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)

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

Rats submitted to focal cerebral ischemia by middle cerebral artery clot embolism were treated with recombinant tissue plasminogen activator (rt-PA) at increasing delays (1.5, 3 and 4.5 h) after the onset of ischemia. Treatment efficacy was evaluated by NMR imaging of the apparent diffusion coefficient of water (ADC). In untreated animals the size of the ADC-detectable lesion gradually increased after clot embolism, expanding over 8 h to 174 +/- 17% of the volume visible at 30 min. Thrombolysis initiated 1.5 h after embolism did not reverse the ischemic lesion but reduced its growth to 113 +/- 19% (p < 0.05). Lesion size increased to 135 +/- 14% after 3 h (NS) and to 214 +/- 35% after 4.5 h delay (NS). Thrombolysis with rt-PA attenuates infarct expansion but does not reverse ischemic injury.
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PMID:Thrombolysis of cerebral clot embolism in rat: effect of treatment delay. 1059 32

Thrombolytic therapy has become a standard treatment for selected patients with acute myocardial infarction (MI). Various thrombolytic agents have been shown to decrease mortality. However, current thrombolytic agents still suffer significant shortcomings, such as a low optimal reperfusion rate delayed reperfusion. and incomplete myocardial perfusion. Furthermore, cyclic flow variations and reocclu.sions remain a significant cause of late morbidity and mortality. In thrombolysis with tissue plasminogen activator (t-PA), heparin seems to play an important role. However, it has several features that suggest that it may not be the optimal adjunct to thrombolytics, including weak and indirect action on thrombin, little access to clot-bound thrombin, inhibition by acute-phase plasma proteins, and its direct stimulation of platelet aggregation. Argatroban (NOVASTAN(R)), a small-molecule, synthetic, direct thrombin inhibitor, has several potential advantages over heparin, and prior studies suggest superior thrombin inhibition with favorable pharmacokinetic and pharmacodynamic properties warranting further investigation The Myocardial Infarction using NOVASTAN (R) and t-PA (MINT) study is a phase II, single-blind, angiographic trial directly comparing heparin versus two doses of argatroban in 120 patients with ST-elevation MI who present within 6 hours of symptom onset. The primary objective of the MINT trial is to assess the TIMI grade 3 flow and TIMI Frame Count at 90 minutes after the initiation of t-PA. This trial will also evaluate the safety of the combination of t-PA, argatroban, and aspirin. The incidence of clinical or silent ischemia, will be monitored. All patients will be followed up to 30 days for the composite endpoint of death, nonfatal recurrent myocardial infarction, coronary artery bypass surgery, PTCA, recurrent ischemia, and shock/new-onset heart failure.
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PMID:A Randomized, Blinded Study of Two Doses of Novastan(R) (Brand of Argatroban) Versus Heparin as Adjunctive Therapy to Recombinant Tissue Plasminogen Activator (Accelerated Administration) in Acute Myocardial Infarction: Rationale and Design of the Myocardial Infarction using Novastan(R) and T-PA (MINT) Study. 1060 50

Despite all the technical improvements in microvascular surgery and the experience gained in clinical practice, thrombosis at the site of microanastomosis remains a significant problem and a continuous source of frustration to most microsurgeons. Early recognition of vascular complications and prompt reexploration with vascular revision remain an essential and standard conduct for salvage. However, in situations where conditions for no-reflow have been established due to severe vasospasm or prolonged ischemia time, it becomes obvious that surgical reexploration alone is not enough to salvage a failing flap or a replanted limb. In such situations, the loss of the revascularized tissues seems to be inevitable. The authors describe their experience in partially salvaging a failing free flap with recombinant tissue plasminogen activator (rt-PA), reversing an established state of no-reflow. Pharmacologic manipulation of the complex and variable factors influencing anastomotic patency in microvascular tissue transfer seems to offer a new hope for preventing failures, as well as for salvaging failing flaps. It appears also that free-tissue transfer failure is not an all-or-none phenomenon.
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PMID:Pharmacologic partial salvage of a failing free flap with recombinant tissue plasminogen activator (rt-PA). 1060 39

Little data exist on the value of intravenous thrombolysis for acute myocardial infarction in patients with previous coronary bypass surgery. The Thrombolysis In Myocardial Infarction (TIMI) 4 trial was a randomized study comparing tissue plasminogen activator, anistreplase, or a combination in patients with evolving myocardial infarction; patients with previous coronary bypass surgery were not excluded. Coronary angiography was performed 90 minutes and 18-36 hours after randomization, a myocardial perfusion scan was performed at 18-36 hours and predischarge, and a radionuclide ventriculogram was obtained predischarge. Angiographic and clinical outcome variables were determined in patients with and without a history of coronary bypass surgery. A total of 416 patients were randomized and 13 of them had previous bypass surgery; of these, 6 had an occluded vein graft as the infarct-related vessel. The incidence of TIMI grade 3 flow at 90 minutes was lower in patients with previous coronary surgery as compared with controls (42% vs. 49%), and overall patency was significantly lower (50% vs. 77%, p = 0.04). This trend persisted at 18-36 hours after randomization. Furthermore, patients with previous coronary surgery had more thrombus in their infarct-related arteries, especially with occlusion of a vein graft (83% vs. 32%, p = 0.04) and higher rates of recurrent ischemia (15% vs. 8%) and recurrent infarction (23% vs. 5%, p = 0.03) than controls. Thus, in patients with previous coronary bypass surgery intravenous thrombolysis yields results that are inferior to those achieved in patients without such a history and alternative methods of reperfusion should be considered.
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PMID:Thrombolytic Therapy for Acute Myocardial Infarction in Patients with Prior Coronary Bypass Surgery: Results from the Thrombolysis in Myocardial Infarction (TIMI) 4 Trial. 1063 12

Stroke is an emergency. Treatment must begin as soon as possible because significant sustained neurological improvement has been demonstrated when thrombolytic treatment, mainly with recombined tissue plasminogen activator (rtPA) is initiated within the first hours of stroke onset. On the other hand in the acute phase of stroke it is critical that patients get adequate management for the prevention of early complications. Management of the acute phase of stroke is the target of this article. Preclinically started treatment must be continued in the neurological emergency unit. Clinical examination is followed by technical investigations: cerebral computer tomography (CCT) is the most useful radiological investigation in the acute phase. It allows to distinguish between ischemia and hemorrhagic lesions and also to rule out nonstroke brain conditions. Multimodal magnetic resonance imaging (mMRI) may provide data on viable versus irreversibly damaged tissue. Sufficient stroke treatment is based on well managed in-hospital infrastructure. Thrombolysis is the only causative treatment of stroke in selected patients. Complications of acute stroke comprise changes of blood pressure with hemodynamically relevant effects on cerebral perfusion pressure, acute post- ischemic brain edema, and intracerebral bleedings.
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PMID:[Treatment of acute clinical stroke]. 1066 82

Ischemia shifts the anticoaugulant/procoagulant balance of the endothelium in favor of activation of coagulation. We studied whether cheek pouch microcirculation of leukopenic hamsters was protected by tissue plasminogen activator (tPA) (50 microg/100 g body wt) against ischemia-reperfusion injury. Adherent leukocytes, total perfused capillary length (PCL), permeability increase, and arteriolar and venular red blood cell (RBC) velocity were investigated by fluorescence microscopy. Measurements were made at control, 30 or 60 min of ischemia, and at 30 or 60 min of reperfusion. Hamsters were made leukopenic by treatment with cyclophosphamide (20 mg/100 g body wt ip, 4 days before the experiment), which decreased circulating leukocyte count by 85-90%. Leukopenic hamsters undergoing 30 min of ischemia followed by 30 min of reperfusion showed no significant decrease in PCL or increased permeability. Leukopenic hamsters undergoing 60 min of ischemia followed by 60 min of reperfusion presented a significant decrease in microvascular perfusion where PCL was 28 +/- 7% of baseline, low-flow conditions, and increased permeability. In leukopenic hamsters treated with tPA there was complete protection of capillary perfusion with no significant changes in permeability or arteriolar and venular RBC velocity. In conclusion, thrombus formation may be an additional and independent factor that with leukocyte-mediated mechanisms determines ischemia-reperfusion injury.
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PMID:Protective effects of leukopenia and tissue plasminogen activator in microvascular ischemia-reperfusion injury. 1071 Mar 43

Thrombolytic stroke therapy with tissue plasminogen activator (tPA) remains complicated by serious risks of cerebral hemorrhage and brain injury. In this study, a novel model of tPA-induced hemorrhage was used in spontaneously hypertensive rats to examine the correlates of hemorrhage, and test methods of reducing hemorrhage and brain injury. Homologous blood clot emboli were used to occlude the middle cerebral artery in spontaneously hypertensive rats, and delayed administration of tPA (6 hours postischemia) resulted in high rates of cerebral hemorrhage 24 hours later. Compared with untreated rats, tPA significantly increased hemorrhage volumes by almost 85%. Concomitantly, infarction and neurological deficits were worsened by tPA. A parallel experiment in normotensive Wistar-Kyoto rats showed markedly reduced rates of hemorrhage, and tPA did not significantly increase hemorrhage volumes. To examine whether tPA-induced hemorrhage was caused by the delayed onset of reperfusion per se, another group of spontaneously hypertensive rats was subjected to focal ischemia using a mechanical method of arterial occlusion. Delayed (6 hours) reperfusion via mechanical means did not induce hemorrhage. However, administration of tPA plus delayed mechanical reperfusion significantly increased hemorrhage volumes. Since reperfusion injury was implicated, a final experiment compared outcomes in spontaneously hypertensive rats treated with tPA plus the free radical spin trap alpha-phenyl tert butyl nitrone (alpha-PBN) versus tPA alone. tPA-induced hemorrhage volumes were reduced by 40% with alpha-PBN, and infarction and neurological deficits were also decreased. These results indicate that (1) blood pressure is an important correlate of tPA-induced hemorrhage, (2) tPA interacts negatively with reperfusion injury to promote hemorrhage, and (3) combination therapies with anti-free radical treatments may reduce the severity of tPA-induced hemorrhage and brain injury after cerebral ischemia.
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PMID:Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. 1072 8

To explore the relationship between disorders of endogenous fibrinolysis and thrombosis in patients with lower extremity ischemia, we measured the activity of tissue plasminogen activator (tPAac) and plasminogen activator inhibitor (PAlac) and the antigens of tissue plasminogen activator (tPAa) and inhibitor (PAla) in plasma from 420 patients treated for lower extremity ischemia. Values and ratios observed were compared with those in healthy volunteers. Additionally, values and ratios in the patients were examined with respect to the severity of ischemia and site of atherosclerotic occlusion or stenosis (pelvic compared with femoropopliteal or crural). Patients with lower extremity ischemia had higher plasma concentrations of PAla (p<0.01) and PAlac (p<0.0001) than healthy volunteers. In patients with rest pain or gangrene, the ratio of tPAac to PAlac was higher than in patients with claudication (p<0.05). The elevation of tPAac in patients with the more severe form of lower extremity ischemia is probably the feedback protective reaction on prothrombotic mechanisms of the organism suffered from severe atherosclerosis. Results did not vary according to the site of occlusion or stenosis. Our study found defects in endogenous fibrinolysis in patients with lower extremity ischemia. A defect in fibrinolysis may contribute to the development of thrombosis in native arteries and bypasses.
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PMID:Endogenous fibrinolysis in patients with lower extremity ischemia. 1094 87

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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