Speed Of Thrombolysis Research Articles

Thrombolytic effects of recombinant staphylokinase on coronary thrombosis in miniature pigs

To evaluate the thrombolytic effects of recombinant staphylokinase and compare it with those of recombinant streptokinase. Thirty Chinese experimental miniature pigs were divided into five groups, namely, solvent control group, positive drug control group and three recombinant staphylokinase groups, six in each group. The thrombus of coronary artery was formed by surgical thoracotomy and direct current stimulation in anesthetized animals. Intravenous administration was started after the thrombus of coronary artery was formed for 30 minutes, and the method of first injection and then constant speed infusion by peristaltic pump was used. The solvent control group was injected intravenously with solvent, the positive drug control group was given recombinant streptokinase 4 mg·kg-1 intravenously, and the three recombinant staphylokinase groups were given recombinant staphylokinase at the doses of 4, 2 and 1 mg.kg-1 intravenously. The volume of intravenous injection was 5 ml, which was completed within 1 min, the speed of infusion was 0.5 ml·min-1, which was completed within 60 min, and the animals were sacrificed 120 minutes later. Before and 30, 60 and 120 min after administration, the venous blood samples were collected. At the end of the experiment, the coronary artery segments of the thrombosis site were taken, and the euglobulin dissolution time (ELT), blood fibrinogen content (FBG), fibrinogen degradation product (FDP) and wound bleeding volume were measured respectively. The coronary thrombolysis rate, myocardial ischemia degree and ischemia range were measured. Compared with the solvent control group, ELT in the experimental group was significantly shortened (P＜0.05 or P＜0.01), FBG degradation in a few experimental animals was more than 20%, FDP was significantly increased (P＜0.05 or P＜0.01), and there was no significant effect on blood pressure and heart rate of small pigs. Compared with the control group, the maximum thrombus area was decreased by 34.3% and 15.4% (P＜0.05) in the high and middle dose groups of the experimental group. Compared with the same dose of recombinant streptokinase, recombinant staphylokinase had stronger thrombolytic effect (P＜0.05 or P＜0.01) on the coronary thrombus caused by electrical stimulation, less bleeding side effects and the same effect on the degree and range of myocardial infarction as recombinant streptokinase. Compared with recombinant streptokinase, recombinant staphylokinase has faster thrombolysis speed, higher fibrin specificity and less bleeding side effects. In general, 2 mg.kg-1 recombinant staphylokinase has better efficacy and safety.

Thrombolysis Enhancing by Magnetic Manipulation of Fe₃O₄ Nanoparticles.

In this paper, an effective method of accelerating urokinase-administrated thrombolysis through a rotating magnetic field (RMF) of guided magnetic nanoparticles (NPs) in the presence of low-dose urokinase is proposed. The dispersed Fe3O4 NPs mixed with urokinase were injected into microfluidic channels occluded by thrombus prepared in vitro. These magnetic NPs aggregated into elongated clusters under a static magnetic field, and were then driven by the RMF. The rotation of Fe3O4 aggregates produced a vortex to enhance the diffusion of urokinase to the surface of the thrombus and accelerate its dissolution. A theoretical model based on convective diffusion was constructed to describe the thrombolysis mechanism. The thrombus lysis speed was determined according to the change of the thrombus dissolution length with time in the microfluidic channel. The experimental results showed that the thrombolysis speed with rotating magnetic NPs is significantly increased by nearly two times compared with using the same dose of pure urokinase. This means that the magnetically-controlled NPs approach provides a feasible way to achieve a high thrombolytic rate with low-dose urokinase in use.

Acceleration of tissue plasminogen activator-mediated thrombolysis by magnetically powered nanomotors.

Dose control and effectiveness promotion of tissue plasminogen activator (t-PA) for thrombolysis are vitally important to alleviate serious side effects such as hemorrhage in stroke treatments. In order to increase the effectiveness and reduce the risk of stroke treatment, we use rotating magnetic nanomotors to enhance the mass transport of t-PA molecules at the blood clot interface for local ischemic stroke therapy. The in vitro experiments demonstrate that, when combined with magnetically activated nanomotors, the thrombolysis speed of low-concentration t-PA (50 μg mL–1) can be enhanced up to 2-fold, to the maximum lysis speed at high t-PA concentration. Based on the convection enhanced transport theory due to rotating magnetic nanomotors, a theoretical model is proposed and predicts the experimental results reasonably well. The validity and efficiency of this enhanced treatment has been demonstrated in a rat embolic model.

Bigger, Faster?

There is evidence that high-volume hospitals may produce better patient outcomes. We aimed to identify whether there were any associations between hospital thrombolysis volume and speed of thrombolysis (tissue-type plasminogen activator [tPA]) administration in patients with ischemic stroke. Data were drawn from 2 national clinical audits in England: the Stroke Improvement National Audit Program and the 2012 Sentinel Stroke Audit. Hospitals were categorized into 3 groups based on the annualized volume of thrombolysis: 0 to 24, 25 to 49, and ≥50 cases per annum. Arrival-brain scan, onset-tPA, and arrival-tPA times were compared across groups and stratified by onset-arrival time. Multilevel logistic models were used to estimate the odds of receiving tPA within 60 minutes of arrival. Of the 42 024 patients with acute ischemic stroke admitted to 80 hospitals, 4347 received tPA (10.3%). Patients admitted to hospitals with an annual thrombolysis volume of ≥50 cases per annum had median arrival-tPA times that were 28 and 22 minutes shorter than patients admitted to hospitals with volumes of 0 to 24 and 25 to 49, respectively. Onset-tPA times were shorter by 24 to 32 minutes across strata of onset-arrival times. In multivariable analysis, patients admitted to hospitals with a volume of ≥50 cases per annum had 4.33 (2.21-8.50; P<0.0001) the odds of receiving tPA within 60 minutes of arrival. No differences in safety outcomes were observed, with similar 30-day mortality and complication rates across the groups. Hospitals with higher volumes of thrombolysis activity achieve statistically and clinically significant shorter delays in administering tPA to patients after arrival in hospital.

Treatment of acute limb ischemia with focus on endovascular techniques

Acute limb ischemia is still the most frequent cause of major limb loss. Timely and fast revascularization is the key for limb salvage and patient survival. Large randomized trials showed equivalency of surgical and endovascular revascularization by means of local lysis with urokinase (TOPAS, STILE). New lytic agents and their modified application such as via a pulse spray catheter or combined with an ultrasound catheter and the combination with glycoprotein IIb/IIIa receptor antagonists have increased the efficacy and speed of thrombolysis. Recently, mechanical thrombectomy devices have become more widespread because intervention time and bleeding complications can be reduced. This review article summarizes the clinical presentation of and the treatment options for acute arterial occlusive disease caused either by embolism or local thrombosis.

Ischemic stunning of the brain: early recanalization without immediate clinical improvement in acute ischemic stroke.

Early arterial recanalization (ER) with intravenous tissue plasminogen activator (tPA) can lead to dramatic clinical recovery, whereas some patients do not experience immediate clinical improvement. Consecutive patients received tPA 0.9 mg/kg IV within 3 hours after symptom onset. All had M1 or M2 middle cerebral artery occlusions on pretreatment transcranial Doppler. Patients were continuously monitored for 2 hours after bolus. ER was defined as the Thrombolysis in Brain Ischemia intracranial flow increase by >or=1 grade. Stroke severity (National Institutes of Health Stroke Scale [NIHSS]) and recovery (modified Rankin Scale) were assessed independently of transcranial Doppler. One hundred twenty patients (mean age, 68+/-15 years; 63 women; median NIHSS, 17; range, 5 to 29; 90% with >or=10 points) received tPA at a median of 120 minutes, 50% within the first 2 hours. ER was observed in 73 patients (32 complete, 41 partial). No immediate clinical changes (n=23) or worsening (by 1 to 6 points on NIHSS, n=4) was observed in 37% of ERs (nonresponders). Complete ER was found in 8 of these 27 patients. At 24 hours, 22 of 27 patients (82%) had persisting deficits of NIHSS >or=10 points, yet 37% of these nonresponders (10 of 27) still achieved good outcome (modified Rankin score, 0 to 2) at 3 months. Among nonresponders with good outcome, 100% had detectable residual flow signals, and 70% had compensatory flow diversion on prebolus transcranial Doppler compared with 65% and 29% of nonresponders with poor outcome (P<0.05). Compared with responders (n=46), nonresponders had similar prebolus median NIHSS of 16 to 17 points, bolus times of 120 to 132 minutes, median speed of thrombolysis (30 minutes), and ER times of 190 to 193 minutes after onset. Reocclusion occurred in 3 of 4 patients with clinical worsening, 30% of other nonresponders, and 22% of responders. Symptomatic hemorrhage rate was 4% in both groups. At 3 months, mortality was 33% in nonresponders compared with 9% in responders (P=0.001). After successful arterial ER with tPA therapy, lack of early clinical changes or worsening is relatively common (37%) and appears to be independent of time to tPA bolus or reperfusion. However, with tPA alone, at least one third of these nonresponders still achieved good outcomes at 3 months, suggesting the possibility of a "stunned brain" syndrome with delayed recovery. Several different mechanisms may potentially account for this phenomenon.

Dose finding with a novel recombinant plasminogen activator (BM 06,022) in patients with acute myocardial infarction: Results of the German recombinant plasminogen activator study

Objectives. The aim of this study was to determine the appropriate dose of a novel recombinant tissue-type piasminogen activator (BM 06.022) for thrombolysis in patients with acute myocardial infarction.Background. BM 06.022 is a mutant of tissue-type plasminogen activator expressed in Escherichia colithat can be given as a single bolus because of a prolonged half-life, which might obviate the need for complicated regimens.Methods. BM 06.022 given as a single bolus was investigated in 142 patients in a multicenter sequential dose-finding study. Efficacy of the drug was assessed from infarct-related artery patency by coronary angiography.Results. With the first dose of 10 MU of BM 06.022, the predefined minimal 90-min patency of 70% was not achieved, as indicated by the sequential probability ratio test after treatment of 42 patients (group A). The second dose of 15 MU of BM 06.022 was given subsequently in the preset maximum of 100 patients (group B). Angiography 30, 60 and 90 min after the bolus injection of BM 06.022 revealed a patent infarct-related artery (Thrombolysis in Myocardial Infarction trial [TIMI] grade 2 or 3) in 65% and 66%, 73% and 74% and 66% and 75% of patients in groups A and B, respectively. Very early reocclusion up to the 90-min angiogram occurred in 17% and 13%, late reocclusion until predischarge angiography occurred in 7% and 5%, and rescue percutaneous transluminal coronary angioplasty after the 90-min angiogram was performed in 6 and 14 patients in groups A and B, respectively. Plasma fibrinogen decreased from 2.79 g/liter (range 0.94 to 4.75) to 1.69 g/liter (range 0.0 to 3.95) in group A and from 2.54 g/liter (range 0.0 to 5.02) to 0.92 g/liter (range 0.0 to 2.68) in group B. Two bleeding complications requiring transfusion or surgical intervention and one nonfatal intracranial hemorrhage were encountered. Eight patients had a reinfarction, and five patients died, all of cardiac causes.Conclusions. With BM 06.022 given as a single bolus, a high early patency rate of the infarct-related coronary artery can be achieved. The speed of thrombolysis seems to be superior to standard thrombolytic drugs. The compound warrants further evaluation with respect to safety and efficacy by clinical end points.

Streptokinase and Recombinant Tissue Plasminogen Activator (rt-PA) Are Equally Effective in Treating Acute Myocardial Infarction

In recent trials, patients with myocardial infarction who received either recombinant tissue-type plasminogen activator (rt-PA) or streptokinase showed essentially no difference in the amount of myocardial salvage, in mortality reduction, or in the incidence of bleeding complications. These findings thus failed to fulfill the expectation that rt-PA would be twice as effective as streptokinase as a thrombolytic agent. The basis for this mistaken prediction was an unfortunate overemphasis on an inadequate surrogate endpoint, namely, the patency or reperfusion rate at 90 minutes after the start of therapy. Using the 90-minute patency or reperfusion rate as an endpoint has several serious limitations. First, it is an observation made at only one point in time during a dynamic process that may change even during the infusion proper. Second, a single view at 90 minutes completely disregards the possibility of subsequent reocclusion which often occurs within 1 hour after treatment. Third, an image at 90 minutes is more a reflection of the speed of thrombolysis than of whether lysis will eventually occur; the pace of clot lysis depends on both the agent used and the age of the thrombus. Fourth, lysis at 90 minutes is of minimal relevance for myocardial salvage unless observed within the time frame when infarction size can be limited significantly, which is generally less than 4 hours between symptom onset and the time that reperfusion is accomplished. Fifth, a stable state of vessel patency is meaningful for mortality reduction even if stabilization occurs after completion of the infarction. Such "late," but lasting, patency is a critical component of the "open vessel" principle and explains, at least in part, the survival benefit that accrues to patients treated even 24 hours after the onset of symptoms. There is currently no evidence that rt-PA has a more beneficial effect on survival or function than does streptokinase or any other plasminogen activator used in treating acute myocardial infarction; nor is there any evidence that patients who receive rt-PA therapy show a decreased incidence of bleeding complications compared with those who receive streptokinase, despite the relative fibrinogen-sparing attribute of rt-PA. Given the poor predictive value of the 90-minute angiogram for ultimate clinical advantage of one agent over another, studies that are limited to this endpoint are of marginal use in evaluating treatment regimens used in mortality studies. The best evidence to date indicates that streptokinase and rt-PA are of equivalent value for survival after acute myocardial infarction, a conclusion that can be justifiably challenged only with a valid mortality study.

Reperfusion Adjunctive Therapy: Platelet Active Agents

Changes in a coronary artery thrombus resulting from platelet activation may affect the speed of thrombolysis and the frequency of reocdusion after thrombolytic therapy. In studies performed in canine models, we have found that selected thromboxane and serotonin receptor antagonists given in combination markedly enhance the thrombolytic effect of tissue plasminogen activator, probably by preventing further platelet activation and their incorporation into a thrombus during thrombolytic therapy. The combination of a thromboxane and serotonin receptor antagonist given with heparin and tissue plasminogen activator is effective in delaying or preventing reocdusion after discontinuation of tissue plasminogen activation in experimental canine models in whom coronary artery thrombosis has been induced by an indwelling copper coil.

Simultaneous administration of thromboxane A2- and serotonin S2-receptor antagonists markedly enhances thrombolysis and prevents or delays reocclusion after tissue-type plasminogen activator in a canine model of coronary thrombosis.

Dynamic changes of the thrombus after its formation due to platelet activation may affect the speed of thrombolysis. In the present study, we wanted to evaluate the role played by thromboxane A2 (TXA2) and serotonin (5HT) in mediating platelet activation during lysis of intracoronary thrombi with human recombinant tissue-type plasminogen activator (t-PA). Coronary thrombi were induced in 26 anesthetized, open-chest dogs by inserting a copper coil into the left anterior descending coronary artery (LAD). LAD blood flow was monitored throughout the experiment by means of a Doppler flow probe placed proximally to the coil. Presence of the thrombus was documented for 30 minutes. The dogs were then assigned to one of four groups as follows: group 1 dogs (n = 8), serving as controls, received a bolus of heparin (200 units/kg) and a bolus of t-PA (80 micrograms/kg) followed by a continuous infusion (8 micrograms/kg/min) for up to 90 minutes or until reperfusion was achieved; group 2 dogs (n = 10) received, immediately before heparin and t-PA, an intravenous bolus of SQ29548 (SQ) (0.4 mg/kg, a selective TXA2-receptor antagonist) and LY53857 (LY) (0.2 mg/kg, a selective serotonin S2-receptor antagonist); group 3 dogs (n = 7) received, before heparin and t-PA, an intravenous bolus of SQ alone (0.4 mg/kg); and group 4 dogs (n = 7) received, before heparin and t-PA, an intravenous bolus of LY alone (0.2 mg/kg). After thrombolysis, all dogs were monitored for 90 minutes or until a persistent reocclusion occurred.(ABSTRACT TRUNCATED AT 250 WORDS)