Medico-Legal Aspects of Using Tissue Plasminogen Activator in Acute Ischemic Stroke

Intravenous alteplase or tissue plasminogen activator (tPA) has been the standard of care with proven efficacy for acute ischemic stroke for over a decade. Despite this, only a small fraction of potentially eligible stroke patients receive this medication. There seems to be a fear among practitioners of legal repercussions as a result of an increased risk of intracerebral hemorrhage due to tPA. This review of legal cases involving tPA will show that instead, physicians are often found liable as a result of not treating with tPA.     

组织型纤溶酶原激活物及其抑制剂与动脉粥样硬化的关系

组织型纤溶酶原激活物（tPA）和纤溶酶原激活物抑制剂（PAI）是纤溶系统外激活途径的重要活性物质,绝大多数由小血管内皮细胞合成。内皮细胞损伤和功能紊乱是动脉粥样硬化形成的重要始动环节。文章综述了内皮细胞产生的tPA和PAI与动脉粥样硬化和缺血性脑血管病之间的关系。     

A Randomized Trial of Intravenous Streptokinase Versus Tissue Plasminogen Activator for the Treatment of Acute Myocardial Infarction: Results Using an Aggressive Approach

Seventy-six patients presenting within 6 hours of the onset of an acute myocardial infarction were randomized to either treatment with 1.5 million units of Streptokinase or 100 mg of recombinant tissue plasminogen activator intravenously. Patients not demonstrating clinical reperfusion within 1 hour were taken emergently for “salvage” angioplasty or coronary bypass surgery. Those patients demonstrating clinical reperfusion underwent early (12 to 72 hours) elective angiography and either elective angioplasty or bypass surgery. The mean time from pain onset to treatment was 149 minutes in the Streptokinase group and 134 minutes in the recombinant tissue plasminogen activator group (P = NS). There were no statistical differences between groups with regard to prior myocardial infarction, infarct location, prior coronary bypass surgery and Killip classification. Clinical reperfusion was demonstrated in 56% of the Streptokinase group and 53% of the recombinant tissue plasminogen activator group (P - NS). Angiographic patency was demonstrated in 70% of the Streptokinase group and 66% of the recombinant tissue plasminogen activator group (P = NS). Left ventricular ejection fraction at discharge was no different: 47% in the Streptokinase group and 43% in the recombinant tissue plasminogen activator group (P = NS). Recurrent ischemic events were found more often in the recombinant tissue plasminogen activator group, 18%, versus the Streptokinase group 3% (P = 0.05). Treatment outcomes did not differ between groups. There was one (3%) death in the Streptokinase group versus two (6%) deaths in the recombinant tissue plasminogen activator group (P = NS). There was a trend toward a greater need for emergent coronary bypass surgery after attempted angioplasty in the recombinant tissue plasminogen activator group, four of 18 patients (22%) versus one of 23 patients (4%) in the Streptokinase group (P = 0.14). In summary, in the setting of acute myocardial infarction treated by thrombolysis, those patients treated with recombinant tissue plasminogen activator experienced significantly more recurrent ischemic events and required emergent coronary bypass surgery more frequently for failed angioplasty compared to those treated with Streptokinase. The results suggest there may be agent specific increases in complications dependent upon the thrombolytic agent of choice when salvage or early coronary angioplasty is used.     

The Western Washington Myocardial Infarction Registry and Emergency Department Tissue Plasminogen Activator Treatment Trial

This study comprised a registry and an emergency department treatment trial using recombinant tissue plasminogen activator. During 1 year, 1,028 patients with documented acute myocardial infarction (AMI) were evaluated for eligibility for thrombolytic therapy. Of these, 221 patients (22%) were eligible for thrombolytic therapy under currently accepted criteria, 175 (79%) of them were correctly identified by emergency department physicians for thrombolytic therapy, and 160 were enrolled in the trial. Only 3 patients (2%) enrolled by emergency department physicians did not subsequently evolve documented AMI. In all, 807 patients (78%) were ineligible for thrombolytic therapy: 335 (33%) because of greater than or equal to 1 contraindications, 364 (36%) because of nondiagnostic electrocardiograms on presentation, and 105 (10%) because of age greater than 75 years, or greater than 6 hours of chest pain at presentation, or both. Mortality in treated patients at 14 days was 5.6%, and survival at 1 year was 92%. The mean time from hospital arrival to thrombolytic treatment was 55 +/- 27 minutes. Initial management of AMI with recombinant tissue plasminogen activator in the emergency department provided rapid and safe treatment comparable to that reported in trials that started treatment in the coronary care unit. The proportions of eligible patients could be increased from 1 in 5 to 1 in 3, if patients currently excluded only because of age greater than 75 years or because of greater than 6 hours of chest pain were offered treatment.     

Low-Dose Versus Standard-Dose Tissue Plasminogen Activator in Acute Ischemic Stroke in Asian Populations: A Meta-Analysis

Recent studies have investigated the most efficacious dose of intravenous tissue plasminogen activator (IV-tPA) for acute ischemic stroke (AIS) patients. There remains no definitive consensus concerning the superior efficacious IV-tPA dose (standard- vs. low-dose), prompting us to perform a meta-analysis comparing the efficacy and safety profile of standard- versus low-dose IV-tPA.We identified relevant studies pertaining to the specific aim of our meta-analysis by searching PubMed and EMBASE (January 1990–September 2015) Either a fixed- or random-effects model was employed (dependent upon data heterogeneity) to analyze the efficacy and safety outcome.Ten cohort studies involving 4389 sum patients were included in the meta-analysis. By using the random-effects model, the meta-analysis indicated no statistically significant difference in favorable functional outcome (modified Rankin scale 0–1) at 3 months (heterogeneity: χ² = 17.45, P = 0.04, I² = 48%; OR: 0.88 [95% CI: 0.71–1.11]; P = 0.28) and incidence of symptomatic intracranial hemorrhage (SICH) (heterogeneity: χ² = 14.41, P = 0.11, I² = 38%; OR: 1.19 [95% CI: 0.76 to 1.87]; P = 0.45) between the standard- and low-dose groups. The fixed-effects model demonstrated no significant difference in mortality within 3 months (heterogeneity: χ² = 6.73, P = 0.57, I² = 0%; OR: 0.91 [95% CI: 0.73–1.12]; P = 0.37) between the standard- and low-dose groups.Low-dose IV-tPA is comparable to standard-dose IV-tPA in both efficacy (favorable functional outcome) and safety (SICH and mortality). Confirmation of these findings through randomized trials is warranted.     

Acute Ischemic Stroke Successfully Treated Using Sequenced Intravenous and Intra-Arterial Thrombolysis and Argatroban Anticoagulation: A Case Study

BACKGROUND: Direct thrombin inhibitors, a class of anticoagulants distinct from heparins, have not been evaluated for immediate use after thrombolytic therapy in acute ischemic stroke. We report a case of ischemic stroke and prothrombotic state treated using sequenced intravenous and intra-arterial thrombolytic therapy and argatroban anticoagulation. CASE DESCRIPTION: A 19-year-old man with a complicated history of recurrent life-threatening thrombosis presented at the emergency department with acute ischemic stroke. The patient received standard-dose intravenous alteplase starting 2.25 hours after symptom onset without change in his global aphasia and right hemiparesis. Five hours after symptom onset, intra-arterial reteplase was administered for treatment of a left internal carotid "T" occlusion, with successful recanalization of the left internal carotid artery, A1 and M1 segments, and right middle cerebral anterior division and with improvement in symptoms. Argatroban therapy was started after completion of intra-arterial thrombolysis, i.e., 8.5 hours after symptom onset, and was maintained for 14 days. Although the patient sustained a small left basal ganglia infarct, he improved significantly over the course of therapy and was discharged to home without bleeding or further thrombotic episodes. CONCLUSIONS: Sequenced intravenous and intra-arterial thrombolytic therapy and argatroban anticoagulation was used successfully to safely treat a patient with ischemic stroke and comorbid prothrombotic state within 8.5 hours of symptom onset.     

AMI患者尿激酶与组织型纤溶酶原激活剂治疗结果的对比

比较31例尿激酶(UK)及14例组织型纤溶酶原激活剂(t-PA)静脉溶栓辅以阿斯匹林及肝素治疗急性心肌梗塞(AMI)的疗效.t-PA组与UK组相比较:血管再通率分别为78.6%与58.1%(P>0.05);脑、消化道及呼吸道出血并发症在t-PA组稍多,而UK组以局部皮肤出血较多.血管再通组心力衰竭、严重性心律失常、室壁瘤及梗塞后心绞痛的发生率较低,但两组间均无显著性差异;再通组病人心脏破裂的发生明显低于未再通组(0与17.6%P<0.05).本研究提示静脉t-PA溶栓治疗血管再通率高于静脉UK,有条件者可以首选t-PA.溶栓再通可以减少心力衰竭、室壁瘤、心梗后再缺血的发生,特别是心脏破裂的发生,从而改善病人的预后.     

Serum Creatinine May Indicate Risk of Symptomatic Intracranial Hemorrhage After Intravenous Tissue Plasminogen Activator (IV tPA)

Symptomatic intracranial hemorrhage (sICH) is a known complication following administration of intravenous tissue plasminogen activator (IV tPA) for acute ischemic stroke. sICH results in high rates of death or long-term disability. Our ability to predict its occurrence is important in clinical decision making and when counseling families. The initial National Institute of Neurological Disorders and Stroke (NINDS) investigators developed a list of relative contraindications to IV tPA meant to decrease the risk of subsequent sICH. To date, the impact of renal impairment has not been well studied. In the current study we evaluate the potential association between renal impairment and post-tPA intracranial hemorrhage (ICH).Admission serum creatinine and estimated glomerular filtration rate (eGFR) were recorded in 224 patients presenting within 4.5 hours from symptom onset and treated with IV tPA based on NINDS criteria. Neuroimaging was obtained 1 day post-tPA and for any change in neurologic status to evaluate for ICH. Images were retrospectively evaluated for hemorrhage by a board-certified neuroradiologist and 2 reviewers blinded to the patient’s neurologic status. Medical records were reviewed retrospectively for evidence of neurologic decline indicating a “symptomatic” hemorrhage. sICH was defined as subjective clinical deterioration (documented by the primary neurology team) and hemorrhage on neuroimaging that was felt to be the most likely cause. Renal impairment was evaluated using both serum creatinine and eGFR in a number of ways: 1) continuous creatinine; 2) any renal impairment by creatinine (serum creatinine >1.0 mg/dL); 3) continuous eGFR; and 4) any renal impairment by eGFR (eGFR <60 mL/min per 1.73 m²). Student paired t tests, Fisher exact tests, and multivariable logistic regression (adjusted for demographics and vascular risk factors) were used to evaluate the relationship between renal impairment and ICH.Fifty-seven (25%) of the 224 patients had some evidence of hemorrhage on neuroimaging. The majority of patients were asymptomatic. Renal impairment (defined by serum creatinine >1.0 mg/dL) was not associated with combined symptomatic and asymptomatic intracranial bleeding (p = 0.359); however, there was an adjusted 5.5-fold increased odds of sICH when creatinine was >1.0 mg/dL (95% confidence interval, 1.08–28.39), and the frequency of sICH for patients with elevated serum creatinine was 10.6% (12/113), versus 1.8% (2/111) in those with normal renal function (p = 0.010).Our study suggests that renal impairment is associated with higher risk of sICH after administration of IV tPA. As IV tPA is an important and effective treatment for acute ischemic stroke, a multicenter study is needed to determine whether the observation that renal dysfunction is associated with sICH from this retrospective study holds true in a larger prospective trial.     

缺血性心脑血管疾病患者血浆纤溶酶原激活物及纤溶酶原激活物抑制剂1的测定及临床意义

目的研究缺血性心脑血管疾病患者血浆尿激酶型纤溶酶原激活物及其受体、组织型纤溶酶原激活物及其抑制剂1的水平及意义。方法应用酶联免疫吸附试验测定急性脑梗死、急性心肌梗死及不稳定型心绞痛患者血浆尿激酶型纤溶酶原激活物及其受体、组织型纤溶酶原激活物及其抑制剂1的水平。结果(1)脑梗死患者急性期血浆尿激酶型纤溶酶原激活物轻度升高(P>0.05),恢复期明显回落(P<0.05),尿激酶型纤溶酶原激活物受体水平在急性期明显升高(P<0.01),恢复期进一步升高;血浆中组织型纤溶酶原激活物含量在急性期明显低于对照组(P<0.01),而纤溶酶原激活物抑制剂1含量则明显高于对照组(P<0.01),恢复期纤溶酶原激活物抑制剂1水平趋于正常,而血浆中组织型纤溶酶原激活物水平与对照组比较仍存在一定差异(P<0.05)。(2)急性心肌梗塞患者血浆尿激酶型纤溶酶原激活物受体水平急性期明显升高(P<0.05),恢复期进一步升高(P<0.01),尿激酶型纤溶酶原激活物水平均大致正常;急性期血浆中血浆中组织型纤溶酶原激活物及纤溶酶原激活物抑制剂1含量均明显高于对照组(P<0.01),恢复期明显回落,纤溶酶原激活物抑制剂1趋于正常,血浆中组织型纤溶酶原激活物水平仍高于对照组(P<0.05)。(3)不稳定型心绞痛患者急性期(入院时)血浆尿激酶型纤溶酶原激活物受体水平明显升高(P<0.01),恢复期(入院后二周)回落,但仍明显高于对照组(P<0.05),尿激酶型纤溶酶原激活物水平与对照组比较均未见明显差异(P>0.05);急性期血浆中组织型纤溶酶原激活物含量明显低于正常组(P<0.01),而纤溶酶原激活物抑制剂1含量略高于对照组(P>0.05),恢复期两者含量均趋于正常(P>0.05)。结论缺血性心脑血管疾病患者存在不同程度的凝血纤溶系统失平衡,对疾病的发生发展起重要作用。     

血浆I型纤溶酶原激活物抑制剂基因多态性与缺血性脑卒中的关系

目的:探讨血浆I型纤溶酶原激活物抑制剂基因多态性与中国人缺血性脑卒中之间的关系.方法:利用PCR技术和分子杂交技术对北京地区294例缺血性脑卒中患者进行血浆I型纤溶酶原激活物抑制剂基因G11053T及5G/4G多态性的检测和分析,并与279例北京地区的非卒中对照比较. 结果: 缺血性脑卒中患者PAI-1基因G11053T及5G/4G多态性的基因型频率和等位基因频率与对照组相比无明显差异.结论:PAI-1基因G11053T及5G/4G多态性可能不是中国人群缺血性脑卒中发病的遗传学危险因素.     

Intrapericardial Instillation of Recombinant Tissue Plasminogen Activator: A Case Report

On the 43rd day after open heart surgery, pericardial effusion developed in a patient and resulted in cardiac tamponade. Since the drainage could not be obtained by subxiphoid window technique due to location of fluid and presence of fibrinous adherence and a thrombus in pericardial space, transcatheter intrapericardial recombinant tissue plasminogen activator (tPA) was instilled in the patient. Thus, the intrapericardial fibrinous adherence and the thrombus disappeared, and the effusion was drained efficiently.     

血浆I型纤溶酶原激活物抑制剂基因多态性与缺血性脑卒中的关系

目的：探讨血浆Ｉ型纤溶酶原激活物抑制剂基因多态性与中国人缺血性脑卒中之间的关系。方法：利用ＰＣＲ技术和分子杂交技术对北京地区２９４例缺血性脑卒中患者进行血浆Ｉ型纤溶酶原激活物抑制剂基因Ｇ１１０５３Ｔ及５Ｇ／４Ｇ多态性的检测和分析,并与２７９例北京地区的非卒中对照比较。结果：缺血性脑卒中患者ＰＡＩ－１基因Ｇ１１０５３Ｔ及５Ｇ／４Ｇ多态性的基因型频率和等位基因频率与对照组相比无明显差异。结论：ＰＡＩ－１基因Ｇ１１０５３Ｔ及５Ｇ／４Ｇ多态性的基因型频率和等位基因频率与对照组相比无明显差异。结论：ＰＡＩ－１基因Ｇ１１０５３Ｔ及５Ｇ／４Ｇ多态性可能不是中国人群血性脑卒中发病的遗传学危险因素。