Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The primary objective of this study was to characterize a large cohort of patients receiving thrombolytic therapy for acute myocardial infarction with respect to the group with a prior event. Patients were randomly assigned to 1 of 4 thrombolytic strategies. Baseline characteristics, 30-day outcomes, and 1-year mortality were compared between patients with (n = 6,704) and without (n = 34,143) prior myocardial infarction. Patients with prior myocardial infarction presented to the hospital earlier than those having their first event, but institution of thrombolytic therapy was delayed. Mortality at 30 days (11.7% vs 5.9%, p = 0.001) and 1 year (17.3% vs 8.2%, p < 0.001) was greater among patients with prior infarction, and independent of other demographic variables. Accelerated alteplase was more effective than streptokinase or combination therapy (30-day mortality 10.4% vs 12.2%, p = 0.012; 1-year mortality 15.9% vs 17.8%, p = 0.041). Infarct vessel patency did not differ between those with and without prior myocardial infarction (67.3% vs 67% at 90 minutes, p = 0.92); however, recurrent ischemia was more common in patients with prior myocardial infarction. Patients with healed myocardial infarction should be educated to ensure early hospital admission if they develop symptoms suggestive of acute infarction, and upon hospital arrival should be promptly triaged to receive reperfusion therapy with accelerated alteplase.
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PMID:Benefit of early sustained reperfusion in patients with prior myocardial infarction (the GUSTO-I trial). Global Utilization of Streptokinase and TPA for occluded arteries. 946 68

Sudden extreme physical stress is associated with an increased risk of myocardial infarction mainly in people with preexisting atherosclerosis. In this study we compared the effect of submaximal exercise on coagulation and fibrinolysis in patients with peripheral arterial occlusive disease (PAOD) with that in healthy control subjects. Fifteen PAOD) patients with intermittent claudication and 15 healthy control subjects, matched for age, sex, medication use, smoking habit, and conditioning, were studied. Thrombin-antithrombin III complex (TAT), D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI)-1 antigens (Ag), t-PA activity, and plasmin-alpha2-antiplasmin complex (PAP), as well as plasma catecholamines, were measured before and after a treadmill exercise test. At rest, fibrinogen (3.3+/-0.5 versus 2.9+/-0.5 g/L [mean+/-SD]; P<.05), D-dimer (392+/-128 versus 271+/-113 ng/mL; P<.05), t-PA Ag (9.1+/-5.1 versus 5.5+/-1.2 ng/mL; P<.02), and PAI-1 Ag (14.9+/-7.1 versus 7.6+/-3.8 ng/mL; P<.002) levels in plasma were markedly higher in the patient group than in the control group. In patients but not in control subjects, exercise of similar intensity elevated circulating concentrations of TAT (from 3.43+/-1.45 to 4.83+/-2.27 ng/mL; P<.05). Exercise caused a parallel increase in D-dimer, t-PA Ag, t-PA activity, PAP, and catecholamines in both groups, whereas PAI-1 Ag remained stable. Plasma lactic acid was significantly higher in patients after exercise and was associated with lower-limb ischemia. Compared with healthy control subjects, patients with PAOD showed higher t-PA Ag, PAI-1 Ag, and D-dimer levels both at rest and after exercise. Notably, submaximal exercise on a treadmill enhanced thrombin formation in patients with PAOD but not in the control subjects. Sudden catecholamine release and local ischemia during exercise may accelerate the preexisting prothrombotic potential of the atherosclerotic vessel wall.
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PMID:Physical exertion induces thrombin formation and fibrin degradation in patients with peripheral atherosclerosis. 948 89

Prompt restoration of coronary flow is the principal mechanism by which reperfusion therapy improves survival and other clinical outcomes in patients with acute myocardial infarction. Thrombolytic therapy has been the standard for care over the past decade. The use of accelerated administration of tissue plasminogen activator (t-PA) and modified or mutant t-PA which can be administered with a single bolus intravenous injection might bring further benefits. Primary balloon angioplasty (percutaneous transluminal coronary angioplasty: PTCA) is safe and effective when it can be performed quickly by experienced operators, resulting in better coronary flow and short-term survival rates than are obtained with thrombolytic therapy. However, several studies reporting data from more than 5,000 patients, of whom many were treated in low-volume local hospitals showed mortality with primary angioplasty was substantially higher than that reported from high-volume medical centers, and similar to that observed with thrombolysis with accelerated t-PA. The strategy of rapid administration of thrombolytic therapy and subsequent angioplasty only for recurrent ischemia seems to be as effective as primary angioplasty. Recently several reports have indicated that coronary stenting, when performed for suitable lesions and with good technique by experienced operators, is superior to the results obtained with balloon angioplasty and thrombolysis. However, further studies are required to establish the efficacy of primary stenting compared to PTCA.
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PMID:[Reperfusion therapy in acute myocardial infarction today: thrombolysis, balloon angioplasty and stenting]. 948 50

Indications of interventional radiological procedures in patients with chronic critical limb ischemia are not clearly defined. PTA of limb arteries is used only in 3 of 4% of patients, although 20 to 40% might be candidates for a proximal intervention in the iliac arteries. Following PTA of intrapopliteal arteries, limb salvage varies from 56 to 82% and arterial patency rate from 34 to 100% after 1 to 2 years follow-up in non controlled case series studies. Arterial local thrombolysis shows better results than surgery in subgroups of patients in a few studies. Pulse spray technique does not show better clinical results than conventional infusion of the plasminogen activator. Overall, radiological interventions give similar results compared with surgery, concerning limb salvage rate, length of hospital stay, morbidity and mortality, but significantly more patients are discharged home versus a nursing institution after radiological treatment than after surgery. Radiological techniques seem to be cost effective compared to surgery. Amputation should be carried out only after all revascularization possibilities have been ruled out at a multidisciplinary vascular center.
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PMID:Chronic critical limb ischemia: what is the benefit of radiological intervention? Indications and results. 964 Aug 78

Strategies directed against activated neutrophils have reduced ischemia-induced brain injury. However, therapies targeted specially against the neutrophil adhesion protein L-selectin have not yet been examined in stroke. This study therefore examined the effects of a monoclonal antibody directed against L-selectin in a rabbit model of thromboembolic stroke with (n = 16) or without (n = 10) concomitant t-PA therapy. Rabbits received either the humanized monoclonal antibody DREG200 directed against the L-selectin receptor or humanized control monoclonal antibody HuDREG55 which does not bind to rabbit L-selectin in addition to t-PA therapy (n = 8, each group). HuDREG200 (2 mg kg-1 i.v.) was given as a bolus 3 h following clot embolization, followed immediately by a 2 h intravenous infusion of t-PA (6.3 mg kg-1. Without t-PA therapy rabbits received HuDREG200 (2 mgkg-1, i.v.; n = 5) or HuDREG55 (n = 5) 1 h following clot embolization. The group receiving HuDREG200 in addition to t-PA demonstrated a moderate improvement in brain infarct size (8.4 +/- 2.4 vs. 13.5 +/- 3.5, %hemisphere, mean +/- sem), ICP (final reading 10.0 +/- 1.6 vs. 12.4 +/- 3.0 torr) and restoration in regional cerebral blood flow (30.2 +/- 7.8 vs. 21.6 +/- 10.9 cc 100 g-1 min-1) when compared to t-PA therapy alone although statistical significance was not achieved. No efficacy was demonstrated in the group receiving HUDREG200 without concomitant t-PA therapy. The results suggest the addition of a humanized anti-L-selectin monoclonal antibody HuDREG200 in combination with t-PA may further improve outcome in acute thromboembolic stroke, although future studies are necessary to support these findings.
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PMID:Humanized anti-L-selectin monoclonal antibody DREG200 therapy in acute thromboembolic stroke. 966 85

Oxygen deprivation, as occurs during tissue ischemia, tips the natural anticoagulant/procoagulant balance of the endovascular wall to favor activation of coagulation. To investigate the effects of low ambient oxygen tension on the fibrinolytic system, mice were placed in a hypoxic environment with pO2 < 40 Torr. Plasma levels of plasminogen activator inhibitor-1 (PAI-1) antigen, detected by ELISA, increased in a time-dependent fashion after hypoxic exposure (increased as early as 4 h, P < 0.05 vs. normoxic controls), and were accompanied by an increase in plasma PAI-1 activity by 4 h (P < 0.05 vs. normoxic controls). Northern analysis of hypoxic murine lung demonstrated an increase in PAI-1 mRNA compared with normoxic controls; in contrast, transcripts for both tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) decreased under hypoxic conditions. Immunocolocalization studies identified macrophages as the predominant source of increased PAI-1 within hypoxic lung. Using a transformed murine macrophage line, striking induction of PAI-1 transcripts occurred under hypoxic conditions, due to both increased de novo transcription as well as increased mRNA stability. Consistent with an important role of the fibrinolytic system in hypoxia-induced fibrin accumulation, PAI-1 +/+ mice exposed to hypoxia exhibited increased pulmonary fibrin deposition based upon a fibrin immunoblot, intravascular fibrin identified by immunostaining, and increased accumulation of 125I-fibrinogen/fibrin in hypoxic tissue. In contrast, mice deficient for the PAI-1 gene (PAI-1 -/-) similarly exposed to hypoxic conditions did not display increased fibrin accumulation compared with normoxic PAI-1 +/+ controls. Furthermore, homozygous null uPA (uPA -/-) and tPA (tPA -/-) mice subjected to oxygen deprivation showed increased fibrin deposition compared with wild-type controls. These studies identify enhanced expression of PAI-1 as an important mechanism suppressing fibrinolysis under conditions of low oxygen tension, a response which may be further amplified by decreased expression of plasminogen activators. Taken together, these data provide insight into an important potential role of macrophages and the fibrinolytic system in ischemia-induced thrombosis.
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PMID:Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition. 972 60

Much attention has been paid to proteinases derived from not only neurons but also microglia in relation to neuronal death. There is accumulating evidence that intra- and extracellular proteinases in these cells are part of the basic machinery of neuronal death pathways. Some members of the ced-3/interleukin-1 beta converting enzyme (ICE) (caspase) family of cysteine proteinases have been thought to play a major role in apoptosis of not only non-neuronal cells but also neurons. Calpain has also been demonstrated to be a mediator of the neurodegenerative response. Recent studies have shown that excitotoxic and ischemic neuronal injury could be attenuated by inhibitors of caspases and calpain. Several recent studies have suggested the involvement of endosomal/lysosomal proteinases, including cathepsins B, D and E, in neuronal death induced by excitotoxins and ischemia. Furthermore, it has been reported that the extracellular tissue-type plasminogen activator/plasmin proteolytic cascade is involved in excitotoxic injury of the hippocampal neurons. In addition to such neuronal proteinases, microglial proteinases are believed to be important for the modification of neuronal functions positively or negatively. Cathepsins E and S derived from microglia have been suggested to contribute to neuronal survival through degradation and removal of beta-amyloid, damaged neurons and cellular debris. On the other hand, 6-hydroxydopamine-induced microglial cell death was inhibited by inhibitors of aspartic proteinases and caspases, suggesting the involvement of cathepsins E and D and caspases in microglial cell death. Therefore, identification of which proteinases play a causative role in neuronal death execution and clarification of the regulators and substrates for such proteinases is very important for understanding the molecular basis of the neuronal death pathways and to develop novel neuroprotective agents.
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PMID:[Involvement of proteinases produced by both neurons and microglia in neuronal lesion and death pathways]. 978 98

The primary goal of treatment for patients with evolving infarction should be the rapid and sustained restoration of antegrade coronary blood flow. Thrombolytic therapy is an effective and widely available therapy to achieve this aim. However, thrombolysis does not achieve recanalization of the infarct-related artery in 20% of patients and early complete reperfusion (TIMI 3 flow) is achieved in only 50%. Some small randomized trials suggested that primary angioplasty was more effective than thrombolytic therapy in restoring patency and preventing reocclusion of the infarct-related artery. Furthermore, the patients treated with immediate angioplasty had a lower incidence of recurrent ischemia, reinfarction and death than those given thrombolysis. More recently, the GUSTO IIb primary angioplasty substudy, found that primary angioplasty provided only a small short-term clinical benefit over thrombolytic therapy with t-PA, in the combined end-point of death, reinfarction and nonfatal disabling stroke at 30 days. At six months, this small benefit had vanished. The major limitation for primary angioplasty is the restricted availability of the procedure. Only when angioplasty can be performed promptly, in centers with extensive experience in angioplasty and with adequate catheterization facilities and support personnel, may it be used as the reperfusion strategy of choice. Nowadays, for the vast majority of patients, thrombolysis remains the best available treatment for acute myocardial infarction.
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PMID:[Primary angioplasty is elective reperfusion therapy in the treatment of acute myocardial infarction. Arguments against]. 992 44

We used an adaptation of a well-established rat model of middle cerebral artery occlusion (MCAO) that is both minimally invasive and reproducible to determine the effects of time to reperfusion and administration of tissue plasminogen activator (t-PA) on the development of hemorrhagic transformation (HT) in a rat model of acute stroke. Animals were randomized to receive either t-PA 10 mg/kg (29 rats) or an equal volume of saline (29 rats) over 20 minutes, beginning 5 minutes before reperfusion. Time to artery reopening varied between 1 and 24 hours after MCAO in both groups. At 18-24 hours after ischemia, the animals were sacrificed and their brains were preserved for analysis of HT. Logistic regression was used to determine the influence of time on HT risk and calculate the time at which 50% of animals developed HT (HT50%). At 24 hours, HT was present in 17 of 29 animals in each group and was significantly influenced by the time of artery reopening: 3 (15%) of 20 animals reperfused less than 3 hours after onset of ischemia and 32 (84%) of 38 reperfused 3 or more hours after the onset of ischemia (p<0.001). There was no difference in HT50% between groups. Time to artery reopening is an important determinant of HT risk in this model of cerebral ischemia. This model may have utility in developing strategies to reduce HT formation after thrombolytic therapy in patients with acute stroke.
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PMID:Hemorrhagic transformation in focal cerebral ischemia: influence of time to artery reopening and tissue plasminogen activator. 1003 Jul 60

The contribution of the complement system to cerebral ischemic and ischemia/reperfusion injury was examined in a rabbit model of thromboembolic stroke by delivery of an autologous clot embolus to the intracranial circulation via the internal carotid artery. A two-by-two factorial design was employed to study the impact of complement depletion via pretreatment with cobra venom factor (CVF, 100 U/kg i.v.) in the setting of permanent (without tissue plasminogen activator; t-PA) and transient (with t-PA) cerebral ischemia. Thirty-two New Zealand white rabbits were assigned to one of four groups (n=8, each group): control without t-PA, control with t-PA, CVF without t-PA and CVF with t-PA. In the complement intact animals, t-PA administration resulted in an approximate 30% reduction in infarct size when compared to the group not receiving t-PA (20.4+/-6.6% of hemisphere area vs. 30.1+/-7.2%; mean+/-SEM). However, infarct sizes in the complement depleted rabbits, with (30.7+/-8.2%) or without (30.2+/-7.9%) t-PA, were no different from the control group receiving no therapy. Similarly, no difference in regional cerebral blood flow or final intracranial pressure values was noted between any of the four groups. Complement activation does not appear to be a primary contributor to brain injury in acute thromboembolic stroke.
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PMID:Complement depletion does not reduce brain injury in a rabbit model of thromboembolic stroke. 1022 42


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