PURPOSE: To investigate the recanalization rate after intravenous administration of recombinant tissue plasminogen activator (IV-tPA) for acute major arterial occlusion of the anterior cerebral circulation and to investigate the relationship between atrial fibrillation and recanalization. METHODS: From April 2005 to April 2006, 16 patients with acute major arterial occlusion of the anterior cerebral circulation were treated with IV-tPA. Recanalization was classified as good (as compared with an unoccluded contralateral vessel; thrombolysis in myocardial infarction (TIMI) classification grade II and III) and poor (TIMI grade 0 and I). The clinical and radiological parameters associated with recanalization were analyzed. The clinical outcomes were evaluated by use of the National Institute of Health Stroke Scale (NIHSS) at 3 months after treatment. RESULTS: Of all of the 16 patients, 11 patients (68.8%) showed good recanalization. Among these 11 patients, nine patients survived (81.8%). However, only one patient survived (20%, p = 0.036) of the other five patients who showed poor recanalization. The pretreatment NIHSS score and atrial fibrillation were significantly correlated with the recanalization rate. Atrial fibrillation was found in 8 of 16 patients (50.0%) as the cause of the cerebral embolic infarction. Among the patients with atrial fibrillation only three patients showed good recanalization (37.5%); patients without atrial fibrillation showed good recanalization (100%, p = 0.026). CONCLUSIONS: I.-tPA appears to be effective and safe as a recanalization method for acute major cerebral arterial occlusion in patients that do not have atrial fibrillation. Good recanalization was associated with a good clinical result. Atrial fibrillation is a significant associated factor of poor recanalization and high mortality.
Administration, Intravenous ; Atrial Fibrillation ; Classification ; Humans ; Infarction ; Mortality ; Myocardial Infarction ; Stroke ; Tissue Plasminogen Activator*

administration of human tissue-type plasminogen activator (t-PA). Nine rabbits weighing about 2 kg were used. After exposure of both femoral veins, the veins were crushed by the jaws of smooth needle holder in order to create a thrombosis model. Transectional incision was made in the vein. The animals were then divided into 3 groups: 1) Experimental Group I, topical irrigation of lumen with t-PA saline solution (n=6); 2) Experimental Group 2, Intravenous administration of t-PA (0.75 mg/kg) via the marginal ear vein for 3 days; 3) Control Group, topical irrigation of lumen with saline solution (n=6). The patency was evaluated with empty-and-refill test and thrombus formation was judged by surgical microscope. The histologic findings were also evaluated. Thirty minutes after microvascular anastomosis, the patency of all Experimental Groups 1 and 2 was more improved than that of Control Group. However, there was no significant difference among groups. Three days after microvascular anastomosis, the patency of all Experimental Groups was much more improved than that of Control Group (P<0.05). There was no significant difference between Experiment Group 1 and Experiment Group 2. Three days after microvascular anastomosis, the amount of thrombus in all Experimental Groups was much less than that of Control Group (P<0.05). In histologic findings, a lot of luminal thrombus were observed around sutured area in Control Group. Few luminal thrombus was observed in all Experimental Groups. The necrotic changes were was observed in the vessel wall of all specimens. These results indicate that topical irrigation and intravenous administration of t-PA are effective measures in improving patency and preventing thrombus formation after microvascular anast omosis.]]>
Administration, Intravenous ; Animals ; Ear ; Femoral Vein ; Humans ; Jaw ; Needles ; Phenobarbital ; Rabbits ; Sodium Chloride ; Thrombosis ; Tissue Plasminogen Activator ; Veins

AIMIn order to elucidate the relationship between homocysteine (Hcy) and the fibrinolytic system, we examined the effect of Hcy on tissue- type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) gene expression in human umbilical vein endothelial cells (HUVEC) in vitro.

METHODSTotal RNA was extracted from HUVEC exposed to physical and pathological concentrations of Hcy (0, 10, 50, 200, 500 micromol/L ) for 24 hours, using the guanidinium isothiocyanate method. The semi-quantification of tPA and PAI-1 mRNA in HUVEC was carried out by reverse transcriptase-polymerase chain reaction (RT-PCR).

RESULTSPAI-1 mRNA levels was enhanced by Hcy at concentrations of 500 micromol/L of Hcy, compared with that of 0 micromol/L Hcy (P < 0.05). The mRNA expression of tPA, however, was significantly decreased at concentrations of 500 micromol/L Hcy, compared with that of 10 micromol/L Hcy (P < 0.05), but compared with the control group, the tPA level of 10 micromol/L Hcy was much higher (P < 0.05).

CONCLUSIONHyperhomocysteinemia increases the incidence of cardio cerebral vascular disease, which may be caused by decreasing the activity of fibrinolytic system, whereas, the physiological concentration of Hcy may be decreased the incidence by enhancing the activity of fibrinolytic system.

Cells, Cultured ; Gene Expression ; Homocysteine ; administration & dosage ; pharmacology ; Human Umbilical Vein Endothelial Cells ; drug effects ; metabolism ; Humans ; Plasminogen Activator Inhibitor 1 ; genetics ; metabolism ; RNA, Messenger ; genetics ; Tissue Plasminogen Activator ; genetics ; metabolism

PURPOSE: The severity of a stroke cannot be described by widely used prehospital stroke scales. We investigated the usefulness of the Kurashiki Prehospital Stroke Scale (KPSS) for assessing the severity of stroke, compared to the National Institutes of Health Stroke Scale (NIHSS), in candidate patients for intravenous or intra-arterial thrombolysis who arrived at the hospital within 6 hours of symptom onset. MATERIALS AND METHODS: We retrospectively analyzed a prospective registry database of consecutive patients included in the Emergency Stroke Therapy program. In the emergency department, the KPSS was assessed by emergency medical technicians. A cutoff KPSS score was estimated for candidates of thrombolysis by comparing KPSS and NIHSS scores, as well as for patients who actually received thrombolytic therapy. Clinical outcomes were compared between patients around the estimated cut-off. The independent predictors of outcomes were determined using multivariate logistic regression analysis. RESULTS: Excellent correlations were demonstrated between KPSS and NIHSS within 6 hours (R=0.869) and 3 hours (R=0.879) of hospital admission. The optimal threshold value was a score of 3 on the KPSS in patients within 3 hours and 6 hours by Youden's methods. Significant associations with a KPSS score > or =3 were revealed for actual intravenous administration of tissue plasminogen activator (IV-tPA) usage [odds ratio (OR) 125.598; 95% confidence interval (CI) 16.443-959.368, p<0.0001] and actual IV-tPA or intra-arterial urokinase (IA-UK) usage (OR 58.733; 95% CI 17.272-199.721, p<0.0001). CONCLUSION: The KPSS is an effective prehospital stroke scale for identifying candidates for IV-tPA and IA-UK, as indicated by excellent correlation with the NIHSS, in the assessment of stroke severity in acute ischemic stroke.
Administration, Intravenous ; Confidence Intervals ; Emergencies ; Emergency Medical Services ; Emergency Medical Technicians ; Emergency Service, Hospital ; Humans ; Logistic Models ; Methods ; National Institutes of Health (U.S.) ; Prospective Studies ; Retrospective Studies ; Stroke* ; Thrombolytic Therapy ; Tissue Plasminogen Activator ; Urokinase-Type Plasminogen Activator ; Weights and Measures

BACKGROUND AND AIMIntravenously-administered tissue plasminogen activator (IV-TPA) induces thrombolysis and remains the only FDA-approved therapy for acute ischaemic stroke. IV-TPA thrombolysis has been approved recently in Singapore for acute stroke. Continuous exposure of clot to 2-MHz pulsed-wave transcranial Doppler (TCD) ultrasound during IV-TPA infusion is known to augment thrombolysis. We aimed to determine the feasibility, safety and efficacy of ultrasound-assisted thrombolysis in acute ischaemic stroke in Singapore.

SUBJECTS AND METHODSConsecutive patients with acute ischaemic stroke due to intracranial arterial-occlusions were treated with standard IV-tPA and continuously monitored with 2-MHz TCD according to the CLOTBUST-trial protocol. Arterial recanalisation was determined with Thrombolysis in Brain Ischemia (TIBI) flow-grading system. Safety and efficacy of ultrasoundassisted thrombolysis were assessed by rates of symptomatic intracranial haemorrhage (sICH) and functional recovery at 1 month, respectively.

RESULTSFive consecutive patients (mean age 58 years, 3 men and 3 of Chinese ethnicity) were included. Mean time elapsed between symptom onset and presentation to emergency room was 98 minutes (range, 50 to 135 minutes) while the mean time interval between symptom onset to IV-TPA bolus was 144 minutes (range, 125 to 180 minutes). Partial or complete recanalisation with reduction in the stroke severity was noted in 4 out of the 5 patients during IV-TPA infusion (mean change in NIHSS = 4 points; range 2 to 8 points). None of our patients developed sICH while 4 patients demonstrated good functional outcome at 1 month.

CONCLUSIONSOur preliminary study demonstrates the feasibility, safety and efficacy of ultrasound-assisted thrombolysis in acute ischaemic stroke in Singapore. Continuous TCD-monitoring during IV-TPA infusion provides real-time information, enhances thrombolysis and improves functional outcomes in acute ischaemic stroke.

Aged ; Brain Infarction ; diagnostic imaging ; Female ; Fibrinolytic Agents ; administration & dosage ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Thrombolytic Therapy ; methods ; Tissue Plasminogen Activator ; administration & dosage ; Ultrasonography, Interventional ; methods

Although intravenous recombinant tissue plasminogen activator (IV rt-PA) is effective in many cases of acute ischemic stroke, the neurologic symptoms can worsen after IV rt-PA because of sustained vessel occlusion. For such cases, several reperfusion modalities are available, including intra-arterial thrombolysis (IAT), carotid endarterectomy, and superficial temporal artery-middle cerebral artery (STA-MCA) bypass. Invasive procedures, such as major surgery, should be generally avoided within 24 hours after the administration of IV rt-PA. A 66-year-old man with no previous medical history developed left hemiparesis. A computed tomography scan revealed no acute lesion and he received IV rt-PA within 1.5 hours after symptom onset. Emergent magnetic resonance imaging showed significant diffusion-perfusion mismatch. He received IAT 2 hours after IV rt-PA administration, but IAT failed because of total occlusion of the cervical internal carotid artery. We initially planned to perform STA-MCA bypass the next morning because he had received IV rt-PA, but, 8 hours after IV rt-PA administration, his hemiparesis worsened from motor grade 3/4 to motor grade 1/2. Because of the large perfusion defect in both MCA divisions, double-barrel STA-MCA bypass was performed 10 hours after IV rt-PA administration. His symptoms rapidly improved after surgery and his modified Rankin Scale score 3 months later was grade 0. We suggest that emergent double-barrel bypass can be a viable option in patients who have perfusion defects of both MCA divisions in acute ischemic stroke after IV rt-PA administration.
Administration, Intravenous* ; Aged ; Carotid Artery, Internal ; Cerebral Arteries ; Cerebral Infarction ; Cerebral Revascularization ; Endarterectomy, Carotid ; Humans ; Magnetic Resonance Imaging ; Neurologic Manifestations ; Paresis ; Perfusion ; Reperfusion ; Stroke* ; Tissue Plasminogen Activator*

BACKGROUND AND PURPOSE: Conventional therapies for ischemic stroke include thrombolytic therapy, prevention of inappropriate coagulation and thrombosis, and surgery to repair vascular abnormalities. Over 10 years have passed since the US Food and Drug Administration approved intravenous tissue plasminogen activator for use in acute stroke patients, but most major clinical trials have failed during the last 2 decades, including large clinical trials for secondary prevention and neuroprotection. These results suggest the presence of heterogeneity among stroke patients. Neuroimaging techniques now allow changes to be observed in patients from the acute to the recovery phase. The role of MRI in stroke evaluation and treatment is discussed herein. MAIN CONTENTS: Three MRI strategies are discussed with relevant examples. First, the following MRI strategies for acute ischemic stroke are presented: diffusion-perfusion mismatch, deoxygenation (oxygen extraction and cerebral metabolic rate of oxygen), and blood-brain barrier permeability derangement in selected patients for recanalization therapy. Second, multimodal MRI for identifying stroke mechanisms and the specific causes of stroke (i.e., patent foramen ovale, infective endocarditis, and nonbacterial thrombotic endocarditis) are presented, followed by MRI strategies for prevention of recurrent stroke: plaque images and flow dynamics for carotid intervention. EXPECTATIONS: The studies reviewed herein suggest that using MRI to improve the understanding of individual pathophysiologies will further promote the development of rational stroke therapies tailored to the specifics of each case.
Atherosclerosis ; Blood-Brain Barrier ; Endocarditis ; Foramen Ovale, Patent ; Humans ; Neuroimaging ; Perfusion ; Permeability ; Population Characteristics ; Secondary Prevention ; Stroke ; Thrombolytic Therapy ; Thrombosis ; Tissue Plasminogen Activator ; United States Food and Drug Administration

Our previous experimental work with tissue plasminogen activator (TPA) suggested the possibility of the clearance of vitreous hemorrhage by repetitive injections of low-dose TPA. We therefore investigated in rabbits the effect of both repeated injections of TPA and the change of the integrity of the vitreous body on the clearance of vitreous hemorrhage. Vitreous hemorrhage was produced by intravitreal injection of 0.05 ml of autologous whole blood in the pigmented rabbit eyes with intact vitreous or gas-compressed vitreous. Three intravitreal injections of 3-g TPA (total dose of 9 microgram), separated by 7-day intervals, were performed. The endpoint for vitreous hemorrhage clearance was defined as clear visualization of the posterior central retina of the rabbits. Regardless of whether gas compression vitrectomy was performed, repeated injections of low-dose TPA resulted in rapid clearance of fresh vitreous hemorrhage in approximately two to three weeks after the last TPA injection. No evidence of retinal toxicity was seen in all experimental groups. Repetitive injections of low-dose TPA may be effective in the treatment of fresh vitreous hemorrhage.
Animals ; Disease Models, Animal ; Injections ; Rabbits ; Tissue Plasminogen Activator/*administration & dosage/therapeutic use ; Vitreous Body/drug effects ; Vitreous Hemorrhage/*drug therapy

OBJECTIVEThe aim of the study was to quest appropriate dose of recombinant tissue-type plasminogen activator (rt-PA) on Chinese patients with acute myocardial infarction.

METHODSAll enrolled patients were randomized into weight-adjusted dose or low dose rt-PA group, and received a basal treatment with aspirin and heparin. Additionally, after an intravenous bolus of 8 mg rt-PA, patients in weight-adjusted dose group (n = 93) were given an intravenous infusion of 42-92 mg rt-PA (1 mg/kg body weight), while patients in the low dose group (n = 91) were treated with an intravenous infusion of 42 mg rt-PA over 90 minutes. The observational endpoint included reperfusion rate of the infarct-related artery by clinical criteria, left ventricular ejection fraction and major adverse cardiovascular events within 30 days in the two groups.

RESULTSThere were 74 patients diagnosed reperfusion by clinical criteria in weight-adjusted dose group and 59 patients in low dose group (79.6% vs 64.8%, P = 0.026). The left ventricular ejection fraction seemed to be better in weight-adjusted dose group than in low dose group (P = 0.259). The major adverse cardiovascular events within 30 days were less in weight-adjusted dose group than in low dose group (P < 0.05).

CONCLUSIONThere was statistical significant superiority of weight-adjusted dose over low dose rt-PA in the treatment of Chinese patients with acute myocardial infarction.

Adult ; Aged ; Body Weight ; Female ; Humans ; Male ; Middle Aged ; Myocardial Infarction ; drug therapy ; Thrombolytic Therapy ; methods ; Tissue Plasminogen Activator ; administration & dosage ; therapeutic use

OBJECTIVE: The T2*-weighted gradient echo image susceptibility vessel sign (GRE SVS) is a well-known indicator of intraluminal thrombi in acute cerebral infarction. The purpose of this study was to evaluate the relationships between thrombus size on GRE SVS and recanalization after intravenous administration of tissue plasminogen activator (IV-tPA). MATERIALS AND METHODS: Fifty five patients with GRE SVSs on the M1 were enrolled. Examination of magnetic resonance image (MRI), including diffusion weighted imaging and MR angiography, was performed within 20 minutes of admission. Thrombus size on GRE was calculated using the Picture Archiving and Communication System upon initial MRI. Recanalization was assessed with follow-up MRI or transfemoral cerebral angiography within 24 hours of treatment. RESULTS: The patient group consisted of 37 males and 18 females with an average age of 63.74 +/- 10.28 years (range: 43 - 77 years). The median NIHSS score was 13. Fifteen of these patients achieved recanalization (27.3%). The average thrombus cross-sectional area in the recanalization group was 38.54 +/- 20.27 mm2, and the corresponding size of the non-recanalization group was 53.38 +/- 24.77 mm2 (p = 0.043). In the receiver operator characteristic curve for thrombus cross-sectional area in relation to recanalization, the cut-off point was 47.28 mm2. The sensitivity at this cut-off point was 73.3%, the specificity was 60%, and the area under the curve was 0.687. CONCLUSION: Thrombus size on GRE is a simple diagnostic tool that can be easily measured, and thrombus size on GRE SVS was found to be associated with recanalization after IV-tPA.
Administration, Intravenous ; Angiography ; Cerebral Angiography ; Cerebral Infarction ; Diffusion ; Female ; Follow-Up Studies ; Humans ; Infarction, Middle Cerebral Artery* ; Magnetic Resonance Imaging ; Male ; Sensitivity and Specificity ; Thrombosis* ; Tissue Plasminogen Activator