Antiangiogenic kringles derived from human plasminogen and apolipoprotein(a) inhibit fibrinolysis through a mechanism that requires a functional lysine-binding site.

Many proteins in the fibrinolysis pathway contain antiangiogenic kringle domains. Owing to the high degree of homology between kringle domains, there has been a safety concern that antiangiogenic kringles could interact with common kringle proteins during fibrinolysis leading to adverse effects in vivo. To address this issue, we investigated the effects of several antiangiogenic kringle proteins including angiostatin, apolipoprotein(a) kringles IV(9)-IV(10)-V (LK68), apolipoprotein(a) kringle V (rhLK8) and a derivative of rhLK8 mutated to produce a functional lysine-binding site (Lys-rhLK8) on the entire fibrinolytic process in vitro and analyzed the role of lysine binding. Angiostatin, LK68 and Lys-rhLK8 increased clot lysis time in a dose-dependent manner, inhibited tissue-type plasminogen activator-mediated plasminogen activation on a thrombin-modified fibrinogen (TMF) surface, showed binding to TMF and significantly decreased the amount of plasminogen bound to TMF. The inhibition of fibrinolysis by these proteins appears to be dependent on their functional lysine-binding sites. However, rhLK8 had no effect on these processes owing to an inability to bind lysine. Collectively, these results indicate that antiangiogenic kringles without lysine binding sites might be safer with respect to physiological fibrinolysis than lysine-binding antiangiogenic kringles. However, the clinical significance of these findings will require further validation in vivo.

The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice.

Plasminogen activation to plasmin protects from lung fibrosis, but the mechanism underlying this antifibrotic effect remains unclear. We found that mice lacking plasminogen activation inhibitor-1 (PAI-1), which are protected from bleomycin-induced pulmonary fibrosis, exhibit lung overproduction of the antifibrotic lipid mediator prostaglandin E2 (PGE2). Plasminogen activation upregulated PGE2 synthesis in alveolar epithelial cells, lung fibroblasts, and lung fibrocytes from saline- and bleomycin-treated mice, as well as in normal fetal and adult primary human lung fibroblasts. This response was exaggerated in cells from Pai1-/- mice. Although enhanced PGE2 formation required the generation of plasmin, it was independent of proteinase-activated receptor 1 (PAR-1) and instead reflected proteolytic activation and release of HGF with subsequent induction of COX-2. That the HGF/COX-2/PGE2 axis mediates in vivo protection from fibrosis in Pai1-/- mice was demonstrated by experiments showing that a selective inhibitor of the HGF receptor c-Met increased lung collagen to WT levels while reducing COX-2 protein and PGE2 levels. Of clinical interest, fibroblasts from patients with idiopathic pulmonary fibrosis were found to be defective in their ability to induce COX-2 and, therefore, unable to upregulate PGE2 synthesis in response to plasmin or HGF. These studies demonstrate crosstalk between plasminogen activation and PGE2 generation in the lung and provide a mechanism for the well-known antifibrotic actions of the fibrinolytic pathway.

Dose escalation trial of the efficacy, safety, and pharmacokinetics of a novel fibrinolytic agent, BB-10153, in patients with ST elevation MI: results of the TIMI 31 trial.

BACKGROUND: Currently available fibrinolytic agents are limited by their ability to restore normal blood flow in only half of patients, the risk of reocclusion, and the risk of intracranial hemorrhage. The genetically engineered agent BB-10153 is activated by thrombin, not plasminogen activator enzymes, which limits its activity to the site of thrombus which may in turn reduce the risk of systemic bleeding. BB-10153 also has a relatively long half-life of 3-4 hours, which may also limit the potential for early reocclusion [1, 2]. METHODS: The study was a phase II, open-label, multi-center, dose escalation, single-dose administration study to determine the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of BB-10153 in ST segment elevation MI (STEMI). STEMI patients (n = 50) received a single dose of BB-10153 at one of six dose levels (1.0, 2.0, 3.0, 5.0, 7.5 and 10 mg/kg). The primary endpoint was TIMI flow grade (TFG) 3 at 60 minutes following the intravenous bolus of BB-10153. RESULTS: Mean area under the curve for drug concentration ranged from 48.0 microg.h/mL in the 1 mg/kg dose group to 788.6 microg.h/mL in the 10 mg/kg dose group. Likewise, mean Cmax generally increased with dose over the entire dose range, from 4.9 microg/mL in the 1 mg/kg dose group to 139.6 microg/mL in the 10 mg/kg dose group. The mean apparent terminal half-life (t1/2) was 4.4 hours (range 2.2 to 7.6 hours). Few patients in the 1-3 mg/kg dosage groups achieved TFG 3 on the one-hour post-dose angiogram (4/20, 20%), and no patients achieved complete ST segment resolution. The 5, 7.5 and 10 mg/kg doses were associated with similar rates of TIMI grade 3 flow of approximately three per seven patients. Pooling TFG 3 data from the 5, 7.5 and 10 mg/kg groups yielded a TIMI grade 3 flow rate of 34% (n = 10/29; range 29-43%). No patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study. One patient experienced recurrent angina and developed recurrent myocardial ischemia requiring urgent revascularization. Three patients sustained TIMI major bleeding events (one in 1 mg/kg group, two in 7.5 mg/kg group), six patients sustained TIMI minor bleeds (one in the 2, 3, 7.5 and 10 mg/kg groups, two in the 5 mg/kg group), twp patients sustained TIMI minimal bleeds (one in each of the 2 and 10 mg/kg groups) and no patients sustained intracranial hemorrhage (ICH). CONCLUSION: In a dose escalation study of a single intravenous bolus, the novel fibrinolytic agent, BB-10153 was associated with a rise in the mean area under the curve and Cmax for drug concentration over the dose range 1 to 10 mg/kg. Higher doses were associated with a range of TIMI grade 3 flow of 29-43%, and no patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study. In a dose escalation study of a single intravenous bolus, the novel fibrinolytic agent, BB-10153 was associated with a rise in the mean area under the curve and Cmax for drug concentration over the dose range 1 to 10 mg/kg. Higher doses were associated with a range of TIMI grade 3 flow of 29-43%, and no patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study.

Safety profile of the intravitreal streptokinase-plasmin complex as an adjunct to vitrectomy in the rabbit.

BACKGROUND: The generation of an atraumatic posterior vitreous detachment (PVD), a common goal in vitreoretinal surgery, is a challenge, particularly in children and young trauma patients. Plasmin has been proposed as an adjunct to vitrectomy to enzymatically generate a PVD. Low doses of streptokinase-activated plasmin were tested in human pilot studies. This dose-escalation study assesses the safety range of intravitreal human streptokinase-plasmin in rabbits. METHODS: Plasminogen was isolated from human plasma by affinity chromatography, followed by activation with streptokinase (1:1), to generate the streptokinase-plasmin complex. Enzyme doses from 0.1-7 activity units (AU, in 0.1 ml) were injected into the mid-vitreous of 35 eyes; six control eyes were injected with balanced salt solution (BSS, 0.1 ml). Thirty minutes after injection, a two-port vitrectomy was performed. Fundus and slit lamp examinations were performed on days 1 and 7. On days 2 and 7, bright flash electroretinography was performed and compared with preoperative recordings. Some animals receiving higher doses of streptokinase-plasmin (1-7 AU) were followed clinically and with electroretinography for up to 9 months. RESULTS: A mild-to-moderate inflammatory response was seen in both control and plasmin-treated eyes on day 1, but had disappeared completely by day 7 in most eyes. In the 7 AU group, inflammation was stronger and more protracted. Two of three eyes from this group developed wrinkling of the medullary rays; one of them showed discoloration and traction at the medullary rays in the late follow-up. Electroretinograms (ERGs) of vitrectomized control eyes showed the following changes from preoperative values: 48 h, a-wave -11.10% [no significant (n.s.)], b-wave -14.62% (P=0.046); 7 days, a-wave +9.18% (n.s.), b wave +11.69% (n.s.). For the enzyme-treated eyes: 48 h: a-wave -20.43% (P<0.001), b-wave -9.57% (p<0.001); 7 days: a wave -14.21% (P<0.001), b-wave +2.48% (P<0.001). There was no evidence of dose-dependent ERG changes in enzyme-treated eyes at doses up to 5 AU. Groups of up to 3 AU were investigated by light and transmission electron microscopy, without evidence of toxicity. CONCLUSION: Streptokinase-plasmin doses up to 3 AU were found to be safe when injected into rabbit eyes followed by vitrectomy.

The role of recombinant lysine-plasminogen and recombinant urokinase and sulfur hexafluoride combination in inducing posterior vitreous detachment.

PURPOSE: To determine the optimal method of generating plasmin in vitreous using recombinant lysine-plasminogen and recombinant urokinase and to determine its efficacy in inducing posterior vitreous detachment when combined with sulfur hexafluoride. METHODS: Plasmin concentration of the rabbit vitreous after separate and combined intravitreal administrations of recombinant lysine-plasminogen and recombinant urokinase was tested in 78 rabbits to determine the optimal method of administration. The safety and efficacy of these agents and sulfur hexafluoride in inducing complete posterior vitreous detachment (total separation of the vitreous apart from vitreous base) were also evaluated. RESULTS: The highest plasmin concentration in vitreous was measured 10 minutes after injection. Intravitreal administration of recombinant lysine-plasminogen and recombinant urokinase did not cause any toxicity findings up to concentrations of 100 microg and 200 IU, respectively, on funduscopy, electroretinography, and histopathologic studies. When combined with sulfur hexafluoride injection, separate intravitreal administrations of 75 microg/0.1 mL of recombinant lysine-plasminogen and 15 IU/0.1 mL of recombinant urokinase induced complete posterior vitreous detachment in 75% of the eyes compared with 13% in eyes that received sulfur hexafluoride injection combined with balanced salt solution, recombinant lysine-plasminogen, or recombinant urokinase. CONCLUSIONS: Plasmin was effectively generated in the vitreous after separate intravitreal administrations of recombinant lysine-plasminogen and recombinant urokinase. When combined with intravitreal gas injection, this method of plasmin production induced complete posterior vitreous detachment in 75% of the eyes.

Plasmin/plasminogen system in colorectal cancer.

Pericellular proteolysis plays a crucial role in tumor cell invasion. The controlled degradation of the extracellular matrix by tumor cell-associated proteases allows tumor cells to invade surrounding tissues and gain access to the circulation. One of the main protease systems involved in tumor cell invasion and metastasis is the plasminogen/plasmin system (PPS). The components of the PPS include the urokinase plasminogen activator (uPA), its cell surface receptor urokinase plasminogen activator receptor (uPAR), and its naturally occurring inhibitors, plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2). Increases in tumor and serum levels of uPA, uPAR, and PAI-1 are associated with a worse prognosis in patients with colon cancer. Use of these proteins as either tumor or serum markers may allow more accurate determination of the prognosis in colon cancer patients. Furthermore, these proteins appear to be attractive as targets for the biologic therapy of colon cancer.

Adverse effects of the antiangiogenic agent angiostatin on the healing of experimental colonic anastomoses.

BACKGROUND: Antiangiogenic cancer therapy is likely to be administered long term for sustained suppression of tumor outgrowth. Surgeons will encounter more patients undergoing such therapy. Therefore, it is essential to know the effects of antiangiogenic agents on physiological angiogenesis, as occurs during the healing of colonic anastomoses. METHODS: Angiostatin was generated from human plasma and administered continuously. In 38 mice, the right colon was anastomosed after transection: group 1 (n = 13), anastomotic healing under angiostatin treatment from surgery until death (day 7); group 2 (n = 13), phosphate-buffered saline controls. For healing on discontinuation of treatment, group 3 (n = 6) received angiostatin treatment preceding surgery during 4 days; group 4 (n = 6) included controls. On day 7, all mice were inspected for signs of anastomotic leakage. Bursting pressure measurements were performed to test anastomotic strength. Neovascularization was assessed semiquantitatively by immunohistochemistry. RESULTS: Mice treated with angiostatin postoperatively showed significantly more signs of leakage, more adhesions, and peritonitis. One mouse died on day 5. Five mice had paralytical ileus. The bursting pressure in group 1 was 135 +/- 20 mm Hg, versus 175 +/- 12 mm Hg in group 2 (mean +/- SEM). Significantly fewer new vessels were found surrounding the anastomosis in the treated group (6.6 +/-.9) versus controls (16 +/- 1.6). All controls, as well as those animals treated with angiostatin only until surgery (group 3), displayed normal healing and showed no signs of peritonitis or ileus. CONCLUSIONS: Angiostatin impairs anastomotic healing in mice. However, on discontinuation of antiangiogenic therapy, normal anastomotic healing is promptly restored.

Angiogenesis and tumor metastasis.

Angiogenesis, the recruitment of new blood vessels, is an essential component of the metastatic pathway. These vessels provide the principal route by which tumor cells exit the primary tumor site and enter the circulation. For many tumors, the vascular density can provide a prognostic indicator of metastatic potential, with the highly vascular primary tumors having a higher incidence of metastasis than poorly vascular tumors. Tumor angiogenesis is regulated by the production of angiogenic stimulators including members of the fibroblast growth factor and vascular endothelial growth factor families. In addition, tumors may activate angiogenic inhibitors such as angiostatin and endostatin that can modulate angiogenesis both at the primary site and at downstream sites of metastasis. The potential use of these and other natural and synthetic angiogenic inhibitors as anticancer drugs is currently under intense investigation. Such agents may have reduced toxicity and be less likely to generate drug resistance than conventional cytotoxic drugs. Clinical trials are now underway to develop optimum treatment strategies for antiangiogenic agents.

Glucocorticosteroids inhibit degradation in bovine cartilage explants stimulated with concomitant plasminogen and interleukin-1 alpha.

OBJECTIVE: Glucocorticosteroids are beneficial in the treatment of osteoarthritis (OA) in humans, and have been shown to protect cartilage in animal models of OA. Therefore, we undertook the present study to investigate the in vitro effect of several glucocorticosteroids on cartilage degradation. METHODS: Bovine articular cartilage explants labeled with [35S] Sulfate and stimulated either with IL-1 alpha alone or with concomitant plasminogen plus IL-1 alpha were used in this study as an in vitro model of cartilage degradation. Clobetasol propionate, fluocinolone-acetonide-21-acetate, prednisolone, triamcinolone and triamcinolone hexacetonide were the glucocorticosteroids investigated in a series of experiments, at concentrations ranging from 10 picomolar to 10 micromolar. Degradation in [35S] Sulfate-labeled bovine articular cartilage explants was induced with IL-1 alpha or with concomitant IL-1 alpha plus human plasminogen. The effects of several glucocorticosteroids were studied, and a comparison between efficacy in explants stimulated with IL-1 alpha alone or IL-1 alpha plus concomitant plasminogen was made. Glucocorticosteroid efficacy was expressed as percent inhibition of degradation, and their IC50S were also calculated. RESULTS: Glucocorticosteroids showed no protective effects on cartilage degradation in the presence of IL-1 alpha alone. When degradation was induced by IL-1 alpha in the presence of concomitant human plasminogen, all the glucocorticosteroids showed statistically significant.inhibition (p < 0.05) with calculated IC50S of 450-2500 picomolar. CONCLUSION: The inhibition of cartilage degradation by glucocorticosteroids may be due to down-regulation of urokinase plasminogen activator (u-PA) activity. It has been shown that u-PA may be the first enzyme in the cascade of activation of pro-matrix metalloproteinases by the fibrinolytic system. Inhibition of u-PA activity may be one explanation for the efficacy of glucocorticosteroids observed in animal models of OA and with intraarticular injection in patients with OA.

Anistreplase: a novel thrombolytic agent for acute myocardial infarction.

Anistreplase, a modified congener of streptokinase, is a recently approved thrombolytic agent used in the treatment of acute myocardial infarction (AMI). Clinical studies have demonstrated anistreplase to be equally efficacious as intracoronary streptokinase when given within four hours of the onset of chest pain. Thirty units, given as a single bolus intravenous injection, result in reperfusion rates of approximately 60-70 percent. The adverse-effect profile of anistreplase compares favorably with that of streptokinase, with hemorrhagic complications being the most serious. Anistreplase has two distinct advantages over both streptokinase and alteplase: (1) it can be administered as a single bolus intravenous injection and (2) it has a longer half-life which may result in decreased reocclusion rates. Anistreplase therapy is associated with reductions in both short- and long-term mortality and has been shown to preserve left ventricular function. A large, long-term, comparative clinical trial (Third International Study of Infarct Survival or ISIS-III) investigating morbidity and mortality rates with streptokinase, alteplase, and anistreplase is ongoing, as is a direct comparative study against alteplase alone (TEAM-3, Multicenter Thrombolytic Trials of Eminase in Acute Myocardial Infarction).

Tolerance and complications in a multicenter trial of intravenous APSAC and intracoronary streptokinase in acute myocardial infarction.

Adverse events data of a randomized, multicenter, angiographically controlled trial of intracoronary streptokinase and intravenous anistreplase, or anisoylated plasminogen streptokinase activator complex (APSAC) are presented. The frequency of severe adverse events is similar for streptokinase and anistreplase; no unexpected adverse experiences were reported with either drug. The most frequently encountered side effect was bleeding, overwhelmingly from the groin puncture site from angiography.

The safety of anistreplase from the placebo-controlled AIMS study (anistreplase Intervention Mortality Study). The AIMS Study Group.

In the anistreplase, or anisoylated plasminogen streptokinase activator complex (APSAC) Intervention Mortality Study (AIMS), 1,258 patients with acute myocardial infarction were randomized in a parallel, double-blind, placebo-controlled mortality study in which they received either anistreplase or placebo, followed by anticoagulation therapy. Data on all adverse clinical events were recorded, regardless of their clinical significance or possible relation to therapy. There was a similar frequency of such events in both groups (anistreplase 80.4%, placebo 76.0%, difference not significant). Cardiovascular events included more reports of bradycardia, idioventricular rhythm, and hypotension in the anistreplase group, and a higher incidence of cardiac arrest, ventricular fibrillation, complete heart block, and pericarditis in the placebo group. Hemorrhagic events occurred in 13.8% of patients in the anistreplase group compared with 4.1% of patients in the placebo group. Most of these events consisted of bleeding or bruising around the puncture sites. There was a low incidence of allergic events after administration of both anistreplase and placebo. Thirteen cerebrovascular events (8 strokes and 5 transient ischemic episodes) were reported in the anistreplase group, compared with 5 in the placebo group (5 and 0, respectively). The mean systolic and diastolic pressures were significantly lower (by 5-10 mmHg) in patients in the anistreplase group during the first 24 hours after dosing. There were no significant differences in temperature and pulse rate between the two groups. The incidence of chest pain during the first 4- to 24-h period was lower in the anistreplase-treated patients than in the placebo group. The frequency of in-hospital reinfarction was higher in anistreplase-treated patients compared with patients given placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiographic patency study of anistreplase versus streptokinase in acute myocardial infarction.

128 patients with acute myocardial infarction of duration 6 h or less were randomised in double-blind fashion to receive 30 U anistreplase over 5 min or 1.5 MU streptokinase over 1 h, both intravenously. Angiographic patency was assessed 90 min and 24 h from the start of therapy. 55% of patients who received anistreplase and 53% of patients who received streptokinase had patent infarct-related arteries (TIMI grade 2-3) at 90 min (95% CI 42-68% and 40-66%, respectively). At 24 h 81% and 87.5% of arteries were patent respectively (95% CI, 71-91% and 83.5-91.5%). Time to therapy had no significant effect on patency rates. There was one early reocclusion within 24 h in each treatment group and clinical evidence of reocclusion was recorded between 24 h and hospital discharge in a further 5 patients (streptokinase 3, anistreplase 2). With these regimens, therefore, anistreplase and streptokinase gave the same patency rates.

Improved left ventricular function in myocardial infarction following intravenous thrombolytic therapy with acylated plasminogen activator.

Forty-six patients with acute myocardial infarction (MI) were treated within three hours of the onset of chest pain with an intravenous bolus (IV) of 30 units of anisolated plasminogen activator streptokinase complex (APSAC). Reperfusion was detected in 31 patients (67%) by clinical, electrocardiographic, and enzymatic criteria. The mean time elapsed between the onset of the chest pain to thrombolytic therapy was 114 +/- 53 minutes. Left ventricular ejection fraction (LVEF) was significantly better in patients with anterior and inferior myocardial infarction who had successful reperfusion, as compared with those who did not (48.8 +/- 13.0 vs 35.3 +/- 10.9, p less than 0.05 and 59.7 +/- 12.6 vs 47.9 +/- 15.3, p less than 0.05, respectively). The rate of reocclusion within three weeks was 22%. The overall one-year mortality was 4%. There were no serious adverse reactions following the thrombolytic treatment. Thus bolus IV injection of 30 units of APSAC is both safe and effective in preserving left ventricular function when given early in the course of acute myocardial infarction.

Acylated plasminogen-streptokinase activator complex: a new approach to thrombolytic therapy.

Acylated plasminogen-streptokinase activator complex (APSAC; antistreplase) is an inactive complex of human plasminogen and streptokinase. When it is injected, a controlled deacylation of the catalytic center occurs, activating the complex so that thrombolysis may begin. This process extends the half-life of streptokinase, allowing for 4-6 hours of fibrinolytic activity. Anistreplase has demonstrated equivalent efficacy to intracoronary streptokinase with regard to reperfusion rates in acute myocardial infarction. In addition, patients have shown a 56% reduction in mortality at 28 days with anistreplase compared to heparin. The adverse effect profile of anistreplase includes minor bleeding and hematoma formation at the site of venipuncture, hypotensive and bradycardic episodes, arrhythmias, facial flushing, fever, and rarely, allergic reactions. Serious bleeding reactions are uncommon, with the frequency of cerebrovascular accident reported at 0.4-0.6%. The special advantage of anistreplase is its administration as a 30-U intravenous bolus injected over 5 minutes, eliminating the need for long infusions and increasing the ease of administration. Based on its efficacy and ease of administration, anistreplase may become the drug of choice in the emergency treatment of acute myocardial infarction.

[The new thrombolytic agents]. / Les nouveaux thrombolytiques.

Among the new thrombolytic agents, two are or will be available in the near future: plasminogen tissue activator and antistreplase or anysoiled plasminogen-streptokinase activator complex (APSAC). The repermeabilization rate provided by these two thrombolytic agents administered intravenously, is practically identical, close to 70 p. cent, i.e. comparable to that obtained by intracoronary administration of streptokinase. The rate of secondary reobstruction is estimated near 17 p. cent for the tissue plasminogen activator and 10 p. cent for APSAC. Secondary reobstruction would be more frequently observed with thrombolytics with a short half-life (5 to 8 minutes of the tissue plasminogen activator whether it has one or two chains, versus 90 minutes with APSAC). Other factors influence it: persistence of a thrombogenic stimulus at the site of the stenosis, presence of thrombin, platelet activation... Both products have been found to be effective in limiting the size of the myocardial infarction and preservation of the left ventricular function. Finally, both have been shown to be effective on the reduction of the immediate and long-term mortality during extensive multicentric trials. The tissue plasminogen activator, although specific for fibrin, results in haemorrhagic complications which are as frequent as those cause by anistreplase which does not present this specificity for fibrin. The fibrin of pathological thrombi and the fibrin of the haemostatic centrifugate are identical. It is therefore lysed in the same fashion by all thrombolytic agents, whether or not specific of fibrin.

Limitation of myocardial infarct size and preservation of left ventricular function by early administration of APSAC in myocardial infarction.

In cases of acute myocardial infarction (MI), it has been shown that preserving left ventricular function and limiting infarct size with early reperfusion of the occluded artery by means of a thrombolytic agent could eventually result in a reduced mortality rate. The aim of the APSIM study (anisoylated plasminogen streptokinase activator complex [APSAC] dans l'infarctus du Myocarde) was to demonstrate that early administration of APSAC in patients with recent acute MI could limit the infarct size and preserve left ventricular systolic function. In all, 231 patients with a first acute MI were randomly allocated to either APSAC (30 U over 5 minutes) or to conventional heparin therapy (5,000 IU in bolus injection) within 5 hours of the onset of symptoms. Of these patients, 112 received APSAC and 119 received heparin within a mean period of 188 +/- 62 minutes after the onset of symptoms. The patency rate of the infarct-related artery was 77% in the APSAC group and 36% in the heparin group (p less than 0.001). Left ventricular ejection fraction determined from contrast angiography was significantly higher in the APSAC than in the heparin group. This was true for the entire population (0.53 +/- 0.13 vs 0.47 +/- 0.13, p = 0.002) as well as for the subgroups of anterior and inferior wall infarctions (0.47 +/- 0.13 vs 0.4 +/- 0.16, p = 0.004 and 0.56 +/- 0.11 vs 0.51 +/- 0.09, p = 0.02). At 3 weeks, the difference remained significant for patients with anterior MI.(ABSTRACT TRUNCATED AT 250 WORDS)

Multicenter trial of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial infarction: effects on infarct size and left ventricular function.

Two hundred thirty-one patients with a first acute myocardial infarction were randomly allocated within 5 h after the onset of symptoms either to treatment with anisoylated plasminogen streptokinase activator complex (APSAC), 30 U over 5 min, or to conventional heparin therapy, 5,000 IU in a bolus injection. Heparin was reintroduced in both groups 4 h after initial therapy at a dosage of 500 IU/kg per day. One hundred twelve patients received APSAC and 119 received heparin within a mean period of 188 +/- 62 min after the onset of symptoms. Both groups were similar in age, location of the acute myocardial infarction, Killip functional class and time of randomization. Elective coronary arteriography was performed on an average of 4 +/- 1.2 days after initial therapy. Follow-up radionuclide angiography and thallium-201 single photon emission computed tomography were performed before hospital discharge. Infarct size was estimated from single photon emission computed tomography and expressed as a percent of total myocardial volume. The patency rate of the infarct-related artery was 77% in the APSAC group and 36% in the heparin group (p less than 0.001). Left ventricular ejection fraction determined from contrast angiography was significantly higher in the APSAC group than in the heparin group. This was true for the entire study group (0.53 +/- 0.13 versus 0.47 +/- 0.12; p = 0.002) as well as for the subgroups of patients with anterior and inferior wall infarction (0.47 +/- 0.13 versus 0.40 +/- 0.11; p = 0.04 and 0.56 +/- 0.10 versus 0.51 +/- 0.11; p = 0.02, respectively). At 3 weeks, the difference remained significant for the anterior myocardial infarction subgroup. A significant 31% reduction in infarct size was found in the APSAC group (33% for the anterior infarction subgroup [p less than 0.05] and 16% for the inferior infarction subgroup [p = NS]). A close inverse relation was found between the values of left ventricular ejection fraction and infarct size (r = -0.73, p less than 0.01). By the end of a 3 week follow-up period, seven APSAC-treated patients and six heparin-treated patients had died. In conclusion, the early infusion of APSAC in acute myocardial infarction produced a high early patency rate, significant limitation of infarct size and significant preservation of left ventricular systolic function, mainly in anterior wall infarction.

[Thrombectomy or thrombolysis in the treatment of proximal phlebitis. Functional long term results]. / Thrombectomie ou thrombolyse dans le traitement des phlébites proximales. Résultats fonctionnels à long terme.

MATERIALS AND METHODS Between 1981 and 1985, 78 iliocaval thrombi were treated by aggressive therapy: 52 surgical thrombectomies were performed by a femoral approach associated, depending on the case, with a caval approach; and 26 iliofemoral thrombi were lysed according to a protocol in which urokinase and plasminogen were used over a 48-h period. Subsequent functional evaluation was based on clinical scoring (0 to 9 points) taking into account functional impairment, edema and trophic disorders. Patency of trunks and the deep valvular state were assessed by Doppler examination and plethysmography. RESULTS In the surgical group, 3 early deaths occurred, only one of which could be attributed to an embolic course. Six weeks after surgery the rate of recurrence of iliac thrombosis was 50% (25% postoperative + 25% secondary). Beyond this period, there were no recurrences of thrombosis. There was a direct, statistically significant relation between the degree of iliac patency and the realization of an ideal thrombectomy on a nonadherent fresh clot. The functional results, assessed after four and a half years of follow-up, are satisfactory (score less than 3) in 80% of patients. The poor results with venous claudication or varicose ulcer all occurred in the case of massive persistent thrombi of the femoral confluence. Valve lesions were signaled in 46% of patients by a massive backflow in orthostatism. In the medical group, a major hemorrhagic complication occurred under urokinase therapy in 11% of patients, including one for whom it was fatal. Sixty percent of patients showed immediate radiological improvement allowing partial or total freeing of a venous confluence. The functional results after 4 years of follow-up were nondisabling in 85% of patients. No leg ulcers were detected. Late iliac patency was low (26%), whereas at the femoral level almost all of the thrombi which remained after lysis became patent again spontaneously. Valve failure was found in 37% of patients. Both groups had very similar late functional results despite rather different anatomical conditions. The iliac patency rate was higher in the surgical group (50% vs 26%), but plethysmographic study showed that in case of therapeutic failure devalvulation was greater after surgery (46% vs 37%).