Molecular basis of fibrinolysis, as relevant for thrombolytic therapy

The fibrinolytic system comprises an inactive proenzyme, plasminogen, that is converted by plasminogen activators to the active enzyme, plasmin, that degrades fibrin. Two physiological plasminogen activators have been identified: tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Plasminogen activation for clot lysis is regulated by specific molecular interactions between tissue-type plasminogen activator (t-PA), plasminogen and fibrin, whereby the lysine-binding sites of the plasminogen molecule play a crucial role by mediating its binding to fibrin, and by controlling the inhibition rate of plasmin by alpha 2-antiplasmin. The recognition that thrombosis within the infarct related coronary artery plays a major role in the pathogenesis of acute myocardial infarction and the observation that early administration of thrombolytic agents results in recanalization of occluded coronary arteries, have provided the basis for the development of thrombolytic therapy in acute myocardial infarction. The elucidation of the biochemical mechanism of fibrin-specific plasminogen activation has fueled the hope that specific and efficacious thrombolytic agents might become available. Comparative studies between the non-fibrin-selective streptokinase and fibrin-selective recombinant t-PA (rt-PA) have shown a difference in efficacy for early coronary artery recanalization, whereas the GUSTO trial has established that clinical benefit in patients with acute myocardial infarction is indeed correlated with the rapidity and frequency of sustained recanalization and that effective thrombolysis requires adequate anticoagulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Overview of randomized trials of intravenous heparin in patients with acute myocardial infarction treated with thrombolytic therapy

Intravenous heparin is routinely given after thrombolytic therapy for patients with acute myocardial infarction in the United States and in some, but by no means all, other countries. Several trials have documented improved infarct-artery patency in patients treated with heparin; however, none was large enough individually to assess the effect of heparin on clinical outcomes. We performed a systematic overview of the 6 randomized controlled trials (1,735 patients) to summarize the available data concerning the risks and benefits of intravenous heparin versus no heparin after thrombolytic therapy. Mortality before hospital discharge was 5.1% for patients allocated to intravenous heparin compared with 5.6% for controls (relative risk reduction of 9%, odds ratio 0.91, 95% confidence interval 0.59 to 1.39). Similar rates of recurrent ischemia and reinfarction were observed among those allocated to heparin therapy or control. The rates of total stroke, intracranial hemorrhage, and severe bleeding were similar in patients allocated to heparin; however, the risk of any severity of bleeding was significantly higher (22.7% vs 16.2%; odds ratio 1.55, 95% confidence interval 1.21 to 1.98). There was no significant difference in the observed effects of heparin between patients receiving tissue-type plasminogen activator and those receiving streptokinase or anisoylated plasminogen streptokinase activator complex, or between patients who did and did not receive aspirin. The findings of this overview demonstrate that insufficient clinical outcome data are available to support or to refute the routine use of intravenous heparin therapy after thrombolysis. It is not known if these findings are due to lack of statistical power, inappropriate levels of anticoagulation, or lack of benefit of intravenous heparin. Large randomized studies of heparin (and of new antithrombotic regimens) are needed to establish the role of such therapy.     

Thrombolytic therapy in stroke. What do clinical tests prove?

Despite the increased risk of intracranial haemorrhage associated with the use of thrombolytic treatment of stroke. American studies have shown patients treated with rt-PA (recombinant plasminogen activator) within three hours of the onset of symptoms to manifest 30 per cent less disability at three-month follow-up than those placebo. However, until satisfactory criteria for the use of rt-PA are available, caution is essential, and thrombolytic therapy should be restricted to specialised centres. It is also important to promote public awareness of the stroke patient's need of immediate treatment at a specialised stroke unit.     

Age-related changes in gastric mucosal repair and proliferative activities in rats exposed acutely to aspirin

OBJECTIVES: (1) To determine whether and how outcome measurements in the ECASS trial are influenced by a shorter time window (0-3 vs. 3-6 h) between onset of symptoms and start of thrombolytic therapy using recombinant tissue plasminogen activator (rt-PA) in acute ischemic stroke. (2) To discuss the results of the ECASS 0- to 3-hour cohort with the results of the National Institute of Neurological Disorders and Stroke Study (NINDSS). DESIGN AND ANALYSIS: Analysis of the 0- to 3-hour and the 3- to 6-hour cohort in accordance with the ECASS protocol. Comparative analysis of the ECASS and NINDSS results following the NINDSS protocol using dichotomized endpoints. MAIN OUTCOME MEASURES: Primary endpoints: modified Rankin Scale, Barthel Index; secondary endpoints: combined Barthel/Rankin, long-term Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, mortality at 30 and 90 days, occurrence of intracranial hemorrhage. NINDS trial endpoint: favorable outcome as defined in the NINDS trial. RESULTS: In ECASS, 87 patients were randomized within 3 h of stroke onset. Differences in favor of rt-PA treatment can be found for all primary and secondary outcome measures in the ECASS 0- to 3-hour cohort, except for mortality at day 30, which is somewhat higher in the rt-pA-treated group. However, due to the small sample size, the differences do not reach statistical significance. Early infarct signs (as defined by the ECASS protocol) are found as early as 2 h after stroke onset. Parenchymal hemorrhages are found significantly more often among rt-PA-treated patients. The results in the ECASS 0- to 3-hour cohort fit well with the results in NINDSS. CONCLUSION: Data from the 3-hour ECASS cohort support the efficacy of early thrombolytic therapy in acute hemispheric stroke patients. Comparing bleeding complications between the ECASS and NINDSS is difficult because of differences in the definition and occurrence of hemorrhagic events.     

Lipid peroxidation in healthy fetuses, preterm and fullterm neonates

Thrombolytic therapy has been accepted in the treatment of acute myocardial infarction. Given historical recommendations that thrombolytic therapy is contraindicated in patients receiving CPR, its potential clinical benefit for facilitating conversion of rhythm in patients in refractory cardiac arrest has not been investigated. We present three case reports in which patients with confirmed acute myocardial infarction had a witnessed cardiac arrest in the ED. Standard Advanced Cardiac Life Support measures failed in all three cases. A bolus infusion of tissue plasminogen activator was administered during CPR in refractory ventricular fibrillation (two cases) and pulseless ventricular tachycardia (one case). Patients were given tissue plasminogen activator and had defibrillation, followed by a spontaneous return of circulation, with resuscitation and subsequent discharge. No postarrest sequelae were observed as a result of thrombolytic use during the resuscitative process. We conclude that bolus thrombolytic infusions during CPR may facilitate spontaneous return of circulation in select patients with confirmed acute myocardial infarction, witnessed cardiac arrest in the ED, and refractory ventricular fibrillation or tachycardia.     

ESPRIT: a European study of the prevention of reocclusion after initial thrombolysis with duteplase in acute myocardial infarction

BACKGROUND: The goal of thrombolytic treatment in acute myocardial infarction is reperfusion of the infarct-related coronary artery. Duteplase is a double-chain recombinant tissue-type plasminogen activator. Its efficacy and safety were evaluated in patients with acute myocardial infarction treated within 4 h of onset of chest pain in this multicentre, open, non-controlled trial. METHODS AND RESULTS: A total of 273 patients were enrolled and treated with duteplase 0.6 MU.kg-1 over 4 h, with concomitant oral aspirin and intravenous heparin. Coronary arteriography was performed at 60 min, 90 min and approximately 24 h after the start of duteplase infusion to assess the perfusion grade (TIMI scoring) of the infarct-related coronary artery. Safety was assessed by monitoring patients closely for bleeding and for all other adverse experiences during the 72-h study period. Reinfarction during the study period was also recorded, and deaths at any time during the period in hospital were documented. TIMI grade 2 or 3 patency of the infarct-related coronary artery at 90 min was achieved in 70% of the patients and 7% of these "patent' infarct-related coronary arteries had reoccluded by 20 to 36 h. Clinical reinfarction during the 72-h study period was observed in 7%. Total in-hospital mortality was 8%. Serious or life-threatening bleeding occurred in 4% of the patients. There was one haemorrhagic stroke, and this was fatal. CONCLUSIONS: Weight-adjusted duteplase infusion, together with oral aspirin and intravenous heparin, in acute myocardial infarction resulted in patency of the infarct-related coronary artery and a safety profile comparable to those reported for the other form of tissue-type plasminogen activator, alteplase. However, there remains a problem with reocclusion and reinfarction after initially successful thrombolysis.     

Possibilities and limitations of thrombolysis. Benefits and risk in acute myocardial infarct, lung embolism, pelvic and leg vein thrombosis as well as cerebrovascular accidents

The indications for thrombolytic therapy in acute myocardial infarction, pulmonary embolism, deep venous thrombosis and ischemic stroke are reviewed on the basis of a risk-benefit analysis. There is strong evidence that thrombolysis benefits the majority of patients with acute myocardial infarction. Nevertheless, the overall proportion of patients actually receiving this therapy is disappointingly low (10-30%). Efforts are mainly required in minimizing delays in initiating thrombolysis (patient, doctor, in-hospital) and in providing thrombolytic therapy to an extended proportion of qualifying patients. This implies that many traditional but inappropriate exclusion criteria (e.g. age, presentation 6 to 12 hours after onset of symptoms, hypertension, reinfarction, brief cardiopulmonary resuscitation) are unfounded. Depending on duration of symptoms, infarct localization and age, we favor a differentiated thrombolytic regimen with rt-PA or streptokinase. In contrast to acute myocardial infarction, the risk-benefit ratio for the other thrombotic disorders discussed favours thrombolytic therapy only in a minority of carefully selected patients.     

HTLV infection among Italian intravenous drug users and North African subjects detected by the polymerase chain reaction and serological methods

The relevance of coagulation abnormalities in ischemic stroke remains uncertain. The purpose of this study was to identify abnormal patterns of coagulation in established ischemic stroke. We measured coagulation parameters in 86 patients with acute ischemic stroke: 10 lacunar, 55 atherothrombotic and 21 cardioembolic. Statistical comparisons were made between different stroke groups and between all stroke patients and 60 healthy controls. A decrease in functional antithrombin III and plasminogen and an increase in thrombin-antithrombin III complexes, total protein S, tissue plasminogen activator, plasminogen activator inhibitor and D-dimer were observed in the stroke group (p < 0.05). A positive correlation was found between tissue plasminogen activator and thrombin-antithrombin III levels in cardioembolic stroke (p < 0.05). Protein C levels showed significant differences between the three groups, and in the cardioembolic group they were lower than in controls (p < 0.05). Antiphospholipid antibodies were positive in two cases. We conclude that activation of coagulation and fibrinolytic pathways was observed during the acute phase of ischemic stroke. Protein C activity is different in the three types of strokes analyzed, and higher levels seem to be associated with lacunar lesions. Antiphospholipid antibodies do not seem to play an important role in the pathogenesis of stroke in a nonselected population.     

Thrombolytic therapy in ischemic infarct

Thrombolytic therapy in acute ischemic stroke is safe and effective in a defined subgroup of stroke patients. Until now, different fibrinolytic substances including urokinase, streptokinase and recombinant tissue plasminogen activator (rt-PA) have been tested regarding safety, efficacy, dosage and economic parameters in patients suffering from both carotid and basilar artery territory strokes. Recently, two large multicenter placebo-controlled intravenous rt-PA studies were published. The results show that thrombolysis of acute carotid territory strokes (European Cooperative Acute Stroke Study) and of strokes with a deficit measurable on the NIH Stroke Scale (National Institute of Neurological Disorders and Stroke rt-PA Stroke Study) improves clinical and economic outcome parameters in patients who were treated within 6 hours of the onset of symptoms and had that no signs of extended early infarction on the initial CT-scan. The occurrence of intracranial hemorrhages is more frequent after thombolytic therapy, but the majority of bleeding complications referred to petechial or more confluent hemorrhage limited to the infarcted tissue, without clinical deterioration. However, the identification of the appropriate patients is difficult and depends on the level of clinical and diagnostic experience. In vertebrobasilar artery territory stroke, local intraarterial thrombolysis with urokinase or streptokinase is performed in most cases. Thrombolytic treatment within twelve hours of the onset of symptoms was associated with significantly better results concerning both survival and neurological recovery.     

Control of peptide deformylase activity by metal cations

Previously, CT was considered insensitive in the evaluation of the acute ischemic stroke patient; however, more recently detection of early CT findings has proved to be of prognostic value in the evaluation of these patients. The use of CT coupled with early acute phase therapy of stroke such as thrombolytic therapy has been shown to improve outcome in the acute stroke patient.     

Reperfusion injury after focal cerebral ischemia: the role of inflammation and the therapeutic horizon

Recent evidence indicates that thrombolysis may be an effective therapy for the treatment of acute ischemic stroke. However, the reperfusion of ischemic brain comes with a price. In clinical trials, patients treated with thrombolytic therapy have shown a 6% rate of intracerebral hemorrhage, which was balanced against a 30% improvement in functional outcome over controls. Destruction of the microvasculature and extension of the infarct area occur after cerebral reperfusion. We have reviewed the existing data indicating that an inflammatory response occurring after the reestablishment of circulation has a causative role in this reperfusion injury. The recruitment of neutrophils to the area of ischemia, the first step to inflammation, involves the coordinated appearance of multiple proteins. Intercellular adhesion molecule-1 and integrins are adhesion molecules that are up-regulated in endothelial cells and leukocytes. Tumor necrosis factor-alpha, interleukin-1, and platelet-activating factor also participate in leukocyte accumulation and subsequent activation. Therapies that interfere with the functions of these factors have shown promise in reducing reperfusion injury and infarct extension in the experimental setting. They may prove to be useful adjuncts to thrombolytic therapy in the treatment of acute ischemic stroke.     

North Carolina stroke prevention and treatment facilities survey: rtPA therapy for acute stroke

BACKGROUND and PURPOSE: North Carolina is situated in the "stroke belt" region of the United States, an area of the country with a particularly high incidence of cerebrovascular disease. The North Carolina Stroke Prevention and Treatment Facilities Survey was carried out to determine the availabilities of a variety of stroke prevention and treatment services throughout the state. The purpose of the present study was to determine how widely recombinant tissue-type plasminogen activator (rtPA) has been adopted for the treatment of patients with acute ischemic stroke and to determine the characteristics of the medical facilities in the state offering this therapy. METHODS: A single-page survey was mailed to the medical center directors of each inpatient medical facility in North Carolina. Data collected included questions related to the availability of selected basic and advanced diagnostic tests and procedures, stroke prevention and treatment programs and services (community stroke awareness program, acute stroke identification program, acute stroke team, stroke rtPA protocol, stroke care map, neurologist), and facilities (Stroke Acute Care Unit or equivalent). RESULTS: Responses were obtained from all 125 inpatient medical facilities in North Carolina. rtPA stroke protocols were adopted in 54 facilities located in 46 of the state's 100 counties. Seventy-four percent of the state's population resides in counties with hospitals providing rtPA treatment. Compared with facilities not offering rtPA, those with rtPA protocols more commonly sponsored stroke community awareness programs (41% versus 17%, P=0.003) and more frequently had an organized stroke team (31% versus 8%, P=0. 001), used stroke care maps (56% versus 17%, P<0.001), had rapid stroke identification programs (33% versus 6%, P<0.001), or had a Stroke Acute Care Unit or its equivalent (33% versus 7%, P<0.001). Neurologists were available in 78% of the facilities offering rtPA compared with 38% in facilities without rtPA protocols (P<0.001). CONCLUSIONS: These data show that this new therapy for ischemic stroke is potentially available to a high proportion of the state's citizens based on their county of residence. However, other services that may improve outcomes and reduce stroke-related costs (eg, stroke teams, stroke units, care maps) are not being widely used, even in centers providing treatment with rtPA. The simple methodology used in this study is potentially applicable in other states and permits targeting of selected centers for development of stroke treatment capabilities.     

Nursing care of acute stroke patients after receiving rt-PA therapy. The NINDS rt-PA Stroke Study Group

Treatment with tissue plasminogen activator (rt-PA) for acute stroke requires intensive care of the patient. The risk of thrombolytic therapy and the need for rapid interventions make it clear that the nursing role during this time is crucial. Nurses should be familiar with safe dosage and administration of rt-PA for stroke, which is clearly different than administration of rt-PA for myocardial infarction. Furthermore, thrombolytic stroke treatment must be accompanied by intensive neurological monitoring to observe for complications. Intracerebral hemorrhage is usually accompanied by an acute change in neurological status and vital sign instability. Intensive monitoring of neurologic condition, vital signs, cardiac status and other standard critical care practices must be initiated immediately to optimize patient outcome.     

The relationship between argyrophilic proteins and some immunophenotypic markers in acute leukemia cells

Stroke is a leading cause of death and disability among Americans. The recent US Food and Drug Administration approval of recombinant tissue plasminogen activator (rt-PA, Activase) for the treatment of acute ischemic stroke offers the first proven therapy to reverse or ameliorate stroke symptoms. rt-PA is thought to restore circulation in the patient with acute ischemic stroke by dissolving an occluding thrombus or embolus. A basic understanding of cerebral circulation and the mechanism by which stroke compromises brain tissue is fundamental to appreciating this new therapy. The importance of prompt stroke diagnosis and treatment cannot be underestimated.     

Increased fibrinogen levels and acquired hypofibrinolysis in young adults with ischemic stroke

BACKGROUND AND PURPOSE: Elevated fibrinogen levels and abnormalities in the fibrinolytic system are related to the occurrence of cardiovascular events. However, the role of these factors in the evolution of cerebrovascular disease has received less attention, in particular in young stroke patients. The aim of this study was to evaluate possible abnormalities in plasma fibrinogen levels and the state of the fibrinolytic system in young adults with a first-ever ischemic stroke. METHODS: This study is based on 102 consecutive patients aged 18 to 44 years admitted between January 1991 and May 1996 as a result of a first ischemic stroke. Forty-one healthy controls were recruited. Evaluations of anthropometric/metabolic variables, plasma fibrinogen levels, and the fibrinolytic system were undertaken >/=3 months (mean, 5.4+/-2.0 months) after admission. RESULTS: Patients had lower tissue plasminogen activator activity and increased plasminogen activator inhibitor type 1 activity at baseline, as well as increased tissue plasminogen activator mass concentration both at baseline and after a venous occlusion test. Overall, there were no significant differences between the main etiologic subgroups regarding plasma fibrinogen levels and fibrinolytic variables. Baseline fibrinolytic variables were strongly correlated with body mass index, serum triglycerides, and cholesterol levels. After adjustments in multivariate models, fibrinogen levels and tissue plasminogen activator mass concentration both at baseline and after venous occlusion test remained significantly increased in patients. Logistic multiple regression analyses indicated that plasma fibrinogen was a strong predictor of ischemic stroke (odds ratio, 11.25; 95% CI, 3.27 to 38. 69). CONCLUSIONS: Increased fibrinogen levels and tissue plasminogen activator mass concentration are independently associated with ischemic stroke in young adults. Metabolic perturbations are closely interrelated with aberrations in tissue plasminogen activator and plasminogen activator inhibitor type 1 activity in these patients, findings consistent with an acquired hypofibrinolysis.     

Time course of lesion development in patients with acute stroke: serial diffusion- and hemodynamic-weighted magnetic resonance imaging

BACKGROUND AND PURPOSE: We sought to characterize the evolution of acute ischemic stroke by MRI and its relationship to patients' neurological outcome. METHODS: Fourteen patients with acute ischemic stroke underwent MRI within 13 hours of symptom onset (mean, 7.4+/-3 hours) and underwent repeated imaging and concurrent neurological examination at 8, 24, 36, and 48 hours and 7 days and >42 days after first imaging. RESULTS: Diffusion-weighted imaging (DWI) lesion volumes increased between the first and second scans in 10 of 14 patients; scans with maximum DWI lesion volume occurred at a mean of 70.4 hours. Initial DWI lesion volume correlated with the largest T2 lesion volume (r=0.97; P<0.001). Final lesion volume was smaller than maximum lesion volume in 12 of 14 patients. There was positive correlation between the follow-up National Institutes of Health Stroke Scale score and the initial DWI lesion volume (r=0.67; P=0. 01) and maximum T2 lesion volume (r=0.77; P<0.01) and negative correlation with initial mean apparent diffusion coefficient ratio (ADCr) (r=-0.64; P<0.05). The ADCr was 0.73 at initial imaging and fell between the initial and second scans in 10 of 14 patients. Mean ADCr did not rise above normal until 42 days after stroke onset (P<0. 001). CONCLUSIONS: Serial MRI demonstrates the dynamic nature of progressive ischemic injury in acute stroke patients developing over hours to days, and it suggests that both primary and secondary pathophysiological processes can be valuable targets for neuroprotective interventions.     

Pharmacologic profile of survivors of acute myocardial infarction at United States academic hospitals

Optimal drug therapy for patients with acute myocardial infarction (AMI) is well described in the medical literature. However, data on the actual pharmacologic management of patients surviving AMI at academic hospitals is unavailable. The purpose of this study was to document treatment profiles in 500 patients surviving AMI at 12 academic hospitals in the United States. These profiles were compared with established guidelines and were evaluated for trends. Overall, thrombolytics (streptokinase > or = tissue-type plasminogen activator) were administered in 29% of the patients, with a greater proportion of patients receiving beta-blockers than calcium channel antagonists in the initial 72 hours (61% vs 40%; p < 0.005) and at discharge (51% vs 35%; p < 0.005). Further, women were less likely than men to receive thrombolytic therapy (odds ratio [OR] = 0.61; confidence interval [CI], 0.54 to 0.69) or beta-blocker therapy within the first 72 hours (OR = 0.61; CI, 0.55 to 0.67) or at hospital discharge (OR = 0.53; CI, 0.48 to 0.58). Overall, improvements could still be made in the number of patients who receive thrombolytic and acute and chronic beta-blocker therapies after AMI, particularly in women. Changes in treatment profiles may be a reflection of the publication of large clinical trials.     

SIOP Working Committee on psychosocial issues in pediatric oncology: guidelines for communication of the diagnosis

A 44-year-old man with a St. Jude mitral valve was admitted because of progressive pulmonary edema. He was diagnosed with prosthetic heart valve thrombosis (PHVT) based on the findings of "muffled" prosthetic valve clicks. Doppler echocardiographic evidence of severe mitral stenosis and transesophageal echocardiographic evidence of limited mitral valve motility. Because the patient hesitated to undergo our recommended surgical treatment, he was immediately treated with intravenous recombinant tissue plasminogen activator (100 mg over 3 h) followed by heparinization. Two hours after the thrombolytic therapy, the prosthetic valve clicks became clearly audible and his congestive symptoms were dramatically improved. Follow-up echocardiography no longer-showed significant mitral valve obstruction. A transient cerebral ischemic attack occurred at the end of thrombolytic therapy but there were no neurologic sequalae. The patient, on warfarin therapy, was well at follow-up 8 months after discharge. Surgical intervention has long been the standard therapy for patients with PHVT. Our case experience suggests that thrombolytic therapy may be considered as an effective alternative to surgical intervention for selected patients with PHVT. In this report, we also review the current literature regarding the indications, effectiveness and safety of thrombolytic therapy in PHVT.     

Three cases of tuberculosis after heart transplantation in Spain

The fibrinolytic capacity of patients with acute myocardial infarction (AMI) is known to be impaired. The primary regulatory element of the fibrinolytic system is plasminogen activator inhibitor (PAI). It has been previously observed that there are 2 peaks in the plasma PAI level of AMI patients at 4h and 16h after thrombolytic therapy with recombinant tissue plasminogen activator (rtPA). Lanoteplase/SUN9216 is a mutant tPA with a biological half-life longer than that of rtPA. Thrombolytic therapy with mutant tPA or rtPA was carried out consecutively in 21 patients with AMI (8 patients as the mutant tPA group, and 13 patients as the rtPA group). The recanalization time of the mutant tPA group was significantly faster than that of the rtPA group (16.1 +/- 3.9 min vs 39.6 +/- 4.8 min, p<0.01). The PAI activity at 4h after the initiation of thrombolysis was significantly lower in the mutant tPA group than in the rtPA group (8.74 +/- 5.46IU/L vs 26.74 +/- 3.35 IU/L, p<0.01). There was a one mild peak in serial plasma PAI activity levels 24h after the initiation of thrombolysis. The results suggest that thrombolytic therapy with mutant tPA reduced the impairment of fibrinolytic capacity. The mutant tPA gives faster recanalization and lower PAI activity after successful thrombolysis, compared with rtPA.     

Assessment of left ventricular function by isometric handgrip exercise after thrombolysis in patients with refractory unstable angina

The handgrip test has been proposed for the evaluation of the hemodynamic reserve in patients with coronary artery disease and to quantitate the impairment of left ventricular (LV) function. The present study was designed to evaluate the effect of thrombolytic therapy in patients with refractory unstable angina in order to test the hypothesis that a reduction in intracoronary thrombosis could ameliorate their hemodynamic response to the handgrip test. During left heart catheterization, 20 patients with refractory unstable angina of recent onset performed a handgrip test before (HG1) and 24-72 hours after (HG2) being randomized to receive recombinant tissue-type plasminogen activator or placebo, according to a double-blind parallel group design. HG1 induced an increase in heart rate (p < 0.001), in systolic pressure (p < 0.001), and a reduction in ejection fraction (p < 0.05). Changes in LV end-diastolic pressure during baseline handgrip were highly different in individual patients, resulting in a trend toward an increase. Similarly, a different individual response was observed in the behavior of the isovolumetric and relaxation indices. In comparison with HG1, no difference was detected during HG2 in the 2 treatment groups with respect to changes in LV volumes, ejection fraction, LV systolic and diastolic pressures, +dP/dt, (dP/dt)/P, -dP/dt, and tau index. In patients with refractory unstable angina of recent onset, the handgrip test performed before and after thrombolysis did not prove to be useful in assessing directional changes of LV performance, mainly because of the different individual response to the baseline handgrip test.