Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our purpose was to evaluate the outcomes of patients with prior coronary angioplasty who underwent thrombolysis for new acute myocardial infarction (AMI) in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries-I trial. Baseline characteristics and clinical outcomes were compared between patients with (n = 1,647) and without (n = 39,150) previous angioplasty. The relations among prior angioplasty, clinical outcomes, and treatment effects were examined with logistic regression modeling. Patients with previous angioplasty tended to be younger and presented sooner after symptom onset, but had more multivessel disease and lower ejection fractions. Unadjusted mortality was significantly lower in the prior-angioplasty group at 24 hours (1.8% vs 2.7%, p = 0.03) and 30 days (5.6% vs 7.0%, p = 0.036). Although most of the survival advantage was due to low-risk characteristics in this group (lower age and heart rate and fewer anterior wall AMIs), prior angioplasty remained a weak but independent predictor of survival. Recurrent ischemia and reinfarction occurred more often in the prior-angioplasty group, as did bypass surgery (12.2% vs 8.5%) and repeat angioplasty (34.5% vs 21.4%). Patients with prior angioplasty and prior AMI had lower 30-day mortality than those with prior infarction alone (6.3% vs 12.6%, p < 0.01). Treatment effects on 30-day mortality were similar among patients with prior angioplasty (odds ratio 1.2 for accelerated tissue-plasminogen activator v. combined streptokinase arms, 95% confidence interval 0.73 to 1.9). Patients with prior angioplasty who present with AMI have fewer in-hospital adverse events and lower 30-day mortality than those without such a history.
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PMID:Thrombolytic therapy for patients with prior percutaneous transluminal coronary angioplasty and subsequent acute myocardial infarction. GUSTO-I Investigators. Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries. 897 Apr 3

We developed a fibrin-rich thrombotic focal cerebral ischemic model with reproducible and predictable infarct volume in rats. In male Wistar rats (n = 77), a thrombus was induced at the origin of the middle cerebral artery (MCA) by injection of thrombin via an intraluminal catheter placed in the intracranial segment of the internal carotid artery (ICA). Thrombus induction and consequent ischemic cell damage were examined by histopathological analysis and neurological deficit scoring, and by measuring changes in cerebral blood flow (CBF) using laser-Doppler flowmetery (LDF), perfusion-weighted imaging (PWI), and by diffusion weighted imaging (DWI). Histopathology revealed that a fibrin-rich thrombus localized to the origin of the right MCA. Regional cerebral blood flow (rCBF) in the right parietal cortex was reduced by 34-58% of preinjection levels after injection of thrombin in rats administered 30 U of thrombin (n = 10). Magnetic resonance imaging (MRI) showed a reduction in CBF and a hyperintensity DWI encompassing the territory supplied by the right MCA. The infarct volume in rats administered 80 U of thrombin was 31.29 +/- 12.9% of the contralateral hemisphere at 24 h (n = 13), and 34.7 +/- 16.4% of the contralateral hemisphere at 168 h (n = 6). Rats administered 30 U of thrombin exhibited a hemispheric infarct volume of 34.0 +/- 14.5% (n = 9) at 24 h and 29.7 +/- 13.9% (n = 8) at 168 h. In addition, thrombotic rats (n = 3) treated with recombinant tissue plasminogen activator (rt-PA) (10 mg/kg) 2 h after thrombosis showed that CBF rapidly returned towards preischemic values as measured by PWI. This model of thrombotic ischemia is relevant to thromboembolic stroke in humans and may be useful in documenting the safety and efficacy of thrombolytic intervention as well as for investigating therapies complementary to antithrombotic therapy.
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PMID:A new rat model of thrombotic focal cerebral ischemia. 904 Apr 91

Adhesions, which occur after 67% to 93% of abdominal operations, represent a major clinical problem, resulting in intestinal obstruction, infertility, and pain and incurring considerable economic costs. The magnitude and seriousness of the problem of adhesions have been underappreciated. Moreover, efforts to prevent or reduce adhesions largely have been unsuccessful, hindered by their empirical basis, the lack of good predictive animal models, and the biochemical complexities of adhesiogenesis. The two major strategies for adhesion prevention or reduction are adjusting surgical technique and applying adjuvants. Modifications in technique that all surgeons should implement include minimizing the invasiveness of surgery, minimizing surgical trauma, such as ischemia from peritoneal suturing, and avoiding the introduction of foreign material, e.g., starch glove powder, into the body. Given the adhesiogenic nature of peritoneal repair, however, improvements in surgical technique alone will help decrease but not prevent adhesion formation. Adjuvant therapy is necessary. Adjuvants fall into two main categories, drugs and barriers. Nonsteroidal anti-inflammatory drugs have shown questionable clinical efficacy, possibly because of difficulties in drug delivery. Corticosteroids, alone or with antihistamines, also have had equivocal clinical results and may be immunosuppressive and delay wound healing. Experimentally, fibrinolytics such as tissue plasminogen activator (tPA), administered systemically or intraperitoneally (i.p.), have demonstrated conflicting results and hemorrhagic complications. However, recently, tPA, administered topically in a carboxymethylcellulose (CMC) gel, has been effective in reducing and preventing adhesions in rabbits. Phosphatidylcholine, given i.p. or orally, also has shown promise in animal studies. Barriers, by separating traumatized surfaces for the critical first five to seven days of peritoneal re-epithelialization, are useful adjuvants, and include macromolecular solutions and mechanical devices. Dextran, a macromolecular solution, has been studied widely, but has not demonstrated consistent clinical efficacy and has been largely abandoned as an anti-adhesion barrier. A newly developed hyaluronic acid-phosphate-buffered saline solution applied intraoperatively to protect peritoneal surfaces from indirect surgical trauma effectively and safely reduced adhesions in a large multicenter study of women undergoing gynecological laparotomy. Three recently developed mechanical barriers also have demonstrated clinical progress in adhesion prevention. A bioresorbable membrane consisting of hyaluronic acid and CMC has gained regulatory approval for clinical use in both general and gynecological surgery following demonstration of efficacy and safety in reducing adhesions. A barrier made of expanded polytetrafluoroethylene and another developed from oxidized regenerated cellulose are currently available for gynecological surgery. With continued research, new and improved approaches hopefully will become available to prevent adhesion formation.
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PMID:Adhesions: preventive strategies. 907 50

We conducted a study using diffusion-weighted (DWI) and perfusion-weighted (PWI) magnetic resonance imaging (MRI) to evaluate the efficacy of thrombolysis in an embolic stroke model with recombinant tissue plasminogen activator (rt-PA) and hirulog, a novel direct-acting antithrombin. DWI can identify areas of ischemia minutes from stroke onset, while PWI identifies regions of impaired blood flow. Right internal carotid arteries of 36 rabbits were embolized using aged heterologous thrombi. Baseline DWI and PWI scans were obtained to confirm successful embolization. Four animals with no observable DWI lesion on the initial scan were excluded; therefore, a total of 32 animals were randomized to one of three treatment groups: rt-PA (n = 11), rt-PA plus hirulog (n = 11), or placebo (n = 10). Treatment was begun 1 h after stroke induction. Intravenous doses were as follows: rt-PA, 5 mg/kg over 0.5 h with 20% of the total dose given as a bolus; hirulog, 1 mg/kg bolus followed by 5 mg/kg over 1 h. MRI was performed at 2, 3, and 5 h following embolization. Six hours after embolization, brains were harvested, examined for hemorrhage, then prepared for histologic analysis. The rt-PA decreased fibrinogen levels by 73%, and hirulog prolonged the aPTT to four times the control value. Posttreatment areas of diffusion abnormality and perfusion delay were expressed as a ratio of baseline values. Significantly improved perfusion was seen in the rt-PA plus hirulog group compared with placebo (normalized ratios of the perfusion delay areas were as follows: placebo, 1.58, 0.47-3.59; rt-PA, 1.12, 0.04-3.95; rt-PA and hirulog, 0.40, 0.02-1.08; p < 0.05). Comparison of diffusion abnormality ratios measured at 5 h showed trends favoring reduced lesion size in both groups given rt-PA (normalized ratios of diffusion abnormality areas were as follows: placebo, 3.69, 0.39-15.71; rt-PA, 2.57, 0.74-5.00; rt-PA and hirulog, 1.95, 0.33-6.80; p = 0.32). Significant cerebral hemorrhage was observed in one placebo, two rt-PA, and three rt-PA plus hirulog treated animals. One fatal systemic hemorrhage was observed in each of the rt-PA groups. We conclude that rt-PA plus hirulog improves cerebral perfusion but does not necessarily reduce cerebral injury. DWI and PWI are useful methods for monitoring thrombolysis.
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PMID:Improved perfusion with rt-PA and hirulog in a rabbit model of embolic stroke. 914 22

The lower temperatures utilized during profound hypothermic circulatory arrest (PHCA) surgery may exacerbate the hypothermia associated platelet and clotting factor dysfunction observed in conventional cardiopulmonary bypass (CPB) procedures. Hypothermia has been shown to impair the activity of the enzymes involved in the platelet activation pathways and to reduce the enzymatic activity of clotting factors upon coagulation activation. The resulting retardation of the generation of fibrin/platelet clot compounded by the presence of heparin may contribute significantly to a bleeding tendency. Excessive fibrinolytic activity may disrupt surgical wound thrombi and exacerbate haemorrhage. There is good evidence that the fibrinolytic activity, mediated predominantly by tissue plasminogen activator (tPA), is a secondary response to thrombin generated by coagulation activation, which is ongoing during CPB despite full heparinization. The effects of hypothermia on the fibrinolytic response remain to be clarified and the extent to which the lower temperatures and blood stasis associated with PHCA moderate this response is unknown. Despite impairment of coagulation activation by hypothermia there appears to be a shift in the hemostatic balance towards thrombosis presumably as a consequence of endothelial cell injury by both hypothermia and stasis induced ischemia. There is evidence that widespread microvascular thrombus deposition may occur as a consequence of stasis in patients undergoing PHCA and that this might result in vascular occlusion and end organ damage. Although it is not uncommon to find laboratory evidence of disseminated intravascular coagulation (DIC) in patients presenting with aortic aneurysm rupture or dissection, the incidence of clinically overt DIC resulting in bleeding is low. The underlying hemostatic disturbance however may contribute to the surgery-associated bleeding diathesis.
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PMID:Hematological consequences of profound hypothermic circulatory arrest and aortic dissection. 927 46

Ischemic stroke occurs after an abrupt reduction in cerebral blood flow, usually related to thrombosis of an intracranial or extracranial artery. The presenting symptoms and signs of stroke vary greatly, depending on the region of the brain involved. Most individuals are unaware of the warning signs or symptoms of stroke and do not seek medical care immediately after stroke onset. Recently, thrombolytic therapy with intravenous tissue plasminogen activator (t-PA) has been shown to be effective for treatment of selected stroke patients if administered <3 hours after stroke onset. This therapy is now approved for stroke treatment, but relatively few stroke patients currently receive t-PA. Neuroprotective agents that improve the intrinsic ability of brain parenchyma to withstand ischemia are currently undergoing intensive clinical evaluation. Their development has been facilitated by significant scientific advances in the understanding of the pathophysiology of acute ischemic neuronal injury. Strategies aimed at interfering with these fundamental processes of ischemic neuronal injury have shown encouraging results in several preliminary clinical trials. However, these agents probably must also be administered within a few hours of stroke onset to be beneficial. Eventually, combined neuroprotective and thrombolytic therapy will likely be used for acute stroke treatment. This strategy's success will depend on increased public and professional education efforts dealing with stroke recognition, evaluation, and treatment.
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PMID:Rationale for early intervention in acute stroke. 928 38

Progesterone stimulation of the estradiol (E2)-primed human endometrium initiates DZ of the stromal cells around the spiral arterioles. Under continued steroid stimulation, DZ spreads wave-like to establish the decidual cell as a major cell type of the luteal phase and pregnant endometrium. Because of their widespread distribution throughout the endometrium and concentration at perivascular sites, decidual cells are spatially and temporally positioned to mediate the opposing requirements of maintaining hemostasis during endovascular trophoblast invasion, yet promoting menstrual hemorrhage in the absence of implantation. The experimental results summarized in this review indicate that the paradoxical properties manifested by endometrial stromal/decidual cells are controlled by several proteins with either hemostatic or ECM-degrading or vasoactive activity, and that their expression is altered in response to changes in levels of circulating ovarian steroids during the menstrual cycle. These conclusions are drawn primarily from studies with a well-characterized in vitro model of DZ using monolayers of stromal cells derived from specimens of predecidualized endometrium. Thus, progestins modify the expression of several DZ-related markers in the cultured stromal cells, and E2 enhances these effects despite the lack of response to E2 alone. These responses are consistent with the differential actions displayed by E2 and progesterone in vivo, by which E2 primes the endometrium for the decidualizing effects of progesterone by elevating progesterone receptor levels. Accordingly, during steroid-induced in vitro DZ, a marked increase in the expression of stromal cell TF and PAI-1 and reciprocal inhibition of tPA activity suggest mechanisms to account for the absence of hemorrhage during invasion of the endometrial vasculature by implanting trophoblasts. In contrast to steroid-induced DZ, the events of menstruation are initiated in response to a decline in circulating levels of ovarian steroids. Accordingly, subjecting in vitro decidualized stromal cells to steroid withdrawal results in pronounced reversal in the expression of all of the end points listed above. Consequently, the local hemostatic environment is transformed into a hemorrhage-promoting milieu. Taken together with vascular injury resulting from ischemia induced by spiral artery vasoconstriction, the net effect is attainment of two prerequisites for menstrual hemorrhage, vascular injury and inadequate hemostasis.
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PMID:Decidual cell regulation of hemostasis during implantation and menstruation. 932 39

In a prospective study, the role of various hemostatic factors known to be associated with thrombotic risk was investigated in 71 patients with peripheral arterial occlusive disease (PAOD, stages II through IV, Fontaine; aged 68 +/- 13 years). Laboratory investigations were done before; 1, 24, and 48 hours after; and 3 and 6 months after percutaneous transluminal angioplasty (PTA). Thirty of 71 (42.3%) patients developed restenosis (> 50% reduction of the lumen diameter) at the site of PTA within 6 months, verified by color-coded duplex sonography. Significantly increased levels of thrombin-antithrombin III complexes (P < .01), prothrombin fragments 1 + 2 (P < .01), and D-dimers (P < .01) were found 1 hour, as well as 24 to 48 hours, after PTA. Fibrinogen (P < .01) and von Willebrand factor (P < .01) were significantly higher 48 hours after PTA. Restenotic patients as a whole had higher plasma fibrinogen (3.46 +/- 1.12 versus 2.95 +/- 0.62 g/L, P < .01) and C-reactive protein (25.4 +/- 46.7 versus 7.9 +/- 6.9 mg/L, P < .05) at baseline, as well as higher fibrinogen (P < .05) and prothrombin fragments 1 + 2 (P < .01) during months 3 to 6 after PTA. There was a nonsignificant tendency for higher values of von Willebrand factor (206 +/- 98% versus 184 +/- 100%, P = .2) at baseline in patients with restenosis, whereas tissue plasminogen activator, plasminogen activator inhibitor, coagulation screening tests, blood cell counts, and serum lipids showed no significant difference between the two groups. The relative risk for developing restenosis within 6 months while having high fibrinogen (> 2.8 g/L) or C-reactive protein at baseline was 2.80 (95% CI: 1.30-6.02, P < .01) and 1.96 (95% CI: 1.07-3.58, P < .05), respectively. Patients with critical limb ischemia (stage III/IV, Fontaine) had significantly higher fibrinogen and von Willebrand factor at repeated points of time, as well as significantly higher C-reactive protein and lower creatinine clearance at entry. In the logistic regression risk factor analysis, baseline plasma fibrinogen, C-reactive protein concentration, and the severity of the arterial disease were significantly predictive of restenosis. Our results indicate that high procoagulant factors and persistent thrombin generation of the hemostatic system might promote restenosis, particularly in patients with extended atherosclerosis. This finding suggests that new treatment strategies should be taken under consideration for patients with PAOD and PTA.
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PMID:Role of hemostatic risk factors for restenosis in peripheral arterial occlusive disease after transluminal angioplasty. 940 13

Current protocols for use of tissue-type plasminogen activator in acute myocardial infarction include heparin estimated by the activated partial thromboplastin time (aPTT). Recent reports indicate a risk of recurrent ischemic events with long aPTT values. Longer aPTT values in the Thrombolysis in Myocardial Infarction-II (TIMI II) Trial, obtained within the first 48 hours, were associated with patency at 18 to 48 hours and better left ventricular function at discharge (average 9.6 days), but also with emergency catheterizations within the first 48 hours and, weakly, with recurrent ischemia during the first 18 hours. A moderate decrease in fibrinogen, compared with a "small" decrease, was also associated with patency, but a "large" decrease was associated with hemorrhagic events. Patency was associated with higher fibrinogen values and higher plasminogen values at baseline. The aPTT results support frequent monitoring during the first 24 to 48 hours to ensure optimal clinical outcome. The coagulation factor results suggest that there may be an optimum window for fibrinogenolysis in this setting.
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PMID:Relation of coagulation parameters to patency and recurrent ischemia in the Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial. 945 18

Intravenous tissue plasminogen activator (tPA) is used to treat acute stroke because of its thrombolytic activity and its ability to restore circulation to the brain. However, this protease also promotes neurodegeneration after intracerebral injection of excitotoxins such as glutamate, and neuronal damage after a cerebral infarct is thought to be mediated by excitotoxins. To investigate the effects of tPA on cerebral viability during ischemia/reperfusion, we occluded the middle cerebral artery in wild-type and tPA-deficient mice with an intravascular filament. This procedure allowed us to examine the role of tPA in ischemia, independent of its effect as a thrombolytic agent. tPA-deficient mice exhibited approximately 50% smaller cerebral infarcts than wild-type mice. Intravenous injection of tPA into tPA-/- or wild-type mice produced larger infarcts, indicating that tPA can increase stroke-induced injury. Since tPA promotes desirable (thrombolytic) as well as undesirable (neurotoxic) outcomes during stroke, future therapies should be aimed at countering the excitotoxic damage of tPA to afford even better neuroprotection after an acute cerebral infarct.
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PMID:Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. 946 Nov 81


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