At the end of the decade of 60s, thrombolytic agents had a significant development and were considered as important therapeutic options. Two plasminogen activators, streptokinase and urokinase were considered therapeutically effective. Streptokinase was under extensive clinical experience in patients with thromboembolic disorders. Pyrogenicity of the early streptokinase preparations led to the searching a non-antigenic and nontoxic plasminogen activator, a research promoted by National Heart and Lung Institute in 1964. Urokinase meanwhile, had been identified as a promising agent with high specific activity, free from thromboplastic contamination and adventitious virus and nontoxic and nonpyrogenic reactions in animals. Additionally, the dissolution of de novo intravascular human thromboembolism founded the path for clinical trials [5].

Acute PE was considered as an ideal clinical entity for the initial evaluations of thrombolytic agents for several reasons: (a) it is a common and important disease; (b) objective methods for diagnosis and course of thrombus in pulmonary arterial circulation were available; (c) these methods allow evaluation of the thrombolytic agent effect on thrombus; (d) in PE, a fresh thrombus consisting mainly of fibrin and red blood cells is lodged in normal pulmonary vessels perfused by a large blood flow. This feature could allow thrombus dissolution by thrombolytic agents [3]. Several preliminary clinical observations established in 1966 that urokinase induced an active fibrinolytic state well tolerated even in critically ill patients. Additionally, the evidence suggested that thrombolysis dissolved thrombus from the pulmonary circulation restoring normal hemodynamics [5].

UPET, a controlled, multi-institutional study, had as primary target to determine whether PE abnormalities, produced by obstructive thrombus, and measured by V/Q lung scan, pulmonary angiography, and pulmonary hemodynamic, would return toward normal more rapidly with a urokinase regimen when compared to heparin alone [5].

Two independent analysis panels for pulmonary angiography and V/Q lung scans reviewed data. Pre-infusion and post-infusion blood samples included fibrinogen, plasminogen, bilirubin, and various enzyme levels. Pulmonary angiography was the basis for inclusion. The minimal angiographic eligibility criterion was occlusion of at least one segmental artery [5].

Patients were considered in: Class 1, without shock at the time of inclusion; Class 2 with persistent shock; Subclass S, with submassive embolism (i.e., less than the equivalent of two lobar arteries with significant filling defects or completely obstructed); subclass M included massive PE patients (i.e., obstructions or significant filling defects present in two or more lobar arteries or the equivalent).

Lung scans with anterior and posterior views were also required in all patients except in those in shock; here the lung scan was optional, in order not to delay therapy and not to decrease the accession of critically ill patients into the trial. Right heart catheterization with pressure measurements was performed immediately before angiography. Fick cardiac output measurements were also made except when patients were receiving oxygen therapy. A well-documented clinical episode suggesting that PE had occurred within 5 days of the institution of therapy was necessary for patient eligibility. Patients with recent operations or with the usual contraindications for the use of anticoagulant or thrombolytic therapy were excluded from the trial [5].

After randomization, 12 h intravenous infusion of urokinase or heparin was started. Patients in urokinase group received a loading dose of 2000 CTA units/lb of body weight followed by 2000 CTA units/lb/h; patients in heparin group had a loading dose of 75 units of heparin/lb of body weight followed by 10 U/lb/h. After infusion, all patients received heparin intravenously for 5 days at least, followed by oral anticoagulation. Heparin was given in to obtain Lee-White clotting time to 30–45 min within 1 h before the next dose. In the follow-up right heart catheterization, V/Q lung scan and pulmonary arteriography were performed [5].

Recurrence was considered if both lung scan and clinical evidence data were obtained. An episode was considered probable if either lung scan evidence or characteristic clinical signs were present. Bleeding complications were classified as: moderate, defined as an estimate of blood loss of 500–1500 mL with an associated hematocrit reading fall of 5–10 points or a blood transfusion of 2 units or less, or severe, defined as one in which any of these limits was exceeded [5].

From October 1968 to August 1970, 160 patients were included; 78 in heparin group and 82 in urokinase group. Regarding demographic characteristics the balance between treatment groups was appropriate. However, patients in urokinase group tended to be younger and with more severe thrombosis. Both factors could be associated with treatment response. To adjust for these imbalances, all data on response to treatment were adjusted by the direct method for imbalances in age and baseline severity [5].

Dyspnea, pleuritic pain, apprehension, and cough, as well as, tachycardia, rales, an increased pulmonary component of the second heart sound, and gallop rhythm were the most common symptoms and physical findings. Peripheral thrombophlebitis was present in only one-third of patients upon entry into the trial. Most patients did not have persistent shock, for only 5 patients given heparin and 9 patients given urokinase were in the class 2 category. The class 1 patients, 73 in each treatment group, had equally distribution between the submassive and massive embolism subclasses [5].

The most common causes for exclusion were normal V/Q lung scan and pulmonary arteriography which did not satisfy diagnostic criteria for the study. A minority of patients were excluded secondary of contraindications to thrombolytic agent. Patients in heparin group did not have any significant change in plasminogen and fibrinogen compared to those in urokinase group in whose a significative fall in both biomarkers was observed [5].

Regarding pulmonary arteriography, the baseline averages for the heparin- and urokinase-treated patients corresponded closely to an average severity class of “moderate.” With heparin, a small improvement in the arteriograms occurred; this amounted to 0.68 on the seven-point scale, lying between “no improvement” and “minimal improvement.” With urokinase, the mean improvement was larger, amounting to 1.56, positioned halfway between “minimal” and “moderate” improvement. The difference in mean change between urokinase and heparin-treated groups was 0.88 grades with a standard error of only 0.17. The critical ratio, i.e., the difference in mean change divided by the standard error, was 5.2, highly significant. While arteriographic improvement after urokinase was only occasionally dramatic, distinct improvement did occur much more frequently after urokinase than after heparin infusion [5].

Only 5 of 57 (9 %) in the heparin group showed “moderate” or greater improvement, while among the urokinase patients 30 of 57 (53 %) showed this improvement. It is of some interest that in no case for patients in either group did an arteriogram worsen sufficiently for a shift to a higher severity class. In patients receiving urokinase, baseline angiography severity appeared to influence treatment response, showing greater improvement patients with more severe baseline findings. Patients given heparin gave no evidence of this trend [5].

Complete hemodynamic measurements were obtained in 71 % and pressures alone in 92 % of patients. Elevated right ventricular systolic pressure (>25 mmHg) and low arterial oxygen tension (PO₂) (<90 mmHg), present in 96 % and 94 %, respectively, were the most common baseline hemodynamic abnormalities. The baseline mean right ventricular systolic pressure of 45 mmHg was moderately high but only 15 % of patients had a baseline value greater than 60 mmHg. The mean 24-h changes were significantly better for urokinase group than for heparin-treated patient [5].

Concerning V/Q lung scans, the baseline mean defect in both groups was 25 % which corresponds to a perfusion defect of one half of one lung. The first day heparin group improved 8.1 % and urokinase group 22.1 %. The greatest effect of urokinase on the lung scans appeared within the first 24 h. It interesting to note that 1-year follow-up lung scan data were available in 59 patients without any evidence of the effect of urokinase [5].

Patients in urokinase group had better response when they were younger (<50 years) and embolus age was <48 h. In addition, patients with PE and cardiogenic shock had greater response [5].

In terms of non-antigenic and nontoxic effects, urokinase was a safe plasminogen activator. The most common complication was overt bleeding or an unexplained fall in hematocrit reading. Some bleedings were expected since patients were under venous cutdowns, arterial punction, and venipunctures. Twenty-one or 27 % of the heparin group and 37 or 45 % of the urokinase group were classified as having a moderate or severe bleeding complication at some time during the 2-week period of hospitalization. The main difference between the two groups was related to severe bleeding complications. Patients receiving urokinase suffer twice as frequently from such episodes as those receiving heparin. The increase in bleeding attributed to urokinase occurred in the first 24 h coinciding with urokinase infusion [5].

Urokinase patients showed no evidence of increased bleeding after the first 24 h. Unexplained hematocrit falls occurred in 26 % of patients given heparin and in 24 % of patients given urokinase. These hematocrit drops usually occurred in the first few days of therapy, were rarely severe, and did not necessitate transfusion. Bleeding from venous cutdowns site for the pulmonary arteriogram catheter was much more troublesome than from arterial sites. Extensive dissection necessary to perform venous cutdowns in obese arms was the most common predisposing factor. Spontaneous bleeding occurred with nearly equal incidence in both treatment groups. In urokinase group one patient with 1-month history of stroke had intracerebral bleeding. The protocol was modified to exclude patients with this characteristics. One patient with chronic alcoholism, died of hemorrhage from multiple gastric stress ulcers approximately 12-h after the completion of the urokinase infusion. This patient had several baseline hemostatic abnormalities including a prothrombin time twice the control [5].

Recurrence of PE occurred in 19 % in heparin group and 15 % in urokinase group in the first 2 weeks. While these episodes were usually well tolerated by the patient, one was fatal for a patient who had received urokinase 10 days earlier. The class-2-M patients (massive PE patients in shock) had a 2-week case fatality rate of 18 %. The surprisingly low mortality in this subgroup emphasizes an interesting observation in which most massive PE, even those desperately ill, had a high rate of spontaneous improvement. On the other hand, all three of the class 2-S patients (submassive embolism in shock) died within the 2-week follow-up period. Each of these latter patients was critically ill prior to pulmonary embolization and this most likely explains the mortality and the fact that these patients with submassive PE presented in shock [5].

The results of this study showed: angiography evidence of clot lysis, reversion toward normal of the hemodynamic abnormalities, and pulmonary capillary perfusion scanning, were significantly different in favor of urokinase treatment. In addition, established that urokinase is capable of dissolving thromboembolism at least in part and that such dissolution is associated with an improvement in the physiological abnormalities created by the occlusive lesion. Pulmonary angiography was the earliest and most consistent indicator of pulmonary reperfusion [5].

This study concluded that pharmacological thrombolysis therapy may well become the preferred treatment for patients in shock with massive embolism, especially for those with borderline cardiac reserve, as surgical embolectomy in this group is associated with a very high mortality. During the study 11 patients underwent pulmonary embolectomy had an operative mortality of 73 %. The complete evaluation of the therapeutic benefit of thrombolysis therapy in PE will be difficult. This trial established that urokinase significantly improved quantitative measurements of cardiopulmonary dysfunction, but the invasive procedures for necessity-enhanced bleeding risk. Furthermore, an attempt to demonstrate a significant improvement in mortality with urokinase in PE would have required limiting the study to a large number of class 2-M, high-risk patients, who are relatively rare (note that only 7 % of patients were in this category) or conducting a trial studying all patients with PE, in addition a sample 20–40 times the size of the study.

In spite of theses results several unmet answers remained: establishing the thrombolytic effects of urokinase, this trial incorporated only one treatment regimen. While clot resolution was unequivocal, nevertheless it was not dramatic in terms of lysis of the entire pulmonary occlusion and, presumably, of resolution of the original venous thrombosis, remembering that recurrent PE was not uncommon. Under these circumstances a reasonable question is whether longer regimens of urokinase therapy can more readily achieve maximum pulmonary and venous thrombolysis without further increasing the risk of hemorrhage. Urokinase proved clot-lysing capacity but, as with all potent drugs, it can be dangerous if used outside strictly prescribed limits. Clearly, further evaluation was required before it can be recommended as a proven clinical pharmaceutical [5].

Pulmonary embolism is very common cardiovascular disease, in the acute phase patients have two possibilities: recover spontaneously or die before treatment can be given. Several previous reports suggesting that streptokinase is superior to heparin. However, these studies were uncontrolled. The necessity to assess the role of streptokinase in a comparative randomized control in this situation was mandatory. This report included 30 patients with life-threatening PE allocated at random to streptokinase plus heparin or heparin alone [6].

Any patient presenting with clinical symptoms and signs of acute or progressive life-threatening PE was considered for inclusion. Patients were excluded at the discretion of the physician in charge if they had: recent surgery, gastrointestinal disease, malignant hypertension, a recent cerebrovascular episode, pregnancy, or recent delivery. In all patients 12-lead electrocardiogram, chest X-ray, full blood count, plasma thrombin clotting time, fibrinogen, serum glutamic oxaloacetic and glutamic pyruvate transaminase, lactic dehydrogenase, and bilirubin was performed [6].

Assessment of the severity of the thrombus and progress after treatment were based mainly on information gained from pulmonary angiography. Hemodynamic measurements were right atrial, right ventricular, and pulmonary arterial phasic and mean pressure; additionally oxygen difference, arterial oxygen saturation, cardiac index calculated by Fick principle from measurement or assumed, oxygen consumption, total pulmonary resistance and brachial arterial oxygen and carbon dioxide tensions, pH, and bicarbonate estimations were obtained. Right heart catheterization was carried out using standard method [6].

Angiographic and hemodynamic studies were repeated at 72-h, after which the cardiac catheter was removed. Six months later patients were clinically reassessed and, if agreed, further pulmonary angiographic and hemodynamic studies were performed. All pulmonary angiographs were subsequently reviewed by two independent radiologists who had no knowledge of the clinical state of the patients or the response to treatment. Miller classification was used to know the severity of the pulmonary arterial occlusion. This system provides a score from 0 to 34, made up of a maximum of 16 for the thrombus itself and 18 for peripheral perfusion as assessed by opacification of the peripheral vessels by contrast medium [6].

Heparin or streptokinase was allocated according to random lists, each center using a separate list. A loading dose of 100 mL of normal saline or 5 % glucose containing 600,000 units of streptokinase or 5000 units heparin, each with 100 mg of hydrocortisone added, was infused through the catheter in the pulmonary artery over 30-min. This was followed by an hourly infusion of either 100,000 units of streptokinase or 2500 units of heparin for 72-h. Sixty-hours after infusion warfarin was prescribed at an initial dose of 25 mg and continued with laboratory control for 6 months. Treatment was monitored as follows: in patients treated with heparin if the protamine heparin titration exceeded 1–5 mg/100 mL the maintenance dose was reduced by 500 U/h and the test repeated in 6 h. In the streptokinase group if the observed fibrinogen titer (in saline) fell below 1 in 4 the dose of streptokinase could be increased by 50,000 U/h and the test repeated in 6 h. Subsequent oral anticoagulation was controlled by the one-stage prothrombin time [6].

Thirty patients entered the trial. Twenty-three patients completed the 72-h trial regimen, 12 in heparin group and 11 in streptokinase group. The 7 patients who failed to complete were excluded from the overall analysis of results. The ages and clinical features were similar in both treatment groups, but there were more men than women in the heparin group and more women than men in the streptokinase group. The severity of illness, as judged by hemodynamic measurements and angiography, was similar in both groups [6].

Of the 8 patients treated with heparin and who had an initial angiographic score greater than 16, none had a score of less than 16 at 72-h. In contrast, in 10 patients of streptokinase group with an initial score above 16, it fell to below this figure in all except 2. Additionally, angiographic findings in 4 heparin group patients showed no change or deteriorated. The mean angiographic score in the streptokinase group fell by 61 %, whereas the score in the heparin group fell by only 15 %. Improvement during the 72 h of treatment, assessed by the two group t test, was significantly greater in the streptokinase group for the angiographic score (p < 0.001), the pulmonary arterial systolic pressure (p < 005), and the mean pulmonary arterial pressure (p < 0.02) [6].

Seven patients failed to complete 72 h of the trial treatment. One patient having made satisfactory clinical progress suddenly died 18 h after starting heparin treatment. The angiography had shown complete occlusion of the right pulmonary artery. At necropsy there was fresh thrombus in the left pulmonary artery and it was concluded, therefore, that the patient had died from a PE recurrence. The clinical condition of the other 6 patients deteriorated, hypotension persisted, therefore they were withdrawn from the trial so that in accordance with the trial, protocol alternative treatment could be instituted. Successful pulmonary embolectomy was carried out on 4 patients (2 from each group). The treatment was changed from heparin to streptokinase in 2 patients: in one the angiographic score fell from 26-0 to 20-5 at 72-h, but in the other the score rose from 24-0 to 27-0 [6].

Four heparin group patients and 7 in streptokinase group had 6-months follow-up. Two patients, one from each group, had mild dyspnea on exertion. In one case pulmonary hypertension remained with a mean pulmonary arterial pressure of 40 mmHg and an angiographic score of 16. Another patient from the streptokinase group had a loud pulmonary valve closure sound. Seven patients agreed to have a third pulmonary angiogram carried out after the purpose of the study had been explained to them. Two had been treated with heparin and 5 with streptokinase. There was a tendency towards further improvement; unfortunately, the pulmonary arterial pressure data was not completed for all three examinations in each case [6].

Eighteen (78 %) of the 23 patients completing 72 h of the trial suffered one or more side effects; 10 in heparin group and 8 in streptokinase group. One patient became severely hypotensive with peripheral vasoconstriction during the loading dose of streptokinase; this responded well to additional intravenous hydrocortisone and chlorpheniramine. Another patient developed a widespread erythematous irritating rash on the third day of streptokinase treatment, which rapidly cleared within 48-h. A rise in temperature was frequent in streptokinase group. Bleeding was not a serious problem, though one patient in each group required blood transfusion.

The results of this trial provide clear evidence that streptokinase was superior to heparin in terms of the early clearance of PE and in the reduction of the pulmonary hypertension. There was significantly evidence in favor of thrombolysis with streptokinase compared with heparin group (p < 0.001). The reduction of systolic and mean pulmonary arterial pressures was also significantly greater (p < 0.05 and p < 0.02 respectively) in the streptokinase group. Seven patients failed to complete 72 h of the trial treatment: five successfully underwent pulmonary embolectomy. Six of these “failures” had initial pulmonary angiographic scores of 24 of more and systemic systolic blood pressure recordings of 100 mmHg or less. Patients with these features should probably be considered for pulmonary embolectomy as the initial treatment. A febrile reaction commonly occurred in the streptokinase group: otherwise side effects were no more common than in the heparin group [6].

Regarding deaths related to PE, about 50 % of them occurred within 2 h. All except 1 of the patients in this trial began treatment more than 6 h after the major episode, raising the need for a trial including larger samples of patients in order to show a significant difference based specifically on mortality between heparin and streptokinase treatment.

Given the clinical deterioration observed in several patients, pulmonary embolectomy with cardiopulmonary bypass was considered as therapeutic option, and authors analyzed indications of these approaches. As has been previously published patients under thrombolysis with streptokinase and poor peripheral lung perfusion seem to have poor outcome. Six out of 10 patients with perfusion indices of 10 or more failed to complete allocated trial therapy. Also, a systemic systolic blood pressure of ≤100 mmHg with an angiographic score of ≥24 was associated with a 70 % chance of death or the need for pulmonary embolectomy. Considering the results a question still remains as to whether the initial accelerated thrombolysis by streptokinase is of value in terms of long-term resolution and survival [6].

In the 6-month follow-up study, 5 patients from streptokinase group had lower scores than the two in heparin group, but these numbers are too small for definitive answers. Side effects of treatment with streptokinase were no more severe than those of heparin. A final consideration was that with an initial pulmonary angiographic score ≥24 or more and systemic systolic arterial blood pressure ≤100 mmHg, pulmonary embolectomy is probably the treatment of choice.

Pulmonary embolism is a common disease in medical and surgical patients. At that time several studies claimed that fibrinolytic treatment with streptokinase or urokinase was superior to heparin. However, only two prospective randomized, controlled trials compared the effect of fibrinolytic treatment and heparin in major PE patients. In UPET trial [5], urokinase compared with heparin alone, significantly accelerated the resolution rate of pulmonary thromboemboli at 24 h. In the trial conducted by Tibutt et al. [6], significantly greater evidence of thrombolysis was reported in streptokinase group (72-h) than in heparin group for the same period. It was not yet settled, however, whether the increased rate of thrombolysis following fibrinolytic treatment reduced the mortality in patients with massive pulmonary embolism. This report concerns a controlled trial in which patients with proven major PE were randomized to heparin alone or streptokinase in standard dose plus heparin [7].

Patients with symptoms of acute major PE were considered. Diagnosis was established by pulmonary angiography in all cases. Angiography was done in the acute stage on admission and repeated after 3 or 4 days of treatment (72 h as a mean). Severity of the pulmonary artery occlusion was assessed by Miller score, which provides a score from 0 to 34, made up of a maximum of 16 for the thrombus itself and 18 for peripheral perfusion as assessed by opacification of the peripheral vessels by contrast medium. Exclusion criteria were known bleeding tendency or recent gastrointestinal or urogenital tract bleeding, major surgery within the last 10 days, recent stroke, severe hypertension (diastolic pressure ≥120 mmHg), hypertensive retinopathy grade 3–4, severe renal or hepatic insufficiency, pregnancy, recent delivery or known malignant disease. An arbitrary upper age limit was set at 70 years [7].

In patients with less severe symptoms, lung VQ scan was performed prior to pulmonary angiography. Additionally blood samples were taken for quantification of hemoglobin, thrombocyte count, activated partial thromboplastin time, fibrinogen, thrombin clotting time, serum creatinine, serum glutamic oxaloacetic and glutamic pyruvate transaminase. Clinical features were noted daily during the first 10 days after the start of treatment, including any sign of bleeding. When possible, a daily electrocardiogram was recorded. Special care was taken to record any sign of deep vein thrombosis or recurrent PE [7].

Streptokinase was given in standard doses. After a loading dose of 250,000 IU I.V. in 20 min, a maintenance dose of 100,000 IU/h was given by continuous I.V. infusion. Infusion was continued until control pulmonary angiography after 72 h was done. Streptokinase was then discontinued and oral anticoagulation with warfarin was started. To avoid anaphylactic reactions, 100 mg of soluble hydrocortisone were given I.V. before the loading dose of streptokinase, where after prednisone, 10 mg three times daily, was given until discontinuation of streptokinase.

Heparin was given in an initial dose of 15,000 IU I.V., followed by a maintenance dose of 30,000 IU/day as a continuous i.v. infusion. The dose of heparin was subsequently adjusted according to the thrombin clotting time. Warfarin was started after control angiography and heparin was discontinued when therapeutic values of thrombotest were obtained. As a mean, heparin was given for 7 days, but was continued for 70 days in one patient with symptoms of persistent massive embolism. Intramuscular injections were avoided in both treatment groups [7].

Twenty-five patients entered the trial and all except 5 were allocated to treatment groups by using sealed envelopes. The demographic characteristics were similar in both treatment groups, excepting higher age and more frequent female gender in heparin group. Only one patient in each group had a systolic blood pressure <90 mmHg and 3 patients in each group had electrocardiogram signs of acute right ventricular strain. The interval from onset of symptoms to initiation of treatment was similar in both groups, excepting 2 patients in the streptokinase group who have had symptoms for more than 5 days. In terms of angiographic scores streptokinase was more severe than heparin group. There was only one patient in each group with an angiographic score >30 and these patients were both in shock on admission [7].

The mean angiographic score fell 52.3 % in the streptokinase group compared with 20.6 % in heparin group. Of the 10 patients treated with streptokinase and who had an initial angiographic score >20, 8 had a score <16 at 72 h. Angiographic deterioration (rise in score from 15 to 24) occurred in one patient treated with heparin. After discontinuation of heparin, this patient experienced clinical and angiographic improvement (fall in score from 24 to 12) following treatment with streptokinase for 3 days. The clinical progress during the treatment period of 72 h was satisfactory in all patients with marked angiographic improvement, regardless of the type of treatment. It should be noted, however, that 8 of the 10 patients in this category had been treated with streptokinase. It is also important to note that clinical improvement might occur in spite of unchanged or even worse angiographic appearance and that the clinical features might be moderate in patients with massive embolism [7].

One patient in heparin group, a 66-year-old woman, failed to complete the 72-h trial. She presented with severe hypotension and an angiographic score of 34, deteriorated and died 15 h after starting heparin treatment. Necropsy demonstrated large, occluding thrombi in both the right and the left pulmonary artery. The other heparin-treated patient who died was a 49-year-old man. Five weeks prior to embolization he was under neurological surgery by a meningioma. He developed severe dyspnea and cyanosis and was also moderately hypotensive. Pulmonary angiography demonstrated central bilateral thrombus with no change in the next 72-h with heparin treatment. Intravenous infusion was continued for 70 with slight clinical improvement until she died. Necropsy revealed multiple partially occluding and organized thrombus in several lobar arteries. A glioblastoma was found in the right hemisphere. As judged form the clinical course, persistent PE contributed to the fatal outcome [7].

In streptokinase group there was one late dead a 66-year-old woman with an undiagnosed pulmonary adenocarcinoma. She had a 1-week history of deep vein thrombosis of the right leg and had complained of dyspnea during the last 2 days. Phlebography demonstrated deep vein thrombosis on both sides, probably affecting the iliac veins. Bilateral major pulmonary embolism was shown by angiography and the angiographic appearance was only slightly improved following streptokinase. Patient died 3 weeks later from phlegmasia cerulea dolens with gangrene of both feet. Necropsy disclosed occluding thrombi in vena cava inferior and in the iliacal and femoral veins on both sides but no evidence of thrombotic occlusion of the arteries. Pulmonary emboli could not be demonstrated. An undifferentiated adenocarcinoma was found in the right lung and metastases were demonstrated in the pancreas, kidneys and adrenals [7].

Major bleeding was more frequent in streptokinase group (4 patients) than in heparin group (2 patients). This complication was most often related to punction or cutdown sites in streptokinase group. Spontaneous bleeding occurred more frequently in heparin patients. A rise in temperature was more frequent in the streptokinase group but more serious anaphylactic reactions were not seen. In no case did streptokinase have to be withdrawn because of side effects [7].

Previous evidence suggesting that in man substantial resolution of PE may occur spontaneously within days or weeks as demonstrated by pulmonary angiography. However, the early resolution rate of major PE is slow, as judged by angiography or lung scanning and significant resolution of major emboli does not seem to occur during the first week. Contrasting with these observation of slow PE resolution during treatment with heparin there are reports of rapid lysis after streptokinase or urokinase. When comparing heparin and streptokinase effects in PE patients, each group needs to be comparable in terms of prognostic factors and factors known to affect resolution as severity and duration of the PE and coexisting cardiorespiratory disease. In this study both groups were comparable, with the exception that the angiographic obstruction was more severe in the streptokinase group than in heparin group and PE duration was longer than 1-week in 2 streptokinase-treated patients. This, however, would be expected to disfavor the spontaneous thrombolysis in the streptokinase group [7].

Angiographic evidence of thrombolysis was significantly greater (p < 0.01) in the 14 patients treated with streptokinase than in the 1 treated with heparin. In streptokinase group the mean angiographic score fell by 52.3 % compared with heparin group 20.6 %. These observations were similar to those obtained by Tibutt et al. [6]. Right-sided pressure measurements were performed in only 4 patients in streptokinase group. Three of them had normal pulmonary arterial pressures. This finding was in accordance with previous observations in which the enhanced thrombolysis obtained with fibrinolytic agent was accompanied by a reduction of systolic and mean pulmonary arterial pressures. One patient deteriorated during treatment with heparin, but was subsequently successfully treated with streptokinase, thus serving as his own control. The systemic fibrinolytic effect was sufficient in all streptokinase groups, as judged from the coagulation assays. Hence, the failure to obtain significant thrombolysis in 2 of the streptokinase-treated patients remains obscure and possibly related with age of the thrombus [7].

Considering that in the present study only one patient in heparin group, suffered early death attributed to massive PE, and based on previous evidence, the authors considered that the only survival chance would probably have been embolectomy. However, its best indications remain unknown. An important contribution in this study was that in critically ill patients with severe hypotension and an angiographic score of 3, streptokinase was a successful therapeutic approach. However, the important question of whether the accelerated thrombolysis obtained with fibrinolytic agent might reduce mortality in massive PE remains unknown. As stressed by several authors, a trial including larger sample was mandatory [7].

Major bleeding complications were more frequently seen in streptokinase group than in those treated with heparin alone. Its higher frequency was closely related to punction or cutdown sites in connection with diagnostic procedures. Three patients developed inguinal hematoma following pulmonary angiography. To avoid this complication, it is advisable that catheterization for pulmonary angiography in patients with suspected PE should be performed via the cubital vein. Also, authors established that acute life-threatening PE patients had three treatment options: heparin, streptokinase or emergency embolectomy [7]. According to Tibutt et al. [6] embolectomy should be restricted to patients with sustained hypotension and an initial angiographic score of ≥24. The final conclusion was that streptokinase is the treatment of choice for most patients with acute life-threatening PE, provided that a careful screening for bleeding tendencies is carried out before treatment is started. It is also important that the number of invasive diagnostic procedures should be kept as low as possible [7].

Despite previous randomized control trials [5–7], several limitations were identified specifically in UPET trial [5], where heparin infusion in therapeutic doses was given also during the diagnostic evaluation before randomization. In addition, the anticoagulant mechanism of heparin was not fully understood. Aditionally, heparin had proved value in the treatment of PE, even in severely ill patients. Furthermore, thrombus resolution reported in the literature as spontaneous, occurred after heparin treatment. So, a fibrinolytic effect of heparin cannot be ruled out. The main target of this study was to compare the effect of heparin infusion with that of urokinase administered alone in acute PE patients [8].

From September 1979 to August 1983, 792 patients were screened for PE by V/Q lung scan. Inclusion criteria were: (a) >9 unperfused lung segments, computed for both lungs on the lateral projections of perfusion lung scans; (b) age <72 years; (c) clinically identified PE not older than 7 days; (d) fibrinogen and plasminogen plasma concentration within the normal plasma level; (e) Lee-White clotting time, platelet count, prothrombin time, also within the normal range. Exclusion criteria included thrombolytic therapy contraindications as and/or angiographic procedure: recent cerebrovascular episodes, severe hypertension, history of occurrence of bleeding, trauma or major surgery within 7 days, pregnancy, and shock. Thirty patients were submitted to confirmatory pulmonary arteriography. None of them had significant cardiac or pulmonary diseases. Mean pulmonary artery pressure was measured [8].

Patients were randomly allocated to the treatment groups: (A) urokinase 800,000 CTA units (IU) infusion for 12 h a day for 3 days (total dose 2,400,000 IU) followed by oral anticoagulants: (B) heparin infusion at a mean daily dose of 30,000 IU for 7 days followed by oral anticoagulants; heparin was adjusted to Lee-White clotting time between 20 and 30; (C) infusion of 3,300,000 IU of urokinase in 12 h followed by oral anticoagulants. The dosages used in A and C of urokinase groups were lower than those employed in the UPET [5] study. The oral anticoagulant treatment was continued in all patients for 1 year [8].

Perfusion V/Q lung scans and arterial blood gas determinations were obtained at 24-h, 3, 7, and 30 days, 6 and 12 months after the start of treatment in all patients. Pulmonary arteriography and mean pulmonary artery pressure were obtained again at day 7 in all the patients. Venous blood samples were drawn in all patients before randomization and at 6, 12, 24, 48, and 60 h of treatment to assess fibrinogen and plasminogen. Oral anticoagulants were given then to keep the prothrombin activity between 20 and 40 % of the normal value. Impairment of pulmonary perfusion was assessed from: (1) the number of unperfused lung segments; (2) the PaO₂, standard value (PaO₂ standard deviation), i.e., the PaO₂ in mmHg corrected to a PaCO₂ of 40 mmHg [8].

In all patients pulmonary arteriography showed massive PE. Pulmonary perfusion impairment was extensive and related with the index of angiographic severity. The number of unperfused lung segments was 13.6, 13.0, and 13.8 in the treatment groups A, B, and C at the moment of admission. No significant difference was found in the pretreatment values for the three groups. Patients in heparin group (B) showed less impairment of some pretreatment values, the difference from the pretreatment values of groups A and C was small and statistically nonsignificant [8].

Multiple comparisons among groups showed a difference of group C vs. groups A and heparin (B), but not between groups A and B.

Simple main effects for time were significant in treatments A and C. In the former, plasminogen was lower at 48 and 60 h than at 6 h and at 60 h than at 12 h. In the latter, plasminogen at 6 h was higher than at all the other times and at 48 h than at 12 h. Regarding the number of unperfused lung segments observed between 24 h and 1-year follow-up, no differences with treatment in spite of significant time reduction. In one patient of group C, bleeding of the urinary tract was observed. This complication did not require any therapeutic measure. In 12 months follow-up no PE recurrence was identified. As to the clinical outcome, no patient showed recurrence of PE after up to 12 months of observation. Moreover, none of total of patients enrolled had mortality [8].

Previously, several reports indicated a possible apparent fibrinolytic effect of heparin due to inhibition of deposition of fresh fibrin onto an established thrombus which facilitates the natural lysis and resolution of the thrombus. In vitro studies failed to show any influence of heparin on the euglobulin lysis time and on the diluted clot lysis time suggesting a lack of effect of heparin on the fibrinolytic mechanisms. However, in other studies heparin was found to have a dual effect on fibrinolysis: high concentrations inhibited lysis of preformed fibrin while low concentrations enhanced it. Additionally, several authors reported enhancement of fibrinolysis after intravenous administration of heparin. A main finding in this study indicates that before treatment, at about 3 days from the episode of PE, the fibrinogen plasma level is within normal limits, whereas, after 6 h of treatment, it falls to the same level in the various treatment groups. After 12 h, groups A and B showed the same plasma level of fibrinogen while group C had a lower level [8].

These data suggest that heparin may induce fibrinogenolysis, and shows the differences with urokinase depending of the respective dose. The behavior of plasminogen showed that its plasma level, up to 24 h of treatment, is reduced to the same extent in groups A and B, and even more in group C, suggesting that heparin has the same effect on plasminogen as urokinase in group A and may determine a systemic lytic state. After the initial decrease and up to 48 h, fibrinogen did not show any significant difference of plasma concentration between the various treatments. At 60 h, group C shows a plasma level of fibrinogen higher than that of group A and group B a level lower than that at 6 h. These results appear to be directly related to the timing of administration and to the amount of urokinase and heparin administered [8].

The authors considered that the stable decrease in the plasma concentration of fibrinogen in group B suggests that, under continuous heparin infusion, a new equilibrium is reached within a few hours between fibrinogen destruction and production. Similar results were observed at 48 and 60 h, for the plasma level of plasminogen with the exception that group B at 60 h shows a plasminogen concentrate on less reduced than group A. Authors commented that fibrinogen and plasminogen plasma levels provide a consistent picture of the fibrinolytic changes induced by the treatments. And also established that decreasing plasminogen and fibrinogen are considered sufficient to define a lytic state [8].

Regarding the mechanism of enhanced fibrinolysis by heparin it has been suggested that this effect is attained through the release of tissue plasminogen activator. Authors observed that fibrinogen level fell by 23, 26, and 27 % after 6 h of treatment in groups A, B, and C, respectively. Induction of a lytic state by heparin might also be the result of the activation by the drug of Hageman factor and prekallikrein. This intrinsic pathway of plasminogen activation qualitatively acts with a urokinase-like mechanism but seems weaker than urokinase. The characteristics of both of these mechanisms might then explain the observation that plasminogen level in group B is less reduced than in group A at 60 h [8].

Another interesting finding was the agreement between angiographic score and the number of unperfused lung segments at the time of diagnosis and after 7 days. While in each group of treatment a significant reduction (p < 0.001) of the number of unperfused lung segments throughout all the period of observation up to 12 months was obtained, no statistical differences between groups were found at any time. The results of the study agree only in part with those reported in the UPET study [5]; in fact, even in this study, after the first 24 h and up to 12 months, no statistically significant difference between heparin and urokinase treatments was found in mean absolute and percentage resolution at perfusion lung scanning [8].

However, the results after the first 24 h, showed a significantly greater angiographic and scintigraphic improvement in urokinase groups than heparin group. Heparin infusion during the diagnostic evaluation of all patients before their random allocation to treatment groups may account for the differences observed in the UPET study [5] after 24 h. The observation of a fibrinolytic activity of heparin infusion alone in this study could be related in some way to this effect observed in human and experimental studies [8].

Regarding bleeding complications, only one patient in this trial (group C) had marked bleeding from the urinary tract. It was an interesting finding compared with 45 % in urokinase group and 27 % in heparin group of bleeding complications in the early phase treatment in UPET [5]. For the authors, this significative differences may be attributed to heparin infusion. In UPET [5] infusion was performed before and immediately after urokinase infusion inducing plasma fibrinogen level reduction and increasing fibrin degradation products. In turn, these products could have impaired the coagulation systems [8].

Considering that different treatments, including tissue plasminogen activator, induce significant decrease in fibrinogen plasma level in PE patients, it may be convenient to use this parameter as an index of a systemic lytic state to compare the dosages of different drugs, especially with reference to bleeding complications. Changes in angiographic and scintigraphic severity and bleeding complications appear correlated with the reduction in fibrinogen levels [8].

Treatment of thrombosis by activation of the plasma fibrinolytic enzyme system provides a nonsurgical method for relieving thrombus in pulmonary arterial circulation. Urokinase and streptokinase, the plasminogen activators approved for the treatment of PE induce early lysis of pulmonary thrombus administered over long-term 12–24 h infusion. These agents are not fibrin specific and convert circulating plasminogen to plasmin inducing systemic lytic state leading to a generalized coagulation defect which could contribute to the increased risk of bleeding complications [9].

Recombinant human tissue-type plasminogen activator (rt-PA), a new plasminogen activator, preferentially activates plasminogen in the presence of fibrin, produce effective thrombolysis in experimental models and because of its relative fibrin specificity induce thrombolysis without generalized coagulopathy; rt-PA has been evaluated in clinical trials in myocardial infarction, PE, and venous thrombosis patients. In all of these studies, rt-PA was administered in short-term (90 min) and long-term (8 h) continuous infusion. These regimens were associated with a systemic lytic state, less fibrinogenolysis than streptokinase, for an equivalent thrombolytic effect, and excessive bleeding [9].

Experimental studies suggesting the effectiveness of rt-PA in inducing lysis of venous thrombus and PE is increased using high concentrations infused over a short interval. In previous studies, a 15-min infusion regimen produced less plasma proteolysis and less experimental bleeding than an identical dose infused over 1 or 4 h. For these results a clinical trial was conducted to determine whether a bolus injection of rt-PA is effective in producing accelerated thrombolysis in patients with acute PE [9].

PE patients proved by either pulmonary angiography or a high probability VQ lung scan (segmental or greater perfusion defect with ventilation mismatch), plus deep venous thrombosis confirmed by venography or ultrasound were included. Exclusion: active bleeding process, active peptic ulcer disease, acquired bleeding diathesis, abnormal platelet count, recent (2 months) stroke or active intracranial process; also recent major surgery, major trauma, obstetric delivery, organ biopsy, severe systolic or diastolic hypertension, pregnancy patients, PE >2 weeks or had under parenteral heparin >72 h. Considering that the experimental bolus regimen was not used in humans, massive PE patients were excluded [9].

All patients were under 5000 IU intravenous heparin bolus followed by continuous infusion at a starting dose of 30,000 units for the first 24-h. The heparin dose was adjusted daily to maintain activated partial thromboplastin time between 55 and 75 s. Patients were randomly assigned to receive either rt-PA or saline solution placebo. They were stratified according pulmonary angiography or not and the time since onset symptoms of PE (<48 or ≥48 h). Patients in rt-PA group received 0.6 mkg ideal body weight reconstituted in 50 mL sterile water by bolus injection over 2 min. Heparin was interrupted only for the duration of the study drug infusion. The same procedure was followed for patients who received placebo [9].

The effectiveness of the regimens for producing lysis of pulmonary thrombus was assessed by comparing the baseline perfusion VQ lung scan with the scan performed at 24-h and 7 days after treatment. The primary outcome measure was relative improvement in perfusion of more than 50 % from the baseline VQ perfusion scan. Three physicians, experienced in the interpretation of lung scans, reviewed the scans. A perfusion defect was defined as an area of absent perfusion or hypoperfusion. The results of lung scanning were interpreted without knowledge of the clinical findings or the treatment group to which the patient had been, randomized. Any disagreement in size of the perfusion abnormality was resolved by consensus [9].

To determine the improvement in pulmonary perfusion between pretreatment and 24 h and 7 days, the change in the total perfusion defect in the anterior and posterior views was used as was described [5]. Patients were examined daily during the 10-day study period for evidence of bleeding. Major bleeding: if it was overt and associated with either a fall in hemoglobin level of 20 g/L or more, or a need for transfusion of two or more units of blood, or if it was retroperitoneal or intracranial. Minor bleeding: if it was overt, but did not meet the other criteria for major bleeding. Daily hemoglobin determination was performed. Mortality and recurrent PE were not primary outcome measures, however, were documented during the first 10 days post-randomization [9].

Fifty-eight patients with proved PE were enrolled, 33 patients were randomized to rt-PA and 25 to placebo. Patients in rt-PA group had chest pain in 20 cases (60.6 %), dyspnea in 27 (81.8 %), hemoptysis in five (15 %), while six (18 %) had syncope. In placebo group, chest pain was experienced by 23 patients (92 %), dyspnea in 22 (88 %), hemoptysis in seven (28 %), and five (20 %) presented with syncope. In rt-PA group 22 patients (67 %) had diagnosis confirmed by pulmonary angiography, 6 (18 %) by a high probability VQ lung scan associated with a positive venogram, and 5 (15 %) by high probability VQ lung scan plus positive duplex ultrasonography. In placebo group, 18 (72 %) had diagnosis by pulmonary angiography, 4 (16 %) by high probability VQ lung scan associated with a positive venogram, and three (12 %) by a VQ high probability lung scan associated with positive duplex ultrasonography. In terms of baseline characteristics age, gender, underlying presence of malignancy, previous history of venous thromboembolic disease, duration of symptoms prior to randomization, and duration of heparin therapy prior to study, both groups were reasonably comparable [9].

At 24 h, mean absolute improvement in the perfusion defect was 9.7 % in rt-PA group compared to 5 % in placebo group (p = 0.07) and the mean relative improvement in perfusion was 37 % compared to 19 % (p = 0.01) respectively. At 7 days, no statistically significant difference was detected for absolute improvement in the perfusion defect, 16 % rt-PA group compared to 11 % placebo group, and mean relative improvement, 58 % compared to 49 % respectively [9]. In this 10-day study period, in rt-PA group 1 patient died compared with no mortality in placebo group. Patient died 10 h post-rt-PA injection and necropsy showed saddle PE. None recurrence in both groups were observed [9].

In this study rt-PA bolus infusion was reasonably well tolerated, however, 3 patients had allergic reactions. One patient felt hot and diaphoretic within 10 min of the infusion; a second patient felt hot and developed mild hypotension within 2 min of the infusion, and a third patient experienced mild hypotension associated with urticaria which resolved within 15 min of injection. In placebo group, one patient experienced hypotension shortly after administration of placebo.

No major bleeding complications were identified in both groups. Three patients in each group required transfusions during the 10-day study period. None of these patients had an overt site of hemorrhage and in all 6 patients who required transfusion it was secondary to medical conditions unrelated with study drug administration. In rt-PA group 9 patients had bruising either in the groin and/or at antecubital fossa venipuncture site used for study laboratory tests [9]. An additional 4 patients who received rt-PA had oozing at either one or both of these sites. One patient in each group experienced epistaxis and one patient who received rt-PA had increased serosanguineous drainage from an abdominal wound site. So, 15 rt-PA patients (45 %) experienced minor bleeding compared to placebo group (p = 0.0005) [9].

Previous evidences with rt-PA in doses between 50 and 100 mg over of 2–7 h infusion were related with a systemic lytic state and high proportion of major bleeding complications. In this study, rt-PA bolus over 2 min in patients fully heparinized showed: (a) significative increase of proportion of patients who achieved >50 % improvement in perfusion defects at 24 h; (b) was associated with a mean absolute improvement in perfusion defect (9.7 %) and a mean relative improvement (37 %). This relative improvement in lung scan perfusion was of the same order of magnitude with rt-PA in higher dose in longer period infusion was used. The improvement in lung perfusion is also comparable with UPET study. In addition, the results were similar when urokinase was given over 12 h period [5]. By 7 days there was no longer any difference in the resolution seen in both groups, similar findings to those reported in UPET trial [5]. Another important apportation was the use of lung scan, a noninvasive and reliable index of pulmonary arterial obstruction as a surrogate outcome [9].

This study introduced for first time in the history of thrombolysis and PE the concept of bolus infusion for patient treatment. The thrombolytic regimen was chosen based on three observations coming from experimental models: (1) thrombolysis was improved when rt-PA was administered in a high concentration over a short period of time; (2) rt-PA produced continuing thrombolysis after cleared from the circulation; and (3) bleeding was reduced when the same dose of the drug was administered over a short period of time. Although a 15-min infusion was used in the experimental models, another clinical observation using a bolus regimen over 2 min was chosen because of its simplicity amid convenience [9].

In spite of the results, the optimal regimen for rt-PA has not been established. Short infusion in high concentration regimens induces more rapid thrombolysis than similar doses infused over a longer time interval in experimental PE and in ST-elevation myocardial infarction patients. The bolus dose regimen, was effective in achieving accelerated thrombolysis, was well tolerated, and easy to administer to PE patients who are also being treated with heparin. Although, rt-PA bolus regimen was safety in terms of major bleeding, invasive procedures and/or venous punction were related with an increase of minor bleedings. The relatively small sample size inducing type two error could explain the absence of major bleeding complications. Finally, the study was not designed to determinate mortality, it is well known that this kind of design requires larger sample size [9].

Considering its pharmacokinetic and pharmacodynamic characteristics, rt-PA has great potential for the treatment of acute PE; however, the experience with this thrombolytic agent is limited, and no comparisons to placebo have been published. The main target of this study was to evaluate the efficacy of rt-PA in combination with heparin compared to placebo plus heparin in patients with acute PE. The thrombolytic effects of rt-PA may be enhanced when administered in combination with heparin because the addition of new fibrin to the thrombus is prevented by heparin during lytic therapy [10].

Between November 30, 1986, and June 30, 1987, 13 patients were studied; group rt-PA included 9 patients and heparin group 4 patients. Among those who received rt-PA, 8 of 9 patients received heparin simultaneously. All patients received either rt-PA or placebo in a randomized double-blind fashion; twice as many patients were randomly assigned to the treatment group as to the control group.

All patients had PE onset symptoms within 7 days of the angiogram. Patients were eligible if they had occlusion of a lobar artery or at least two segmental arteries on pulmonary angiography. Nine patients were men and 4 women with an age range from 20 to 78 years. Patients with shock or clinical instability were excluded. A large number of exclusion criteria were similar to previous studies to enhance safety. Although, six clinical centers with approximately 5500 hospital beds were included, the rate of patient accession was slow. Therefore, the independent Study Policy and Data Safety Monitoring Board recommended that the investigators discontinued recruitment, although the initial study design called for 50 patients [10].

Patients received rt-PA intravenously at a rate of approximately 1 mg/mm. Initially, a dose of 80 mg was selected on the basis of experience with ST-elevation myocardial infarction. After one major hemorrhage, the dose was reduced to 40 mg. Five patients received rt-PA 40 mg, one patient received 64 mg (hemorrhage interrupting an intended 80 mg treatment), and 3 patients received rt-PA 80 mg. The 40 mg dose of rt-PA was administered over 40 min. The 80 mg dose was administered over 90 min. During the infusion of rt-PA, heparin was administered to all but one patient in an open fashion; doses were determined by the attending physician. In one patient, heparin was discontinued during the double-blind administration of rt-PA [10].

Pulmonary angiographies were obtained before the administration of rt-PA and 2 h following the double-blind therapy. Pretreatment pulmonary angiography was bilateral in 12 of 13 patients. Posttreatment pulmonary angiography was obtained in 12 patients and was bilateral in 8. No posttreatment study was obtained in the one patient who hemorrhaged while receiving rt-PA. Pulmonary angiography was obtained in the anterior–posterior projection. Radiologist who interpreted pulmonary angiography was blinded to treatment [10].

Pulmonary angiographies were scored according to the size and number of pulmonary arterial branches that contained intraluminal filling defects. Each vessel, irrespective of its size, received a vessel occlusion score as follows: Size grades entered in each column were added and multiplied by the occlusion grade assigned to the vessel. The total clot size score was then obtained by adding the clot size scores for each vessel. If the entire pulmonary arterial tree were filled with clots, a total of 102 units would be obtained for clot size. The total clot size, therefore, approximated the percentage of obstructed vascular volume in the two lungs [10].

V/Q lung scans and chest X-ray were obtained before the pulmonary angiography; perfusion scans were performed again after double-blind treatment at intervals of 24 h, 48 h, and 7 days; V/Q lung scans were graded by two blinded readers to therapy. Baseline mismatched perfusion defects were assessed as follows: Each segment of the lung was assumed to constitute 11 % of the involved lung. The number of mismatched segments in each lung, therefore, was multiplied by 11 % to determine the percentage of the involved lung that showed a mismatched perfusion defect [10].

Pressures in the right atrium, right ventricle, and pulmonary artery were measured in triplicate with fluid-filled catheters prior to the injection of contrast material. Cardiac output was measured in triplicate by the indicator dilution technique. Total pulmonary resistance was calculated as the fraction of pulmonary arterial mean pressure (mmHg) divided by cardiac output (L/min) times 80. Hemodynamic measurements were repeated 90 min after the onset of therapy. Heart rate, respiratory rate, and blood pressure were recorded during these intervals as well as after 24 h, 48 h, and 7 days. Fragmented dimers were measured prior to thrombolytic therapy and after therapy at intervals of 90 min, 3 h, 24 h, and 7 days. Fibrinogen also was measured [10].

Fragment-D dimers in the blood at one and half and 3 h after beginning therapy indicated the in vivo occurrence of clot lysis. Higher levels of fragment-D dimers were present 3 h after the onset of therapy in the blood of rt-PA group than in heparin-alone group (40 ± 29 vs. 4 ± 3 pg/mL, p < 0.01). At 3 h after the start of treatment among heparin-alone group, plasma fibrinogen was 388 ± 126 mg/dL as compared to 222 ± 182 among group rt-PA and heparin patients (p = 0.14). Among patients under 80 mg of rt-PA, plasma fibrinogen at 3 h was 74 ± 51 mg/dL. The mean angiographic scores were evaluated for patients who had angiographies both before and 2 h after treatment. Among patients who received rt-PA, the angiographic scores of the left lung were 12.2 ± 5.6 before treatment and 12.5 ± 7.4 after treatment. The angiographic scores of the right lung among patients treated with rt-PA were 10.0 ± 4.4 before treatment and 8.2 ± 3.8 after treatment [10].

Among patients in heparin-alone group, the angiographic scores of the left lung were 12.9 ± 2.2 before treatment and 12.8 ± 4.1 after treatment. The angiographic scores of the right lung among patients treated only with heparin were 15.5 ± 6.3 before and 18.0 ± 10.0 after. Changes of the angiographic score with treatment were not significantly different compared rt-PA group with heparin-alone group. A trend suggested improvement over time of mismatched perfusion defects among patients treated with rt-PA plus heparin. The pretreatment, 1, 2 and 7 days mismatched scan deficits respectively were 39 ± 18, 29 ± 21, 28 ± 22, and 19 ± 14 %. Among heparin-alone group, mismatched perfusion defects were unchanged during the first 2 days and decreased only slightly by day 7. Values before treatment, at 1, 2, and 7 days respectively were 41 ± 15, 41 ± 18, 40 ± 16, and 34 ± 18 %. The trend toward improvement among patients treated with rt-PA and heparin did not achieve statistical significance in comparison to the small number of patients in heparin-alone group [10].

In rt-PA group, total pulmonary resistance after one and half hours decreased from 550 ± 220 to 360 ± 180 dyn/cm [5]. Pulmonary arterial mean pressure showed no significant change in these patients (28 ± 9 vs. 25 ± 8 mmHg). The total pulmonary resistance did not change after one and half hours in patients treated with heparin (770 ± 710 vs. 760 ± 700 dyn/s/cm⁵). Pulmonary arterial mean pressure remained unchanged (33 ± 13 vs. 33 ± 13 mmHg) among heparin-alone group. The reduction of total pulmonary resistance among rt-PA group was greater than the reduction among patients treated with heparin alone (p = 0.03). No prominent changes were noted either in the respiratory rate or the heart rate over the 7 days of the investigation [10].

Among the 9 patients who received rt-PA, one major bleeding (upper gastrointestinal tract, sites of catheter insertions and needle punction) episode occurred in an 81-year-old woman who received 64 mg of rt-PA in combination with heparin. Eight units of packed red blood cells were required. Gastroscopy showed oozing from mild superficial mucosal ulcerations. Coagulopathy was corrected and a Greenfield filter was inserted. However, patient continued with clinical instability, developed a ST-elevation myocardial infarction, and died of an arrhythmia 19 days after treatment with rt-PA. Serious bleeding was not observed among the patients included in rt-PA or heparin-alone groups [10].

Fibrinolysis occurred within one and half hours after receiving rt-PA, based upon the prompt elevation of fragment D-dimers. The assay used was specific for fibrin and did not detect fibrinogen degradation products. The observed reduction of fibrinogen levels in each of 3 patients receiving 80 mg of rt-PA was consistent with a fibrinogen systemic lysis. In spite of the prompt onset of fibrinolysis, there was only a limited change of the pulmonary vascular resistance and no significant improvement of the angiograms at 2 h [10].