis after percutaneous transluminal coronary angioplasty. 971 35

We investigated whether antithrombin (AT) can reduce ischemia/reperfusion (I/R)-induced injury of rat liver by promoting prostacyclin release from endothelial cells. Although intravenous administration of AT (250 U/kg) markedly reduced hepatic injury, neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Hepatic levels of 6-keto-PGF1, a stable prostacyclin (PGI2) metabolite, were increased significantly after I/R of the rat liver. AT significantly increased the hepatic level of 6-keto-PGF1, whereas neither DEGR-Xa nor Trp49-modified AT increased it. Hepatic tissue blood flow was markedly reduced after I/R. Although AT significantly increased the hepatic tissue blood flow after I/R, neither DEGR-Xa nor Trp49-modified AT increased the blood flow. Hepatic levels of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO) were significantly increased after hepatic I/R. The levels of these two indicators were reduced by AT but were unaffected by either DEGR-Xa or Trp49-modified AT. Pretreatment of animals with indomethacin (IM) completely inhibited the protective effects of AT on the I/R-induced hepatic damage and the leukocyte activation as well as the AT-induced increase in hepatic 6-keto-PGF1 levels after I/R. Iloprost, a stable analog of PGI2, exhibited effects similar to those of AT and also significantly inhibited the exacerbation of liver injury, the decrease in hepatic tissue blood flow, and the increases in hepatic CINC and MPO levels seen in rats subjected to I/R but pretreated with IM. These findings suggest that AT may prevent I/R-induced hepatic injury by increasing the hepatic levels of PGI2 through the interaction of AT with cell-surface glycosaminoglycans, thus increasing hepatic tissue blood flow and inhibiting leukocyte activation in animals subjected to I/R.
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PMID:Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin. 986 57

NPC 15669, a member of the leumedins family, inhibits leukocyte adhesion to the endothelium by blockage of upregulation of a member of beta2 integrin family Mac-1 (CD11b/CD18). Inhibition of neutrophil-endothelial interactions may alter the course of myocardial reperfusion injury. However, the effects of NPC 15669 supplementation on the hemostatic profile during ischemia-reperfusion are unknown. The aim of the present study was to define changes in the certain hemostatic factors in the natural course of preconditioned myocardial infarction. Twelve consecutive Yorkshire swine underwent myocardial stunning (8 min. left anterior descending artery occlusion followed by 90 min. of reperfusion) and then preconditioned myocardial infarction (50 min. occlusion followed by 3 hours of reperfusion) experiments. NPC 15669 (10 mg/kg loading dose followed by constant infusion at 6 mg x kg(-1) x h(-1)) was administered in 6 animals; another 6 swine received saline and served as controls. Blood samples were obtained at baseline, twice during occlusion; and three times during reperfusion. The levels of antithrombin-III, Protein C, total Protein S, fibronectin, endothelin-1, as well as the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto-PGF1a), were determined. NPC 15669 treatment was associated with diminished endothelin-1, TxB2 levels and increased fibronectin, 6-keto-PGF1a, Protein C and total Protein S concentrations in the setting of preconditioned myocardial infarction. There were no changes in the plasma concentrations of antithrombin-III in NPC 15669 group when compared with controls. The increase in Protein C, total Protein S, and 6-keto-PGF1a (favoring antithrombosis), and decrease in endothelin-1 and TxB2 levels (favoring vasodilatation), following NPC 15669 may explain the reduction in infarct size previously reported with this agent.
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PMID:Effects of a novel Mac-1 inhibitor, NPC 15669, on hemostatic parameters during preconditioned myocardial infarction. 1053 Aug 2

Thrombin activity has been implicated as a mechanism for failed reperfusion and reocclusion following thrombolysis. Aggregating platelets provide a phospholipid surface on which prothrombin is cleaved to form thrombin. We examined markers of thrombin generation and activity in patients enrolled in a randomized, placebo-controlled, dose escalating trial of the platelet glycoprotein IIb-IIIa inhibitor eptifibatide (Integrilintrade mark) administered concomitantly with tissue plasminogen activator for the treatment of myocardial infarction. Measurements were obtained at baseline, at 90 minutes, and at 6, 12, and 24 hours after starting therapy. Eptifibatide inhibited platelet aggregation in response to 20 microM ADP. Levels of fibrinopeptide A (FPA), thrombin-antithrombin complexes (TAT), and prothrombin fragment 1.2 (F1.2) were not lower in patients treated with eptifibatide than in the control group. In the course of dose escalation, two groups of patients received the same 135 microg/kg bolus of eptifibatide, one with and one without a heparin bolus. FPA levels were dramatically lower in the heparin-treated patients. Levels of FPA, TAT, and F1.2 were not higher in patients with than in those without recurrent ischemia, or in patients without than in those with Thrombolysis in Myocardial Infarction (TIMI) grade 3 angiographic flow at 90 minutes. These data suggest that thrombin generation and activity persist following thrombolysis, despite inhibition of platelet aggregation, and that treatment with inhibitors of thrombin activity may be required even when glycoprotein IIb-IIIa inhibitors are used.
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PMID:Inhibition of platelet aggregation with a glycoprotein IIb-IIIa antagonist does not prevent thrombin generation in patients undergoing thrombolysis for acute myocardial infarction. 1059 Jan 83

Disseminated intravascular coagulation (DIC) is a complex disorder, with pathophysiology being variable and highly dependent upon the triggering event(s), host response(s) and comorbid conditions. As a result of these complicated interactions, the clinical expression and laboratory findings are varied, thereby affecting the specifics of diagnosis and therapeutic approaches. The highly complex and variable pathophysiology of DIC often results in a lack of uniformity in clinical manifestations, a lack of consensus in the specific appropriate laboratory criteria of diagnosis, and a lack of specific therapeutic modalities. Indeed, recommendations for therapy are often difficult because the morbidity and survival is more dependent on the specific cause of DIC and because the generally used specific therapeutic approaches, which include for example heparin, low-molecular-weight-heparin antithrombin concentrate and protein C concentrate, have never been subjected to objective prospective randomized trials, except antithrombin concentrates. An analysis of the complex and varied pathophysiological events in DIC provide objective guidelines and criteria for the clinical diagnosis, the laboratory diagnosis, and the definition of severity. These data compounded by an understanding of complex and varied pathophysiology can be used for objective evaluation of therapeutic responses and results. DIC is an intermediary mechanism of disease usually seen in association with well-defined clinical disorders. The pathophysiology of DIC serves as an intermediary mechanism in many disease processes, which sometimes remain organ specific. This catastrophic syndrome spans all areas of medicine and presents a broad clinical spectrum that is confusing to many. Most physicians consider DIC to be a systemic hemorrhagic syndrome; however, this is only because hemorrhage is evident and often impressive. Less commonly appreciated is the profound microvascular thrombosis and sometimes, large vessel thrombosis. The hemorrhage is often simple to contend with in patients with fulminant DIC, but it is the small- and large-vessel thrombosis, with impairment in blood flow, ischemia, and associated end-organ damage that usually leads to irreversible morbidity and mortality. In conclusion, the pathophysiological mechanisms, clinical, and laboratory manifestations of DIC are complex in part due to interrelationships within the hemostasis system. Only by clearly understanding these extraordinarily complex pathophysiological interrelationships can the clinician and laboratory scientist appreciate the divergent and wide spectrum of often confusing clinical and laboratory findings in patients with DIC. Many therapeutic decisions to be made are controversial and lack validation. Nevertheless, newer antithrombotic agents, and agents which can block, blunt or modify cytokine activity and the activity of vasoactive substances appear to be of value. The complexity and variable degree of clinical expression suggests that therapy should be individualized depending on the nature of DIC, age, etiology of DIC, site and severity of hemorrhage or thrombosis and hemodynamics and other appropriate clinical parameters.
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PMID:Disseminated intravascular coagulation. clinical and pathophysiological mechanisms and manifestations. 1062 92

The goal of therapy in acute myocardial infarction is complete and timely restoration of coronary blood flow. Current strategies for reperfusion fail to achieve ideal results and resolution of ischemia in all patients. The platelet plays a pivotal role in the pathophysiology of an acute myocardial infarction, and antiplatelet therapy has been shown to improve clinical outcomes. The final common pathway for platelet activation and aggregation in acute myocardial infarction is the activation of the glycoprotein (GP) IIb/IIIa receptor. Newer reperfusion strategies target the GP IIb/IIIa receptor, thereby preventing the prothrombotic effects of platelets in an acute myocardial infarction. In the past decade, several strategies targeting the use of GP IIb/IIIa inhibitors have been evaluated. GP IIb/IIIa inhibitors have been shown to improve angiographic Thrombolysis in Myocardial Infarction (TIMI) 3 flow rates when used as reperfusion therapy given with heparin and aspirin as compared with heparin and aspirin alone. When GP IIb/IIIa inhibitors are used with full-dose fibrinolytics, early studies have suggested a trend toward more rapid and more complete reperfusion in an acute myocardial infarction. Later trials have examined the use of GP IIb/IIIa inhibitors in conjunction with reduced-dose fibrinolytics. Results from TIMI 14 and Global Use of Strategies to Open occluded arteries-IV pilot trials support the use of combination therapy with reduced- dose fibrinolytics and the GP IIb/IIIa inhibitor abciximab. Given the promising role of GP IIb/IIIa inhibitor therapy in acute myocardial infarction, investigators questioned the need for concomitant antithrombin therapy. However, data from several investigations suggest that antithrombin therapy is required when GP IIb/IIIa inhibitors are used with fibrinolytics, although it appears that the dose of heparin may be reduced. Finally, recent investigations have addressed the safety and efficacy of facilitated early percutaneous intervention. In this strategy, patients presenting with an acute myocardial infarction are treated with reduced-dose fibrinolytics and GP IIb/IIIa inhibitors and are taken to the interventional cardiac catheterization laboratory within the first 60 minutes of therapy.
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PMID:The use of glycoprotein IIb/IIIa inhibitor therapy in acute ST-segment elevation myocardial infarction: current practice and future trends. 1277 11

This study was performed to determine whether human urinary soluble thrombomodulin plays a role in liver ischemia-reperfusion injury. Liver ischemia was induced in two groups of dogs. Group 1 was exposed to 60 min ischemia, and group 2 was exposed to 60 min ischemia after preischemic administration of human urinary soluble thrombomodulin. In group 1, the thrombin-antithrombin complex and hyaluronic acid were significantly elevated after ischemia, compared with the preischemic values. While liver issue blood flow and the plasmin-alpha(2)-plasmin inhibitor complex significantly decreased, AST, ALT and m-AST dramatically increased after reperfusion. In group 2, the increase in the thrombin-antithrombin complex and hyaluronic acid was significantly suppressed, and AST, ALT and liver tissue blood flow significantly improved, compared with group 1. Histologically, in group 2, the hepatic tissue structure, including endothelial cells, was relatively intact. These findings suggest that administration of thrombomodulin inhibits endothelial cell injury and coagulopathy and offers protection from liver ischemia-reperfusion injury.
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PMID:Protective effect of human urinary thrombomodulin on ischemia- reperfusion injury in the canine liver. 1081 Feb 13

Recently, it has been demonstrated in multiple clinical research studies that non-Q-wave myocardial infarction shares many of the features of unstable angina pectoris and that both diseases initially are managed similarly. Important new antiplatelet drugs (glycoprotein IIb-IIIa inhibitors) and antithrombin agents (low-molecular-weight heparin) are currently recommended for patients with unstable angina pectoris/non-ST-segment elevation MI who are at high or intermediate risk on the basis of symptoms, electrocardiographic findings, and the presence or absence of serum markers (eg, troponin I, troponin T, and creatine kinase-MB). This review provides important information concerning the results of clinical studies of glycoprotein IIb-IIIa inhibitors (tirofiban hydrochloride and eptifibatide) when used with unfractionated heparin in patients with this syndrome or with low-molecular weight heparin (enoxaparin sodium) in similar patients. The Thrombolysis in Myocardial Infarction IIIB, Veterans Affairs Non-Q-Wave Infarction Studies in Hospital, and Fast Revascularization During Instability in Coronary Artery Disease II studies evaluating a conservative, ischemia-guided approach vs an early aggressive approach to such patients are presented, with a practical algorithm for treating such patients.
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PMID:New approaches to diagnosis and management of unstable angina and non-ST-segment elevation myocardial infarction. 1186 90

Normal endothelial cells express several membrane components with anticoagulant properties, which include: 1) tissue factor pathway inhibitors (TFPI), i.e. surface molecules able to accelerate the action of antithrombin (AT) on coagulation proteases; 2) thrombomodulin (TM), a thrombin binding surface protein able to inhibit thrombin activity; the complex TM-thrombin, also, activates protein C (PC); 3) endothelium derived factors such as nitric oxide and prostacyclin, which have antiadhesive properties and activate plasminogen. Exposure to inflammatory and/or septic stimuli can rapidly lead to a procoagulant response, activated by bacterial endotoxins, and to a decrease of endothelial anticoagulant membrane components. Activation of coagulation concomitant to impaired fibrinolysis is associated with fibrin deposition, tissue ischemia and necrosis. This review presents the results of different strategies aimed at reducing organ dysfunction and mortality in septic shock by modulating coagulation activity. In various animal models and in phase II clinical studies, the treatment with TFPI, AT and activated PC reduced organ dysfunction and mortality. Two phase III trials showed no efficacy of AT and a reduction of the relative risk of death with activated PC. In animal studies, supplementation with l-arginine and administration of perindopril were able to prevent septic shock-associated endothelial injury. A marked reduction of endothelial injury and improved survival of treated animals were also seen with antiglycoprotein IIb/IIIa which attenuated the role of monocytes in the disseminated intravascular coagulation process.
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PMID:Microthrombosis in sepsis. 1137 28

In France, the incidence of meningococcal infections is increasing. The most severe presentation, called purpura fulminans, has a death rate of 20-25%; 5 to 20% of the survivors need skin grafts and/or amputations. Diagnosis of invasive meningococcal infection is very difficult when purpura and "toxic" appearance are absent: one should take into account parents' impression of their ill child. This diagnosis must be evoked in any child presenting with febrile purpura (like in the United Kingdom, parents should be encouraged to use the "tumbler test" to identify a vasculitic rash); a fulminant form is to be suspected in the presence of only one ecchymosis and signs of infection, remembering that recognition of shock is difficult in children. Recently, the Health Authority has recommended to administer a third generation cephalosporin promptly (before biological investigations) for any child with signs of infection and a necrotic or ecchymotic purpura (> 3 mm of diameter), and then to refer the patient to the hospital. By grouping the patients from 7 studies, it can be observed that preadmission antibiotic administration has a protective effect on mortality (odds ratio: 0.36; 95% confidence interval: 0.23-0.56); a negative effect was observed in only one of these series. Children with purpura fulminans should be referred to a paediatric intensive care unit. Management includes antibiotics, steroids, fluid resuscitation and catecholamines (be aware of hypoglycaemia, particularly in infants, and hypocalcaemia). Treatment of cutaneous necrosis and distal ischemia is difficult and still controversial: antithrombin, protein C, tissue plasminogen activator and vasodilator infusion have no proven efficacy. Cases must be rapidly notified to the Public Health Service who will institute chemoprophylaxis for close contacts. Given the predominance of serogroup B in France, we hope that an efficient vaccine will soon become available.
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PMID:[Treatment of meningococcal purpura fulminans]. 1158 13


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