Thrombolytic therapy in cerebrovascular disorders.

The knowledge obtained from the ongoing investigational trials of tPA for acute ischemic stroke will not only help establish the appropriate dose range and complication rates but will also further develop the clearly mandatory rapid, aggressive team approach needed to truly treat acute ischemic strokes successfully. Experimental cerebral ischemia data have pointed to the need to treat acute clinical stroke within only a few hours or less to effectively reduce stroke morbidity and mortality. Specifically, with reversible MCA occlusion models of focal cerebral ischemia (dogs and cats), the animals uniformly survive without neurological deficit if the occlusion is for less than 2 to 3 hours. Similarly in primates, MCA occlusion for 3 hours or less will lead to clinical improvement and a decrease in infarct size, with complete recovery generally associated with less than 2 hours of MCA occlusion. Therefore, it appears unlikely that ischemic brain can be salvaged if vascular occlusion persists longer than 4 to 6 hours (similar to the pathophysiology of myocardial ischemia). Further, at least one third of ischemic stroke patients reperfuse spontaneously (and obviously too late) within 48 hours of stroke onset. Several factors believed to be related to successful outcome after thrombolytic therapy are summarized in Table 16. A schematic approach to determining the response to thrombolytic agents in acute ischemic stroke is outlined in Table 17. Zivin succinctly reviews thrombolysis for stroke, both experimental and clinical, and summarizes some of the difficulties of the early clinical stroke trials with thrombolytic agents and speculates about future prospects. He believes tPA may prove valuable in the treatment of some forms of thromboembolic stroke. Its usefulness may depend in part on how quickly the drug can be initiated and the risk of side effects; factors that will require further study. The currently used doses of tPA may be too low to lyse large cerebral arterial clots and, therefore, if current trials do not show a positive treatment response, further trials with higher doses may be indicated. The implications of a potentially effective treatment for truly acute stroke are enormous: stroke will need to be considered by all (lay public through to caregivers) as a true medical emergency, analogous to MI and trauma.(ABSTRACT TRUNCATED AT 400 WORDS)     

LATE assessment of thrombolytic efficacy with alteplase (rt-PA) six-24 hours after onset of acute myocardial infarction

Conflicting results on the benefit of thrombolytic therapy administered six to 24 hours after the onset of myocardial infarction (Ml) led to the LA TE trial. Five thousand seven hundred and eleven patients were treated with recombinant tissue plasminogen activator (t-PA) or placebo, treatment was begun between six and 24 hours after the onset of infarction. For patients treated within 12 hours, there was a relative reduction in 35 day mortality of 25%, but no benefit for those treated at 12 to 24 hours. The benefits were confined to those whose treatment was begun within three hours of admission to hospital. These results widen the window for effective treatment from six to 12 hours after the onset of infarction, but emphasise the need for expeditious treatment when the diagnosis of MI is suspected. (Aust NZ J Med 1993; 23: 745–748.)     

Investigational use of tPA in acute stroke

Significant current interest has focused on the possible value of fibrin-selective thrombolytic agents in acute stroke. Acute thrombosis contributes to carotid and vertebrobasilar arterial occlusions in the majority of acute stroke patients. Hence, fibrin(ogen)olytic agents may produce arterial recanalization and clinical benefit in thrombotic stroke. There are, however, unique features of cerebral tissue that suggest caution with the use of fibrin-selective agents in cerebral ischemia. The specific vascular anatomy and collateral flow suggest that salvage of the "ischemic penumbra" following vascular recanalization in focal ischemia is more likely to be successful than attempts in global ischemia. Recanalization may be associated with reperfusion injury and, more importantly, the risk of hemorrhagic transformation. There is little concrete information regarding the relative contribution of either event to post-thrombolysis cerebral injury. Early studies with exogenous fibrinolytic agents (urokinase, streptokinase) in completed stroke were regarded as inconclusive, demonstrating only an increased risk of intracerebral hemorrhage. Subsequent pilot studies in carotid and in vertebrobasilar territory thrombotic stroke have demonstrated that recanalization can result when exogenous agents are infused just proximal to the cerebral artery occlusion by interventional neuroradiological techniques. This experience and the advent of fibrin-selective agents (tissue plasminogen activator [tPA] and single-chain urokinase plasminogen activator) have led to the development of a multicenter prospective safety/dose-ranging study of tPA in acute (less than eight hours from symptom onset) thrombotic stroke. Following initial clinical assessment, computed tomography scan, and angiography, each patient with a documented cerebral artery occlusion appropriate to the clinical syndrome receives a preassigned intravenous dose of tPA over 60 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Use of tissue plasminogen activator in a stroke after radiofrequency ablation of a left-sided accessory pathway

We describe the case of a 12-year-old girl who had a thromboembolic stroke after radiofrequency ablation of a left posterior accessory pathway involving a transseptal procedure. Symptoms of a stroke occurred 7 hours 15 minutes after completion of the procedure. Tissue plasminogen activator (tPA) was given 2 hours 30 minutes after the onset of symptoms, with complete resolution of her neurologic symptoms. No adverse effects from the tPA were seen. Because of the late onset of symptoms in this case, overnight in-hospital observation is warranted for patients who undergo radiofrequency ablation of a left-sided accessory pathway or an accessory pathway in a patient with the ability to shunt right to left. In this case, tPA was an effective and safe drug to use following a cerebral thromboembolic event occurring after a cardiac catheterization procedure.     

A randomized trial confirming the efficacy of reduced dose recombinant tissue plasminogen activator in a Chinese myocardial infarction population and demonstrating superiority to usual dose urokinase: the TUCC trial

BACKGROUND: Reports from Japan suggest effective myocardial infarction (MI) treatment in Asian patients with much lower doses of tissue plasminogen activators (tPA) than used in European and American regimens. Because increasing doses of fibrinolytics lead to increased bleeding complications, identification of patients who respond to reduced doses is of importance. We conducted a trial in the People's Republic of China in which reduced-dose recombinant tPA was compared with the standard local therapy, urokinase. METHODS: Four hundred patients with acute MI within 12 hours of symptom onset were to be randomized to an 8-mg bolus of recombinant tPA followed by a 42-mg 90-minute infusion or 1.5 million units of urokinase as a 30-minute infusion. Patients received aspirin and heparin and underwent angiography to determine infarct artery patency 90 minutes after the start of therapy. RESULTS: The Data and Safety Monitoring Board recommended premature termination after 342 patients were recruited. Infarct artery patency (grade 2 or 3) occurred in 79% of patients receiving recombinant tPA and in 53% of patients receiving urokinase (P <.001); Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow was 48% and 28%, respectively (P <.001). The higher-patency-rate recombinant tPA growth had better posttreatment left ventricular ejection fractions, 58.6% versus 54.7%, P <.01. Adverse events were infrequent and not significantly different in the 2 groups. CONCLUSIONS: This study confirms that a substantially lower dose of recombinant tPA is effective in Asian patients compared with that required in Western patients even after consideration of body weight. Specific dose-response studies should be performed with fibrinolytic regimens to avoid overdosage with its attendant risks of excess bleeding.     

Thrombolysis for Acute Myocardial Infarction: Making Sense of The Clinical Trials Data

Trials during the 1980s established that thrombolytic therapy restores coronary blood flow rapidly and reduces mortality compared to control or placebo therapy in acute myocardial infarction. Comparative studies have generated controversy, however, in that the newer agents tissue plasminogen activator (tPA) and anistreplase (APSAC), shown to open arteries more rapidly than streptokinase (SK), achieve no greater mortality reductions. In these trials, tPA may have been disadvantaged because adjunctive IV heparin therapy was not given. This possibility is being explored in the Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries (GUSTO) study. However, heparin may not entirely explain the discrepancy because (1) among patients in International Studies of Infarct Survival (ISIS-3) given IV heparin out of protocol, no difference in mortality between tPA and SK was observed; (2) reinfarction was actually slightly less after tPA; and (3) APSAC, longer acting and more efficient than SK and not requiring early IV heparin, achieved no greater mortality reductions. Another explanation for the discrepancy between 90-minute patency and mortality effects among agents is that benefit in the usual time frame of treatment (2–6 hours after onset of symptoms) depends more on diastolic effects (improved healing with preserved diastolic size, shape) than on systolic effects (reduction in infarct size) and is less time-dependent. A similar survival outcome is then consistent with the observation that all three agents lead to similar plateau patency rates at ≥ 3 hours. Prehospital throtnbolysis trials are exploring the possibility that greater functional and mortality benefits are associated with therapy given very early (within 1–2 hours). Differential benefits might be seen when regimens with differing thrombolytic efficiencies are given within 1–2 hours of symptom onset, but this possibility must be established by direct comparative trials. Future trials should emphasize improved myocardial salvage by more rapid delivery of thrombolytic therapy as well as the use of more efficient thrombolytic regimens.     

Tissue plasminogen activator (tPA) deficiency exacerbates cerebrovascular fibrin deposition and brain injury in a murine stroke model: studies in tPA-deficient mice and wild-type mice on a matched genetic background

Although the serine protease, tissue plasminogen activator (tPA), is approved by the US Food and Drug Administration for therapy to combat focal cerebral infarction, the basic concept of thrombolytic tPA therapy for stroke was challenged by recent studies that used genetically manipulated tPA-deficient (tPA-/-) mice, which suggested that tPA mediates ischemic neuronal damage. However, those studies were potentially flawed because the genotypes of tPA-/- and wild-type control mice were not entirely clear, and ischemic neuronal injury was evaluated in isolation of tPA effects on brain thrombosis. Using mice with appropriate genetic backgrounds and a middle cerebral artery occlusion stroke model with nonsiliconized thread, which does lead to microvascular thrombus formation, in the present study we determined the risk for cerebrovascular thrombosis and neuronal injury in tPA-/- and genetically matched tPA+/+ mice subjected to transient focal ischemia. Cerebrovascular fibrin deposition and the infarction volume were increased by 8.2- and 6. 7-fold in tPA-/- versus tPA+/+ mice, respectively, and these variables were correlated with reduced cerebral blood flow up to 58% (P<0.05) and impaired motor neurological score by 70% (P<0.05). Our findings indicate that tPA deficiency exacerbates ischemia-induced cerebrovascular thrombosis and that endogenous tPA protects the brain from an ischemic insult, presumably through its thrombolytic action. In addition, our study emphasizes the importance of appropriate genetic controls in murine stroke research.     

脑梗塞早期患者血纤溶系统活性状态分析

为明确血纤溶系统活性状态与脑梗塞发病的关系，采用病例对照研究方法，对３０例皮质动脉区脑梗塞（ＣＡＣＩ）患者、３２例穿通动脉区脑梗塞（ＰＡＣＩ）患者及３０名无心脑血管病等的对照者，以发色底物分解产色法测定血浆组织型纤溶酶原激活物（ｔＰＡ）活性、纤溶酶原激活物抑制物（ＰＡＩ）活性及血管内皮ｔＰＡ释放能力和ＰＡＩ／ｔＰＡ比值，以综合判定其血纤溶系统活性，结果表明两种类型脑梗塞患者发病３天内血纤溶系统活性均显著低于对照者，为脑梗塞早期行溶栓治疗提供了理论依据。同时提出，再次脑梗塞可能与血浆ＰＡＩ活性高有关。     

Intracranial hemorrhage after use of tissue plasminogen activator for coronary thrombolysis

Tissue plasminogen activator (tPA), an approved coronary thrombolytic agent, can cause serious bleeding. We report the cases of six patients with intracranial hemorrhage after tPA treatment for acute myocardial infarction. None of the patients were hypertensive at admission, and only one was hypertensive during therapy. Intravenous tPA, 100 mg, was followed by continuous intravenous heparin infusion; intracranial hemorrhage occurred between 2 and 14 hours after tPA infusion ended and between 3 and 17 hours after heparin therapy was started. The partial thromboplastin time (PTT) was excessively prolonged (from 81 s to more than 150 s) in all patients at onset of intracranial hemorrhage. The intracerebral hematomas were predominantly of lobar location, and two patients had multiple simultaneous hemorrhages. Four patients died from massive intracranial hemorrhage; the mechanism for these hemorrhages was unclear. Factors possibly related to hemorrhage include a systemic fibrinolytic state or a platelet anti-aggregant effect produced by tPA and enhanced hemorrhagic tendency caused by the combined effects of tPA and heparin. Local vascular changes at the bleeding site remain as potential contributing factors for isolated intracranial hemorrhage.     

Fibrinolytic therapy in acute stroke

Acute ischemic stroke is a major cause of morbidity and mortality in Europe, North America, and Asia. Its treatment has completely changed over the past decade with different interventional approaches, such as intravenous trials, intra-arterial trials, combined intravenous/intra-arterial trials, and newer devices to mechanically remove the clot from intracranial arteries. Intravenous thrombolysis with tissue plaminogen activator (tPA) within 4.5 hours of symptoms onset significantly improved clinical outcomes in patients with acute ischemic stroke. Pharmacological intra-arterial thrombolysis has been shown effective until 6 hours after middle cerebral artery occlusion and offers a higher rate of recanalization compared with intravenous thrombolysis, whereas combined intravenous/ intra-arterial thrombolysis seems to be as safe as isolated intravenous thrombolysis. The more recent advances in reperfusion therapies have been done in mechanical embolus disruption or removal. Merci Retriever and Penumbra System have been approved for clot removal in brain arteries, but not as a therapeutic modality for acute ischemic stroke since it is no clear whether mechanical thrombectomy improves clinical outcome in acute stroke. However, mechanical devices are being used in clinical practice for patients who are ineligible for tPA or who have failed to respond to intravenous tPA. We summarize the results of the major thrombolytic trials and the latest neurointerventional approaches to ischemic stroke.     

Essential role of endogenous tissue plasminogen activator through matrix metalloproteinase 9 induction and expression on heparin-produced cerebral hemorrhage after cerebral ischemia in mice

Cerebral hemorrhage associated with antithrombotic and thrombolytic therapy in acute stroke continues to present a major clinical problem. Rupture of the cerebral microvasculature involves the degradation and remodeling of extracellular matrix. Here we demonstrated that the delayed administration of heparin 3 hours after photothrombotic middle cerebral artery occlusion (MCAO) caused cerebral hemorrhage in wild-type (WT) mice but not in tissue plasminogen activator (tPA)-deficient knockout (KO) mice. Heparin administration increased tPA activity and its mRNA expression at 6 and 12 hours after MCAO in the ischemic hemispheres of WT mice. The expression of tPA was enhanced in microglial cells in the ischemic border zone. We also observed an exacerbation of matrix metalloproteinase (MMP) 9 expression at the mRNA level and its conversion to an active form after heparin administration in the ischemic hemisphere in WT mice but not in tPA KO mice. The increased MMP 9 expression was localized in microglial cells and endothelial cells. These findings suggest that endogenous tPA, through the enhancement of MMP 9 expression and proteolytic activation, plays an essential role in the pathogenesis of heparin-produced cerebral hemorrhage. Targeting tPA, MMP 9, or both may provide a new approach for preventing cerebral hemorrhage associated with antithrombotic therapy for stroke in humans.     

Neutrophil and platelet activity and quantification following delayed tPA therapy in a rabbit model of thromboembolic stroke

Although there is considerable interest in the role of neutrophils and platelets in acute cerebral ischemiareperfusion, there are very little data related to the effect of systemic thrombolytic therapy on these blood elements. In the present study a rabbit model was used to examine the effects of cerebral ischemia, tissue-plasminogen activator therapy, or both on neutrophil and platelet peripheral counts and activity, the latter studied by stimulated neutrophil and platelet impedance aggregation and neutrophil oxygen-free radical chemiluminescence. New Zealand white rabbits (n=25) were randomized to receive either tissue-plasminogen activator (6.3 mg/kg IV; 20% bolus, remainder as a 2-hour infusion) or vehicle (0.9% saline) 3 hours following either autologous clot embolization or sham carotid artery isolation. Thus, four groups were examined: sham (n=4), tPA only (n=4), stroke only (n=8), and stroke plus tPA (n=9). Two hours after completion of thrombolytic therapy or vehicle infusion, the experiments were terminated, that is, 7 hours following autologous clot embolization or sham instrumentation. Blood was sampled from the thoracic aorta, and neutrophil and platelet peripheral counts and activity were determined prior to embolization and 0.5, 2.0, 4.0, and 7.0 hours following autologous clot embolization. No significant difference in platelet counts, either over time or between groups, was noted. In contrast to the platelet counts, the neutrophil count significantly increased over time, rising approximately 2.5-fold from baseline in all four groups (p<0.001). No significant increase in neutrophil accumulation (myeloperoxidase assay; 10⁷ PMNs/g tissue; mean ± SEM) was noted within infarcted regions of either the stroke (1.26±0.07; n=5) or stroke plus tissue-plasminogen activator (1.26±0.09; n=5) groups when compared to either viable brain regions within the ischemic hemisphere (1.29±0.03; n=4) or in sham controls (1.36±0.35; n=4). Neutrophil activity (aggregation, oxygen-free radical release) in both groups undergoing autologous clot embolization demonstrated a trend toward higher values when compared to the two sham-operated groups. Tissue-plasminogen activator administration did not significantly affect ex vivo neutrophil activity. In contrast, platelet aggregation was significantly reduced by the administration of tPA with (p=0.001) or without (p<0.01) autologous clot embolization. Thus, in the present rabbit model platelet but not neutrophil activity is modulated by the administration of tissue-plasminogen activator, while autologous clot embolization results in a trend toward acute neutrophil activation.     

Innovative strategies in the management of acute stroke

Advances in acute stroke therapy are rapidly changing our approach to management of patients with ischemic stroke. Intravenous tissue-plasminogen activator (tPA) was the first treatment demonstrated in a randomized controlled trial to improve outcome if given within the first 3 hours of stroke onset. Subsequent trials failed to extend the time window for intravenous therapy beyond 3 hours. Intra-arterial thrombolysis provides an alternative approach, with several advantages over intravenous therapy. The major drawback is the additional time needed for the interventional procedure, and the equipment and personnel requirements. New strategies aimed at reducing the total time from stroke onset to recanalization of occluded arteries include a combined intravenous/ intra-arterial delivery of thrombolysis and mechanical devices. For the millions of stroke survivors, investigations are now underway into the possibility of improvement of function through neuronal transplantation.     

Experience with the use of tPA in the treatment of acute myocardial infarction

Early experience with the use of tissue plasminogen activator (tPA) in acute myocardial infarction is reviewed, including comparisons with other thrombolytic agents, a summary of hemorrhagic complications associated with its use, and the rationale for adjunctive therapeutic strategies. The use of tPA has been associated with improvement in left ventricular function, a lower mortality, and a decrease in congestive heart failure signs and symptoms. A protocol for evaluation of patients with possible myocardial infarction for thrombolytic therapy is presented. Consideration must be given to other possible diagnoses, and the ECG must be evaluated carefully to ensure that appropriate criteria are met. Risk factors for hemorrhagic complications include recent trauma, surgery, gastrointestinal and genitourinary bleeding, stroke, and focal neurologic findings. Greater benefit of therapy is expected in patients with larger infarcts who have more marked ST segment changes or evidence of hemodynamic compromise, especially when they are treated early after the onset of symptoms (within the first several hours). Adjunctive measures that can be considered in the emergency department include prophylactic lidocaine, IV nitroglycerin, beta blockade, aspirin, volume replacement and monitoring for dysrhythmias, bleeding, and recurrent ischemia. A comprehensive understanding of these rapidly evolving concepts will assist the emergency physician in the evaluation and management of patients with acute myocardial infarction.     

Postinfarction cardiac rupture despite immediate reperfusion therapy in a patient with severe aortic valve stenosis

A 74-year-old woman with severe aortic valve stenosis (AS) was admitted to our hospital because of dyspnea on exertion. On day 2, she developed acute anterior wall myocardial infarction (MI) with ST elevation. Tissue plasminogen activator (tPA) was administered 10 min after the onset of chest pain, and emergency percutaneous coronary intervention was performed to induce coronary reperfusion after another 50 min. Five hours after MI onset, however, she suddenly went into electromechanical dissociation and died from cardiac rupture. This is the first case report of postinfarct cardiac rupture with severe AS occurring in spite of instituting immediate reperfusion therapy. High intraventricular pressure may be a critical risk factor for cardiac rupture in patients with AS complicated with acute MI. Further studies are required to clarify the risk and benefit of tPA administration before percutaneous coronary intervention and the necessity of the emergency correction of AS to prevent cardiac rupture.     

急性缺血性脑卒中患者超早期磁共振血管造影对判断预后的价值

目的探讨急性缺血性脑卒中患者超早期磁共振血管造影(MRA)所示有无大血管闭塞对判断预后的价值。方法选择在超早期(发病6 h内)完成MRA检查的急性缺血性脑卒中患者44例,根据MRA显示,将患者分为大血管闭塞组和无大血管闭塞组。患者行MRA检查前完成美国国立卫生研究院卒中量表评分,在3个月时,随访改良的Ranking量表(mRS)评分。结果44例患者中大血管闭塞组21例,无大血管闭塞组23例,两组3个月随访时,mRS 0~2分的比例分别为28.6%和82.6%,两组临床结局的差异有显著性意义(P<0.001)。结论急性缺血性脑卒中患者超早期MRA所示有无大血管闭塞可帮助判断患者的预后。     

Reperfusion therapy for stroke

Stroke is a heterogenous disease, but about 85% of strokes are as a result of cerebral ischaemia due to arterial occlusion. It seems logical to assume that, as in myocardial infarction, treatment designed to dissolve clots should be helpful. We now have a substantial amount of data on the use of aspirin, heparin and thrombolytic drugs in the treatment of acute ischaemic stroke. Aspirin 300 mg daily has a modest effect in reducing mortality and handicap when used within 48 hours of stroke onset. The beneficial effects of low dose, medium dose subcutaneous unfractionated heparin, and various low molecular weight heparins in reducing early recurrent ischaemic stroke seem to be outweighed by haemorrhagic side effects. Streptokinase used within six hours of stroke onset results in excess mortality with some reduction in handicap in survivors, while in carefully selected patients recombinant tissue plasminogen activator (r-TPA) may be less hazardous. At the moment it is unclear which stroke patients will benefit from the use of r-TPA, and the use of criteria, as outlined by the NINDS group, means that only a very small proportion of stroke victims are suitable for thrombolytic therapy. Further research is necessary, while the concept of a ‘Brain Attack’ with appropriate urgency being used in the assessment of possible stroke needs development.     

超早期尿激酶溶栓治疗脑梗死的临床研究

目的评价超早期应用尿激酶(UK)2.0万U/kg溶栓治疗脑梗死的临床疗效及安全性。方法采用国产UK 2.0万U/kg静脉滴注,对66例发病6h内的脑梗死患者进行溶栓治疗,比较治疗前后神经功能缺损评分(NFDI)。另设60例普通治疗病人作为对照组。结果溶栓后2h NFDI为21.39±2.81,较溶栓前25.96±3.29明显减少(P<0.001),治疗后21d溶栓组NFDI为19.01±3.35,明显低于对照组22.67±3.68(P<0.001)。治疗后21d溶栓组的治愈率、显效率、总有效率分别为30.3%、66.7%、83.3%显著高于对照组13.3%、30%、46.7%,两组比较有显著性差异(均P<0.01)。结论在严格掌握溶栓治疗适应证基础上,应用国产UK 2.0万U/kg超早期静脉溶栓治疗脑梗死临床疗效好,并发症少。     

六项蛋白指标联合检测对早期诊断脑梗死的价值

目的分析6项蛋白指标联合检测对早期诊断脑梗死的临床价值。方法选择72 h内急性脑卒中患者160例,分为脑梗死组(80例)和脑出血组(80例),选择同期健康体检者45例作为对照组。用ELISA法检测神经元特异性烯醇化酶(NSE)、血管性血友病因子(v WF)、S100β蛋白(S100β)、基质金属蛋白酶-9(MMP-9)、单核细胞趋化蛋白-1(MCP-1)、血管细胞黏附分子-1(VCAM-1)水平,评估不同蛋白指标组合诊断脑梗死的敏感度和特异度。结果脑梗死组NSE、v WF、S100β、MMP-9、MCP-1和VCAM-1均高于对照组,差异有统计学意义(P<0.01);脑出血组除MCP-1外,各指标均高于对照组,差异有统计学意义(P<0.01)。由NSE、v WF、S100β、MCP-1和VCAM-1组成的诊断标志组,其诊断脑梗死的敏感度为73.75%、特异度为72.00%,发病6 h内诊断脑梗死的敏感度为80.77%,特异度为76.32%。结论蛋白指标联合诊断早期脑梗死的敏感度较高。     

Thrombolytic therapy of acute myocardial infarction

Thrombotic coronary artery occlusion is now recognized as the usual cause of acute myocardial infarction. The thrombus usually forms at the site of intimal disruption over an atherosclerotic plaque. Following coronary occlusion, myocardial necrosis begins within 40 minutes in the subendocardium and progresses outward toward the epicardium over the next several hours. The intracoronary infusion of streptokinase will produce lysis of the occluding thrombus in up to 80% of patients. It appears that reperfusion with streptokinase in the first few hours following the onset of the myocardial infarction produces a small increase in late left ventricular function, though ECG and enzyme evidence of acute myocardial infarction are not prevented. The improvement in left ventricular function is variable from patient to patient and has not been demonstrated in all the randomized studies to date. The time limit for myocardial salvage may not be the same in all patients. The greatest benefit is probably achieved with reperfusion in the first 4-6 hours, although some benefit may occur as late as 18 hours after the onset of infarction. Many patients who receive intracoronary infusion of streptokinase develop a systemic lytic state, though serious bleeding complications in carefully selected patients are infrequent. High-dose IV streptokinase is easier, cheaper, and quicker to initiate than intracoronary streptokinase but is probably less effective than the intracoronary route in producing rapid lysis of the occluding coronary thrombus. The optimal dose and rate of administration of IV streptokinase have not been determined. The final role and ultimate benefit of thrombolytic therapy of myocardial infarction have not yet been determined, but some of the issues may be clarified by the larger randomized trials now under way. It appears, at present, that the use of intracoronary streptokinase may have a role in the treatment of selected patients with acute myocardial infarctions in institutions with the facilities and the personnel necessary to perform this procedure safely. In the future, thrombolytic therapy may also have a place in the treatment of selected patients with unstable angina and post-myocardial infarction angina. The future availability of more selective thrombolytic agents may make the early IV therapy of myocardial infarction a safer, more effective option and expand the indications for thrombolytic therapy.