Thrombolytic therapy with tissue plasminogen activator or streptokinase induces transient thrombin activity

We have determined the plasma level of fibrinopeptide A as a specific index of thrombin activity during the infusion of a thrombolytic agent in patients with acute myocardial infarction. Peripheral venous plasma levels of fibrinopeptide A increased following the initiation of thrombolytic therapy from 2.7 nmol/L to a peak of 13.0 nmol/L at 30 minutes with streptokinase and from 1.1 nmol/L to a peak of 10.7 nmol/L at 90 minutes with tissue plasminogen activator. The amount of fibrinogen converted to fibrin I was determined by integration of the plasma level of fibrinopeptide A over time. The amount of fibrin I formed over the five-hour period from the start of drug infusion was approximately 10 mg/dL in response to either streptokinase or recombinant tissue plasminogen activator. We conclude that activation of coagulation occurs in response to thrombolytic therapy despite heparin administration. This thrombin action, though transient, would be sufficient to cause rethrombosis if localized and incompletely opposed by fibrinolytic activity.     

尿激酶型纤溶酶原激活剂治疗血栓栓塞性疾病的研究

尿激酶型纤溶酶原激活剂（u-PA／Pro—UK）是第二代溶栓剂，具有纤维蛋白特异性。多项Pro-UK治疗急性心肌梗死的随机对照试验证实，其早期冠脉开通率高，再栓率低。动脉内局部应用Pro—UK治疗急性缺血性脑卒中，可以将溶栓窗延长至6个小时，并明显改善预后。Pro—UK应用于急性大面积肺栓塞可以改善血流动力学指标，是一种理想的溶栓剂。     

Thrombolytic therapy in canine pulmonary embolism. Comparative effects of urokinase and recombinant tissue plasminogen activator

We compared thrombolytic and pulmonary hemodynamic effects of recombinant tissue plasminogen activator (rtPA) and urokinase (UK) in canine micropulmonary thromboembolism. Dogs were embolized with radioactive autologous blood clot to increase mean pulmonary artery pressure (from 13 to 34 mm Hg, p less than 0.005) and decrease cardiac output (2.5 to 1.6 L min, p less than 0.005). Four groups of six dogs were treated. We employed two doses of UK, 30,000 U/kg (UK30) and 60,000 U/kg (UK60), and two doses of rtPA, 1 mg/kg (rtPA1) and 2 mg/kg (rtPA2). Drugs were infused over 15 min. Rate and extent of pulmonary thrombolysis were assessed by continuously counting over both lung fields with a gamma camera. Compared with treatment with UK, both rtPA regimes significantly increased thrombolysis. Mean total pulmonary thrombolysis was 14 and 23% with UK30 and UK60, respectively, and 35 and 43% with rtPA1 and rtPA2. Corresponding to the increased thrombolysis, pulmonary hemodynamics improved most with rtPA. From 90 min to 3 h, pulmonary artery pressure was significantly lower with both rtPA regimes than with either UK regime. These results indicate, at least in the model employed, that compared with treatment with UK, pulmonary thrombolysis and corresponding hemodynamic improvement are greatest with rtPA.     

Thrombolytic therapy of massive pulmonary embolism during prolonged cardiac arrest using recombinant tissue-type plasminogen activator

Cardiac arrest caused by massive pulmonary embolism is highly refractory to conventional resuscitation. Emergency surgical embolectomy has been considered the only effective intervention. We present the case of a 33-year-old woman who suffered a massive pulmonary embolism with circulatory arrest refractory to one half hour of aggressive CPR. A 10-mg bolus of recombinant tissue-type plasminogen activator was administered through a central line followed by a further 90-mg IV infusion over two hours. Rapid hemodynamic and clinical improvement followed the bolus dose. The patient was discharged later without neurological or other sequelae. This is the first reported case of successful thrombolytic therapy of massive pulmonary embolism during prolonged CPR.     

Increased levels of tissue plasminogen activator with a low plasminogen activator inhibitor-1 in a patient with postoperative bleeding

Recurrent postoperative bleeding in a previously healthy man with a moderate prolongation of PT and PTT which did not correct with vigorous fresh-frozen plasma infusion was identified as a unique abnormality of the fibrinolytic system: a combination of an excess of tissue plasminogen activator (t-PA) at 300% of normal activity accompanied by a concurrent deficiency of plasminogen activator inhibitor-1 activity (PAI-1) of 10-20% of normal activity. This observation underscores the potentially important regulatory role of PAI-1 in the degree to which clinical manifestations of bleeding tendencies may occur in patients in whom an excess amount of t-PA is expressed.     

Thrombolytic therapy with streptokinase and tissue plasminogen activator in a patient with suspected acute myocardial infarction: A decision analysis.

Two commonly used thrombolytic agents are streptokinase (SK) and tissue plasminogen activator (t-PA), which have different impacts on the incidence of mortality and thrombolysis-related acute intracranial hemorrhage. A decision-analytic model was developed to compare the use of SK and t-PA in the treatment of a patient with suspected acute myocardial infarction (AMI). The outcome was health-related quality of life as quantified in a measure of utility from the patient's point of view. The model included three outcome states: death, nonfatal yet disabling stroke, and survival with no disabling stroke. The utility for disabling stroke was determined relative to the reference states of no disabling stroke (1.00) and death (0.00) by means of the time trade-off estimation technique. Probabilities were derived from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Artery trial, which revealed that although administering t-PA results in a lower percentage of deaths compared to SK, it may lead to a higher percentage of strokes. A decision tree was constructed to model the options and outcomes. The tree was analyzed by standard decision analytic techniques using SMLTREE software, and the stability of the results was examined as values of parameters were varied systematically in a sensitivity analysis. In the baseline analysis, SK yielded 0.9235, whereas t-PA yielded 0.9329. The sensitivity analysis revealed that if the probability of a disabling stroke attributable to t-PA were greater than 2.08%, SK would yield the higher expected utility. This threshold value, however, was much greater than the probability established in major trials. The administration of t-PA leads to a slightly better outcome than does the administration of SK in a patient with suspected AMI.     

Thrombolytic retreatment with tissue plasminogen activator for threatened reinfarction and thrombotic coronary reocclusion

Following successful coronary arterial thrombolysis, thrombogenic substrate persists, increasing the risk of recurrent thrombosis, reocclusion, and reinfarction. The preferred treatment in this setting has not been established. Although many patients receive mechanical revascularization, it is conceivable that repeat thrombolysis. primarily with tissue plasminogen activator, represents the most readily available and effective alternative.     

小剂量重组织型纤溶酶原激活剂与尿激酶、重组链激酶溶栓治疗急性心肌梗死的临床对比分析

目的观察小剂量重组织型纤溶酶原激活剂（rt—PA）、尿激酶（UK）和重组链激酶（r—sK）治疗急性心肌梗死的疗效和安全性。方法114例急性心肌梗死患者随机分为rt—PA组38例，UK组37例，r—SK组39例。分别应用纤溶酶原激活剂50mg、尿激酶150万U、链激酶150万U静脉输入。结果rt—PA组、UK组、r—sK组临床血管再通率分别为84．21％、51．35％、69．23％，三者之间疗效比较P〈0．05。3组溶栓后不良反应、5周病死率比较P〉0．05，差异无显著性。结论rt—PA治疗急性心肌梗死的疗效明显优于UK和r—SK，而r—SK的疗效优于UK。溶栓后不良反应、5周病死率比较差异无显著性。     

Determination of a weight-adjusted dose of TNK-tissue plasminogen activator

BACKGROUND: TNK-tissue plasminogen activator (TNK-tPA) is a potent new thrombolytic agent for treatment of acute myocardial infarction. TNK-tPA was evaluated in 4214 patients in two dose-ranging trials (Thrombolysis in Myocardial Infarction [TIMI] 10B and Assessment of the Safety and Efficacy of a New Thrombolytic Agent [ASSENT] I). This article describes the rationale for the weight-adjusted dosing regimen of TNK-tPA that was selected for evaluation in the large phase III clinical trial ASSENT II. METHODS: Weight-based analyses were conducted with data from both the angiographic TIMI 10B trial, which compared TNK-tPA in doses of 30 mg, 40 mg, and 50 mg with the accelerated regimen of tPA in 889 patients, and the ASSENT I trial, which evaluated the safety of TNK-tPA in doses of 30 mg, 40 mg, and 50 mg in 3301 patients. Graphic and statistical analytic methods were used to assess relationships between weight and efficacy or safety measurements. RESULTS: The plasma clearance, initial plasma concentrations, and plasma steady-state volume of distribution all increased with decreasing body weight (all P<.001). The corrected TIMI frame count decreased (flow was faster) (P =.001) and the TIMI grade 3 flow increased with an increasing weight-standardized dose of TNK-tPA (P<.008). Mortality was inversely related to dose, but this relationship was not statistically significant. There was no clear relationship between intracranial hemorrhage and dose and weight. Serious bleeding events increased with increasing weight-standardized dose (P<.02). CONCLUSIONS: On the basis of these analyses, a weight-adjusted dosing regimen was devised for TNK-tPA that included five dosing increments and was based on a target weight-standardized dose of 0.53 mg/kg.     

Intrapleural tissue plasminogen activator and deoxyribonuclease therapy for pleural infection

Pleural infection remains a global health burden associated with significant morbidity. Drainage of the infected pleural fluid is important but can often be hindered by septations and loculations. Intrapleural fibrinolytic therapy alone, to break pleural adhesions, has shown no convincing advantages over placebo in improving clinical outcome. Deoxyribonucleoprotein from degradation of leukocytes contributes significantly to high viscosity of infected pleural fluid. Recombinant deoxyribonuclease (DNase) is effective in reducing pleural fluid viscosity in pre-clinical studies. The combination of tissue plasminogen activator (tPA) and DNase was effective in animal model experiments of empyema. The benefits were established in a randomized clinical trial: those (n=48) treated with tPA/DNase had significantly improved radiological outcomes and reduced need of surgery and duration of hospital stay. A longitudinal observational series of 107 patients further confirmed the effectiveness and safety of tPA/DNase therapy, including its use as ‘rescue therapy’ when patients failed to respond to antibiotics and chest tube drainage. Overall, a short course of intrapleural tPA (10 mg) and DNase (5 mg) therapy provides a cure in over 90% of patients without requiring surgery. The treatment stimulates pleural fluid formation, enhances radiographic clearance and resolution of systemic inflammation. Serious complications are uncommon; pleural bleeding requiring transfusion occurred in ~2% of cases. Pain can occur, especially with the first dose. Treatment is contraindicated in those with significant bleeding diathesis or a bronchopleural fistula. Future research is required to optimize dosing regimens and in refining patient selection.     

Activity of tissue plasminogen activator and plasminogen activator inhibitor in noninsulin-dependent diabetes mellitus

The activity of free tissue plasminogen activator (f-tPA) and plasminogen activator inhibitor (PAI) in the plasma of 82 noninsulin-dependent diabetics (NIDDM) was measured by bioimmunoassay of the euglobulin fraction obtained from the plasma, and the levels were compared with those of age- and gender-matched normal subjects. Comparison of these levels in both groups revealed that the f-tPA activity tended to be lower in NIDDM than in the controls, although the differences were not significant. Normal activity of PAI was seen, but f-tPA in NIDDM, when accompanied by macroangiopathy such as ischemic heart disease, was significantly depressed. When glycosylated hemoglobin levels were in excess of 10%, the f-tPA activity was significantly decreased, but no reduction was found in PAI activity as compared with controls. When NIDDM is associated with either macroangiopathy or high glycosylated hemoglobin levels, a decreased f-tPA activity, rather than an increased PAI activity, may contribute to the development of a defective fibrinolytic state.     

Systemic and local saphenous vein graft thrombolysis using a tissue plasminogen activator

Many studies are currently evaluating the potential role of thrombolytic therapy in patients with ischemic syndromes who have undergone previous coronary artery bypass grafting. Limited experience has been published regarding the use of local urokinase and streptokinase infusions and the use of systemic recombinant tissue-type plasminogen activator as thrombolytic agents in patients with previous coronary artery bypass surgery. To date, however, there has been no published experience regarding the use of recombinant tissue-type plasminogen activator (rt-PA) either systemically or locally in the post-bypass patient where angiographic demonstration of aortocoronary saphenous vein graft obstruction was available pre- and post-therapy. Similarly there has been no previous report of the use of rt-PA infused locally to recanalize an occluded aortocoronary saphenous vein graft. This report describes successful thrombolysis and subsequent balloon angioplasty of saphenous vein grafts with angiographically documented thrombus using systemic and local rt-PA infusion.     

Controversies about tissue plasminogen activator: Extending the window of therapy

The management of stroke has undergone significant development over the past 15 years. Perhaps the single most important landmark has been the approval by the Food and Drug Administration of intravenous (IV) tissue plasminogen activator (t-PA) for the treatment of ischemic stroke. However, the approval of this drug has not met with unanimous support by the medical community and, at present, only a minority of stroke patients receive t-PA. Although this is partly due to the fact that many patients do not meet criteria for treatment with IV t-PA, others simply do not arrive at medical facilities sufficiently early to be safely managed using thrombolysis. The appropriate use of IV t-PA in the treatment of ischemic stroke requires proper selection of patients and strict adherence to clinical protocols of treatment. The ideal stroke patient for treatment with IV t-PA is one who suffers occlusion of a small artery that leads to a disabling deficit.     

Future directions in plasminogen activator therapy

Thrombotic disorders such as myocardial infarction and stroke are the leading causes of death and disability in industrialized nations. Timely institution of thrombolytic therapy can achieve a reduction of infarct size, a preservation of left ventricular function, and a reduction in mortality. The administration of streptokinase, urokinase, and acylated plasminogen-streptokinase activator complex (APSAC) can be associated with a complete breakdown of the hemostatic system. Tissue-type plasminogen activator (t-PA) and single-chain urokinase-type plasminogen activator (scu-PA, prourokinase) are more fibrin specific; however, at the large dosages of activator needed for therapeutic efficacy, bleeding complications are still a problem. New approaches to optimizing the risk/benefit ratio for the patient by improving efficacy without sacrificing specificity include the use of synergistic combinations of plasminogen activators, mutants of t-PA and scu-PA, chimeric molecules, and antibody-targeted thrombolytic agents. The last approach opens the possibility of targeting several different components of the clot with either fibrinolytic or antiplatelet effector functions in one optimized molecule.     

Thrombolytic activity of a novel plasminogen activator, LY210825, compared with recombinant tissue-type plasminogen activator in a canine model of coronary artery thrombosis

LY210825, a recombinant tissue-type plasminogen activator (rt-PA), which contains the kringle-2 and serine protease functional domains of native tissue-type plasminogen activator, was previously produced by site-directed mutagenesis in a Syrian hamster cell line. We studied the thrombolytic potential of this molecule in a canine thrombosis model. Male hounds (16-22 kg) were anesthetized; a 2.0-cm segment of the left circumflex coronary artery (LCX) was isolated proximal to the first main branch, and the dogs were instrumented with an electromagnetic flow probe to measure coronary blood flow. An occlusive thrombus was formed after injury of the intimal surface of the LCX with an electrical current applied by a needle-tipped anode placed distal to the electromagnetic flow probe. After 1 hour of occlusion, either LY210825 or rt-PA was administered intravenously according to the following protocols: 1) a 1-hour infusion of either 0.25 mg/kg LY210825 or 0.4 mg/kg rt-PA, 2) single injections of 0.15-0.6 mg/kg LY210825, and 3) a single injection of 0.45 mg/kg LY210825 and a 3-hour infusion of 1.0 or 1.7 mg/kg rt-PA. Plasma half-lives of LY210825 and rt-PA were 58 +/- 7 and 3.3 +/- 0.3 minutes, respectively. LY210825 produced more rapid reperfusion of the LCX than did rt-PA. In the third study, 90% of the rt-PA-treated vessels reoccluded within 1 hour after cessation of drug, whereas only 25% of the LY210825-treated vessels reoccluded during a 4-hour washout period. There were significant, but relatively small, reductions produced by both plasminogen activators on plasma fibrinogen and plasminogen (25-35% decreases). Because of its longer plasma half-life, LY210825 could be administered intravenously as a single injection. In a canine model of coronary artery thrombosis, LY210825 was a more effective thrombolytic agent than was rt-PA.