Dose Of TPA Research Articles

Stroke severity and residual flow determined by transcranial colour-coded ultrasound (TCCD) predict recanalization and clinical outcome during thrombolysis

ObjectiveTo determine clinical, neuroradiological or ultrasonographic parameters associated with early recanalization and clinical outcome in patients treated with intravenous (IVT) or combined intravenous–intra-arterial (IVT–IAT) thrombolysis. MethodsFrom 2004 to 2007, all consecutive ischemic stroke patients admitted within a 3-hour window and who underwent thrombolytic therapy were reviewed. Degree of occlusion and recanalization during IVT was assessed by transcranial color-coded ultrasound (TCCD) using Thrombolysis In Brain Ischemia (TIBI) classification. According to our protocol, in case of recanalization (modification of TIBI grade≥1) after 30min of IVT, the procedure was maintained over 1h. When TIBI grade failed to improve after 30min, IVT was discontinued and IAT performed using the remaining tPA dose. The study endpoints were early recanalization defined as achievement of TIBI≥3 grade at 30min (for this endpoint all patients presenting a TIBI grade 3 at admission were excluded from the model) and clinical outcome at 3months assessed by the modified Rankin scale. ResultsSeventy-one patients underwent either IVT (n=41) or IVT-IAT (n=30). Among all the variables, NIHSS and TIBI grades assessed at baseline were the only independent factors associated with early recanalization and clinical outcome. Furthermore, the combination of these two parameters was superior in predicting early recanalization and outcome to either one of them taken separately. An inverse correlation between NIHSS, TIBI grades and early recanalization was found: the lower the TIBI grade, the lower the probability to recanalize for any given NIHSS. ConclusionBaseline NIHSS and TIBI grades were the only independent factors associated with early recanalization and clinical outcome. The combination of these two parameters was superior to each single variable in predicting the study endpoints and could therefore be used to improve the selection of patients for IVT or more aggressive therapies.

Efficacy and safety of different doses of intravenous tissue plasminogen activator in Chinese patients with ischemic stroke

Intravenous tissue plasminogen activator (tPA) at 0.9 mg/kg improves outcome in acute ischemic stroke. The dose response to tPA may be different in Chinese patients compared with Western populations, but this has not been systematically examined. We aimed to compare the efficacy and safety of different doses of tPA in Chinese stroke patients. We included all acute ischemic stroke patients treated with tPA within 4.5 hours of onset. Patients were treated with three dose regimens of tPA (0.6–0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg). The following data were collected: patient demographics; vascular risk factors; neuroimaging results; time of tPA administration; clinical assessment before treatment, at 24 hours and 3 months; and modified Rankin Scale (mRS) score at 3 months. A total of 105 patients with stroke of Han Chinese origin were included in the study. The baseline characteristics of the three dose groups were well matched. In the 0.9 mg/kg group ( n = 51), 51.1% had favorable outcome at 3 months, compared with 38.7% of patients in the 0.8 mg/kg group ( n = 31) (odds ratio [OR] to 0.9 mg/kg group, 0.57; 95% CI, 0.19–1.73; p = 0.32) and 34.8% in the 0.6–0.7 mg/kg group ( n = 23) (OR to 0.9 mg/kg group, 0.31; 95% CI, 0.08–1.16; p = 0.08). There were no statistically significant differences in the incidence of symptomatic intracerebral hemorrhage and mortality rate. There was a higher proportion of patients with good functional outcomes in the 0.9 mg/kg group. Although not significant, these results strongly support the feasibility and urgent need for a dose ranging trial to establish an optimal tPA dose in Chinese stroke patients.

Abstract 3470: Effects of combined phytochemicals on skin tumorgenesis in SENCAR mice

Abstract The purpose of our study was to determine the effect of combined action of phytochemicals on early stages of skin tumorgenesis, i.e., initiation and promotion. We tested calcium D-glucarate (CG) given in the diet, while resveratrol (RES) and ursolic acid (URA) were applied topically. The 7,12-dimethylbenz[a]anthracene (DMBA)-initiated, 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted multistage skin carcinogenesis model in SENCAR mice was used. Mice (6-7 weeks old) with shaved backs received one topical dose of DMBA (20 nmol), then after one month, two weekly doses (2 µg each) of TPA (tumor promoter) for 14 weeks until sacrifice. The phytochemicals RES (2.5 μmol) or URA (1 μmol) were applied topically 20 min prior to DMBA or TPA treatment and 2% dietary CG was given in the AIN-93G diet from 2 weeks prior to 2 weeks after the DMBA dose or continually beginning 2 weeks prior to the first dose of TPA. We determined the tumor incidence (% of mice with tumors) and tumor multiplicity (number of tumors per mouse) and using RT-PCR and immunochistochemical analyses, we checked the expression of some cell proliferation and inflammation related genes. URA applied alone and in combination with CG during the promotion stage was a strong inhibitor of tumor multiplicity and tumor incidence. Combinations of URA with dietary CG appeared to show some synergistic effects. All compounds and their combinations reduced epidermal proliferation, but only URA and a combination CG/URA applied during promotion significantly reduced hyperplasia, as determined by epidermal thickness measurements taken at 14 weeks of TPA treatment. DMBA/TPA treatments resulted in epidermal hyperplasia, characterized by significant increase in transcription factor AP-1 components and nuclear factor kappa B (NFkB) expression levels with a simultaneously increased expression of the inflammation markers COX-2 and IL-6, compared to untreated controls. All anti-promotion treatments (either single compounds or their combinations) caused a marked decrease of inflammation related genes levels compared to the DMBA/TPA control. On the other hand, only URA and URA with dietary CG diminished the induced expression of proto-oncogenes c-jun and c-fos (components of AP-1) and the expression of NFkB protein p50. These results show that URA is a potent inhibitor of skin tumor promotion and it may be useful in the prevention of skin cancer and other epithelial cancers in humans. Supported by NIH grants CA 102747 and P30 CA 54174-16S1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3470.

Fibrinolytic Therapy in Mechanical Valve Thrombosis in a One-Year-Old Girl

This 16-month-old girl (weight 7 kg) was a patient with a complete form of endocardial cushion defect, and she received total correction at the age of 2 months. Severe mitral regurgitation persisted despite surgery, and mechanical valve replacement was performed at the age of 4 months. Two episodes of mitral valve thrombosis with severe mitral stenosis complicated her recovery, and she underwent 2 more operations for mitral valve replacement and double valve replacement with aortic root enlargement at the age of 6 months and 1 year, respectively. Impaired heart function and complete atrioventricular block complicated the operation, and a pacemaker was also inserted. She received warfarin therapy and was followed up regularly at our clinic. Mitral valve thrombosis occurred again, with a presentation of progressive dyspnea and poor activity. Chest radiography and transthoracic echocardiography showed severe mitral stenosis with lung edema (Figures 1 and 2A). Pulmonary hypertension was also found, with estimated systolic pulmonary artery pressure of 75 mm Hg. Intubation was provided with ventilator support, and inotropic agents were given, accompanied by heparin infusion. Fluoroscopy then showed poor motion of both leaflets of the mitral valve (Movie IA in the online-only data supplement). Because of the history of repeated operations and the family’s decision, fibrinolytic therapy with tissue plasminogen activator (tPA) was attempted. We discontinued warfarin first, checked the fibrinogen level, and then discontinued heparin and started tPA treatment. We gave a loading dose of 0.1 mg/kg first and then 6 courses of escalating doses of tPA at 0.1 mg kg 1 h 1 for 6 hours and then 0.15, 0.2, 0.3, 0.3, and 0.4 mg kg 1 h 1 . The fibrinogen level was checked after

Annexin A2 Combined with Low-Dose tPA Improves Thrombolytic Therapy in a Rat Model of Focal Embolic Stroke

Recent studies showed that soluble annexin A2 dramatically increases tissue plasminogen activator (tPA)-mediated plasmin generation in vitro, and reduces thrombus formation in vivo. Here, we hypothesize that combining annexin A2 with tPA can significantly enhance thrombolysis efficacy, so that lower doses of tPA can be applied in ischemic stroke to avoid neurotoxic and hemorrhagic complications. In vitro activity assays confirmed tPA-specific amplification of plasmin generation by recombinant annexin A2. In a rat focal embolic stroke model, combination therapy with tPA and recombinant annexin A2 protein at 2 h post-ischemia decreased the effective dose required for tPA by four-fold and reduced brain infarction. Combining annexin A2 with tPA also lengthened the time window for thrombolysis. Compared with tPA (10 mg/kg) alone, the combination of annexin A2 (5 mg/kg) plus low-dose tPA (2.5 mg/kg) significantly enhanced fibrinolysis, attenuated mortality, brain infarction, and hemorrhagic transformation, even when administered at 4 h post-ischemia. Combination with recombinant annexin A2, the effective thrombolytic dose of tPA can be decreased. As a result, brain hemorrhage and infarction are reduced, and the time window for stroke reperfusion prolonged. Our present findings provide a promising new approach for enhancing tPA-based thrombolytic stroke therapy.

Retinal Toxicity of Intravitreal Tissue Plasminogen Activator on Submacular Hemorrhage

Purpose: To present the clinical feature of retinal toxicity of intravitreal tissue plasminogen activator which was used for treatment of submacular hemorrhage. Case summary: An intravitreal injection of tPA (100 ) with gas tamponade (0.2 cc) was given to treat the submacular hemorrhage in a patient with ARMD. The therapeutic effect was measured by visual acuity, slit lamp examination, indirect funduscopy and fluorescein angiogram. Three months after the operation, the hemorrhage was decreased but a pigmentary change was observed on the peripheral retina. After 8 months, the submacular hemorrhage completely reabsorbed but the peripheral pigmentary change had increased. Ten months later, the retinal pigmentary change was observed on the entire retina except the posterior pole. The fluorescein angiogram showed peripheral hyperfluorescene of the retina due to window defect from the pigmentary change but no leakage was detected. The electroretinogram showed reduced amplitude in the right eye. Conclusions: Intravitreal tPA injection of 25 to 100 with pneumatic displacement is typically used for the treatment of submacular hemorrhage. However, there is no established safety dose of tPA for use in human eyes. In the present study, 100 of tPA was used and retinal toxicity was noted. Establishing a safety dose of tPA to prevent dosage dependent complications is necessary.

Practical model-based dose finding in early-phase clinical trials: optimizing tissue plasminogen activator dose for treatment of ischemic stroke in children.

A safe and effective tissue plasminogen activator (tPA) dose for childhood stroke has not been established. This article describes a Bayesian outcome-adaptive method for determining the best dose of an experimental agent and explains how this method was used to design a dose-finding trial for tPA in childhood. The method assigns doses to successive cohorts of patients on the basis of each dose's desirability, quantified in terms of the tradeoff between efficacy and toxicity. The tradeoff function is constructed from several pairs of equally desirable (efficacy, toxicity) probabilities specified by the physicians planning the trial. Each cohort's dose is chosen adaptively, based on dose-outcome data from the patients treated previously in the trial, to optimize the efficacy-toxicity tradeoff. Application of the method to design the tPA trial is described, including a computer simulation study to establish design properties. A hypothetical cohort-by-cohort example is given to illustrate how the method works during trial conduct. Because only a dose that is both safe and efficacious may be selected and the method combines phase I and phase II by integrating efficacy and toxicity to choose doses, it avoids the more time-consuming and expensive conventional approach of conducting a phase I trial based on toxicity alone followed by a phase II trial based on efficacy alone. This is especially useful in settings with low accrual rates, such as trials of tPA for pediatric acute ischemic stroke.

Catheter-directed Thrombolysis with the Endowave System in the Treatment of Acute Massive Pulmonary Embolism: A Retrospective Multicenter Case Series

To evaluate the efficacy of thrombolysis with the EndoWave peripheral infusion system in the treatment of patients with massive pulmonary embolism (PE) as compared to patients treated with catheter-directed thrombolysis. Ten patients (five men and five women; age range, 31-85 years; mean age, 54.20 years) with massive acute PE (17 lesions) were treated with ultrasonography (US)-assisted catheter-directed thrombolysis with the Endowave system. All patients had hypoxia and dyspnea. No patient had contraindication for thrombolysis. Angiographic findings, duration of lysis, dose of thrombolytics used, and procedural complications were recorded. Thrombolytics used were urokinase, tissue-type plasminogen activator (tPA), and Reteplase. Complete thrombus removal was achieved in 13 of the 17 lesions (76%), near complete thrombolysis was achieved in three lesions (18%), and partial thrombolysis was achieved in one lesion (6%). The mean time of thrombolysis was 24.76 hours +/- 8.44 (median, 24 hours). The mean dose of tPA used for the Endowave group was 0.88 mg/h +/- 0.19 (13 lesions). US-assisted catheter-directed thrombolysis is an effective method for treating massive thrombolysis. It has the potential to shorten the time of lysis and lower the dose of thrombolytics.

Increased retinal toxicity of intravitreal tissue plasminogen activator in a central retinal vein occlusion model

Intravitreal injection of tissue plasminogen activator (tPA) is used to treat several ocular conditions, although excessive doses of intravitreal tPA cause retinal toxicity. Toxicity may increase in the ischemic retina, such as in central retinal vein occlusion (CRVO), because tPA toxicity to neural tissues increases under ischemic conditions. We investigated tPA toxicity to the retina in a CRVO rat model. CRVO was induced in pigmented rats with rose Bengal-assisted laser photothrombosis. One hour after CRVO induction, 3 microl of tPA (0.075, 0.75, 3, or 7.5 microg) was injected intravitreally. Eyes that did not receive laser treatment, which served as non-CRVO controls, received tPA (0.75, 3, or 7.5 microg). The same amount of balanced salt solution (BSS) was injected as a nondrug control. Eyes were enucleated at 12 hours after injection, and terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) staining was performed to evaluate retinal cell apoptosis. The number of TUNEL-positive cells increased in a dose-dependent manner in both non-CRVO and CRVO group and significantly (P = 0.002) increased when 0.75, 3, or 7.5 microg of tPA was injected into the CRVO eyes. When comparing the number of TUNEL-positive cells between the eyes with and without CRVO that received the same treatment, apoptosis significantly increased in CRVO eyes. Retinal toxicity associated with intravitreally injected tPA can increase in a dose-dependent manner and be exacerbated in CRVO eyes, suggesting that the dose of tPA should be reduced when tPA is used to treat eyes with CRVO.

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Effects of tissue plasminogen activator on cerebral microvessels of rats during focal cerebral ischemia and reperfusion

The time window in the treatment of ischemic stroke with tissue plasminogen activator (tPA) is narrow, arbitrarily within 3 hours after the onset of symptom. Hemorrhagic transformation resulting from cerebral ischemia may be related to damage of the microvascular basal lamina of the brain, which may in turn cause microvascular fibrin deposition and aggravate cerebral ischemia. Here, we investigated the effect of tPA on the microvascular tissue changes during cerebral ischemia/reperfusion. Sprague–Dawley rats were subjected to focal cerebral ischemia by ligation of the right middle cerebral artery and bilateral common carotid arteries for 90 minutes. Sixty minutes after the onset of ischemia, escalated dosages of tPA from 2.5 to 10 mg/kg or saline were intravenously infused for 60 minutes. Twenty-four hours after reperfusion, the animals were allowed to be killed for examination. Low dosage of tPA (2.5–7.5 mg/kg) reduced post-ischemic brain infarction, suppressed metalloproteinase 2 (MMP-2) activity and restored blood–brain barrier (BBB) integrity. In contrast, high dose of tPA (10 mg/kg) aggravated brain infarction, increased MMP-2 activity and exacerbated BBB disruption. Cerebral ischemia/reperfusion decreased the immunoreactivity of both collagen type IV- and laminin-positive microvessels, whereas the low dosage of tPA (2.5–7.5 mg/kg) attenuated the reduction. When these molecules in whole cortical tissues were analysed, tPA dosage-dependently decreased the total content of collagen type IV, laminin and fibronectin. Although the detailed mechanisms regarding the action of tPA are yet to be investigated, our findings demonstrate that the detrimental effect of tPA was mediated, at least in part, through the destruction of the basal lamina in the cerebral microvessels by activating MMP-2.

The phenylpropanoid micronutrient chlorogenic acid improves clinical rating scores in rabbits following multiple infarct ischemic strokes: Synergism with tissue plasminogen activator

The present study assessed whether chlorogenic acid (CGA), a phenylpropanoid molecule that has multiple mechanisms of action would be useful to attenuate behavioral deficits associated with embolic strokes using the rabbit small clot embolic stroke model (RSCEM). Quantal analysis for each treatment determines the quantity of microclots (mg) that produce neurologic dysfunction in 50% of a group of animals ( P 50), with intervention considered beneficial if it increases the P 50 compared to controls. CGA (50 mg/kg) injected 5 min post-embolization significantly increased behavioral function and the P 50 to 3.61 ± 0.52 mg ( n = 19) compared to 1.58 ± 0.15 mg ( n = 26) in controls. In addition, CGA also increased the P 50 to 2.57 ± 0.28 mg ( n = 18) when administered 1 h post-embolization, but was ineffective when given 3 h following embolization ( P 50 = 1.22 ± 0.24 mg, n = 18). For combination studies with the thrombolytic tissue plasminogen activator (tPA), we used tPA at a standard dose of 3.3 mg/kg, which significantly increased the P 50 to 2.89 ± 0.29 mg ( n = 17) when administered 1 h after embolization, but not 3 h after embolization ( P 50 = 1.54 ± 0.27 mg, n = 18). However, when tPA (3.3 mg/kg) was combined with CGA (50 mg/kg) and administered 3 h following embolization, there was a significant increase in behavioral function as evidenced by an increase in the P 50 value to 3.40 ± 0.76 mg ( n = 23). In conclusion, as a mono-therapy CGA effectively reduced behavioral deficits when given up to 1 h following embolic strokes in rabbits. Moreover, there was a synergistic effect of the combination of tPA with CGA when administered 3 h following embolization. The results show that the therapeutic window for a standard effective dose of tPA could be increased by administration of CGA, suggesting that it may be most useful as a co-therapy with a standard thrombolytic treatment regimen.

The Glycocalyx Protects Erythrocyte-Bound Tissue-Type Plasminogen Activator from Enzymatic Inhibition

Coupling tissue-type plasminogen activator (tPA) to carrier red blood cells (RBC) prolongs its intravascular life span and permits its use for thromboprophylaxis. Here, we studied the susceptibility of RBC/tPA to PA inhibitors including plasminogen activator inhibitor-1 (PAI-1) that constrain its activity and may reduce the duration of its effect. Despite lesser spatial and diffusional limitations, soluble tPA was far less effective than RBC/tPA in dissolving clots formed in vitro from blood of wild-type (WT) mice (40 versus 80% lysis at equal doses of tPA). Furthermore, after i.v. injection, soluble tPA lost activity faster in transgenic mice expressing a high level of PAI-1 than in WT mice, whereas the activity of RBC/tPA was unaffected. PAI-1 inactivated soluble tPA at equimolar ratios in vitro, but it had no effect on the amidolytic or fibrinolytic activity of RBC/tPA. RBC/tPA was also more resistant than soluble tPA to in vitro inhibition by other serpins (alpha2-macroglobulin and alpha1-antitrypsin) and pathologically high levels of glucose. However, coupling to RBC did not protect a truncated tPA mutant, Retavase, from plasma inhibitors. Chemical removal of the RBC glycocalyx negated tPA protection from inhibitors: tPA coupled to glycocalyx-stripped RBC bound twice as much 125I-PAI-1 as did tPA coupled to naive RBC, and susceptibility of the bound tPA to inhibition by PAI-1 was restored. Thus, the RBC glycocalyx protects RBC-coupled tPA against inhibition. Resistance to high levels of inhibitors in vivo contributes to the potential utility of RBC/tPA for thromboprophylaxis.

Ultrasound Accelerates Thrombolysis of Acutely Induced Platelet-Rich Thrombi Similar to Those in Acute Myocardial Infarction

Although sonothrombolysis has been studied for development of recanalization that is safer and more efficacious than the methods currently used, there have been no studies of the efficacy of sonothrombolysis for the platelet-rich thrombi that typically cause acute myocardial infarction (AMI). The effects of adding ultrasound (US) to pharmacological lysis of platelet-rich thrombi was examined in a rabbit model of femoral artery occlusion. In 35 rabbits, the right femoral artery was balloon-injured repeatedly at 4-week intervals to induce platelet-rich thrombi. Two hours after the induction of occlusive thrombi, 27,500 IU/kg tissue plasminogen activator (tPA) were injected via an ear vein, with or without transcutaneous US (continuous wave, 1 MHz, 0.75 W/cm2), or 13,750 IU/kg tPA was administered with US (n=10). Significantly higher rates of successful thrombolysis (Thrombolysis In Myocardial Infarction grade 3) were observed with US (90.0%) than without it (10.0%), irrespective of the dose of tPA used (p<0.01). The peak flow velocity in affected femoral arteries was significantly higher with US (p<0.01), and histological examination confirmed complete dissolution of thrombi. However, the thrombi were not affected by US alone (n=5). US facilitates thrombolysis of platelet-rich thrombi and could be a useful component of thrombolytic therapy following AMI.

Is exogenous tissue plasminogen activator necessary for antithrombotic efficacy of an inhibitor of thrombin activatable fibrinolysis inhibitor (TAFI) in rats?

Introduction TAFI indirectly reduces the action of tPA on plasminogen. Whether exogenous tPA is necessary for TAFI inhibitor efficacy is unclear. Potato carboxypeptidase inhibitor (PCI), a TAFI inhibitor, has shown variable tPA dependence in rat models of arteriovenous shunt thrombosis (required) and microthrombosis (not required). This study was designed to further explore the importance of exogenous tPA in revealing PCI activity in rat models of venous and arterial thrombosis and provoked bleeding. Methods PCI was given as a bolus (5, 10 mg/kg) ± infusion (5, 10 mg/kg/h) and with or without low dose tPA (5, 10, 25 μg/kg/min). In each instance tPA was adjusted to produce subthreshold thrombus reduction. Arterial thrombosis was induced by FeCl 2; venous thrombosis by tissue factor or FeCl 2. Bleeding was induced by kidney incision with PCI given (5 mg + 5 mg/kg/h) in the presence or absence of tPA (10, 150, 200 μg/kg/min). Results PCI was ineffective without exogenous tPA in all tested thrombosis models. With exogenous tPA, PCI decreased thrombus weight 85% in tissue factor thrombosis, 59% in FeCl 2 thrombosis, and 46% in arterial thrombosis. PCI prolonged bleeding only when combined with a relatively high tPA dose (200 μg/kg/min) that increased bleeding alone. Conclusions If the current results predict clinical efficacy, the need for exogenous tPA in combination with TAFI inhibition is a potential problem. However, in acute settings where intravenous fibrinolytics are administered, or indications in which tPA production increases, TAFI inhibitors may prove to be safe and moderately effective profibrinolytic agents.

Human complement receptor type 1–directed loading of tissue plasminogen activator on circulating erythrocytes for prophylactic fibrinolysis

AbstractPlasminogen activators (PAs) are not used for thromboprophylaxis due to rapid clearance, bleeding, and extravascular toxicity. We describe a novel strategy that overcomes these limitations. We conjugated tissue-type PA (tPA) to a monoclonal antibody (mAb) against complement receptor type 1 (CR1) expressed primarily on human RBCs. Anti-CR1/tPA conjugate, but not control conjugate (mIgG/tPA), bound to human RBCs (1.2 × 103 tPA molecules/cell at saturation), endowing them with fibrinolytic activity. In vitro, RBC-bound anti-CR1/tPA caused 90% clot lysis versus 20% by naive RBCs. In vivo, more than 40% of anti-CR1/125I-tPA remained within the circulation (∼90% bound to RBCs) 3 hours after injection in transgenic mice expressing human CR1 (TgN-hCR1) versus less than 10% in wild-type (WT) mice, without RBC damage; approximately 90% of mIgG/125I-tPA was cleared from the circulation within 30 minutes in both WT and TgN-hCR1 mice. Anti-CR1/tPA accelerated lysis of pulmonary emboli and prevented stable occlusive carotid arterial thrombi from forming after injection in TgN-hCR1 mice, but not in WT mice, whereas soluble tPA and mIgG/tPA were ineffective. Anti-CR1/tPA caused 20-fold less rebleeding in TgN-hCR1 mice than the same dose of tPA. CR1-directed immunotargeting of PAs to circulating RBCs provides a safe and practical means to deliver fibrinolytics for thromboprophylaxis in settings characterized by a high imminent risk of thrombosis.

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Repeated Tissue Plasminogen Activator Treatment for Early Stroke Recurrence: Protocol Violation Is Not an Option

To the Editor: We read with interest and concern the article by Topakian et al1 in which the authors describe the clinical case of a stroke patient successfully treated with tissue plasminogen activator (tPA) that experienced a recurrence and therefore was treated again with a low dose of tPA 90 hours after the first event. Authors argued that the rationale for the second treatment was the “evidence of vessel reocclusion and profound perfusion/diffusion mismatch”; this statement raises several considerations. The diffusion/perfusion (DWI/PWI) mismatch concept to select acute stroke patients suitable for reperfusion therapies is currently under investigation with promising expectations.2,3 However, this concept is being applied in patients who do not present subacute ischemic lesion, a major exclusion criterion in all to-date thrombolysis studies. Although DWI/PWI mismatch may represent a surrogate marker of potential salvageable brain tissue if rapid restoration of blood flow is achieved, its presence does not provide by itself safety information. Extent and severity of cerebral ischemia are considered major determinants …

3α-OL-5-β-pregnan-20-one hemisuccinate, a steroidal low-affinity NMDA receptor antagonist improves clinical rating scores in a rabbit multiple infarct ischemia model: Synergism with tissue plasminogen activator

We previously showed that the neuroactive steroid 3α-ol-5-β-pregnan-20-one hemisuccinate (ABHS), a low-affinity NMDA receptor antagonist, improves behavior in rabbits following spinal cord ischemia. The present study assessed whether this also occurs following cerebral ischemia. We used the rabbit small clot embolic stroke model (RSCEM), a model of multiple infarct ischemia, which has a well-defined behavioral endpoint. Quantal analysis for each treatment determines microclots (mg) that produce neurologic dysfunction in 50% of a group of animals ( P 50), with treatment considered beneficial if it increases the P 50 compared to controls. ABHS (25 mg/kg) injected 5 min post-embolization significantly ( P = 0.046) increased the P 50 to 2.60 ± 0.69 mg compared to 1.15 ± 0.19 mg in controls but was ineffective at longer intervals. For combination studies with tissue plasminogen activator (tPA), a cumulative control curve ( P 50 = 1.18 ± 0.25 mg) was used for statistical comparisons. Low-dose tPA (0.9 mg/kg) and ABHS, given 60 min post-embolization, improved behavior synergistically ( P 50 = 2.44 ± 0.44 mg), compared to tPA ( P 50 = 1.25 ± 0.25 mg) or ABHS ( P 50 = 1.05 ± 0.24 mg) alone. A standard tPA dose (3.3 mg/kg) significantly increased the P 50 at 60 (2.69 ± 0.19 mg) but not 180 min (1.28 ± 0.31 mg) post-embolization. However, when combined with ABHS, an effect was evident even 180 min post-embolization ( P 50 = 2.31 ± 0.48 mg). Although the therapeutic window for ABHS is limited, it significantly enhanced neuroprotection by low-dose tPA and increased the therapeutic window for tPA, suggesting that it may be most useful as a co-therapy with thrombolytics for stroke.

Multimodal Therapy for the Treatment of Severe Ischemic Stroke Combining GPIIb/IIIa Antagonists and Angioplasty After Failure of Thrombolysis

Intraarterial and intravenous thrombolysis are often ineffective for the treatment of acute ischemic stroke and are associated with a significant risk of intracranial hemorrhage (ICH). Multimodal rescue therapy combining mechanical disruption and platelet GPIIb/IIIa receptor antagonists may improve recanalization. Patients who did not recanalize with thrombolysis were treated with GPIIb/IIIa antagonists, angioplasty, or an embolectomy device. Treatment was individualized based on vascular anatomy, stroke mechanism, patient status, and symptom duration. Twelve patients were treated within 3.8+/-2.2 hours. The mean National Institutes of Health Stroke Scale (NIHSS) score was 19.4+/-4.1. Six patients had carotid terminus occlusion, whereas 5 had middle cerebral artery and 1 had basilar artery occlusion. The average doses of intraarterial tPA and reteplase were 17.1+/-8.6 mg and 2+/-0.6 units, respectively. All patients received either an intravenous or intraarterial abciximab bolus (mean 11.8+/-5.8 mg) and heparin (mean 3278+/-1716U). Eleven were treated with angioplasty and 4 had mechanical embolectomy or stenting. Complete (8) or partial (3) recanalization was achieved in 11 cases. There was only one (8.3%) symptomatic hemorrhage. Patients had a favorable outcome at discharge (mean NIHSS 8.9+/-8.7) and 6 (50%) had an NIHSS < or =4 at discharge. Multimodal rescue therapy was effective at recanalizing occluded cerebral vessels that failed thrombolysis without an excess risk of ICH.