tPA Thrombolysis Research Articles

Abstract TP108: Blood Occludin Level Indicates the Extent of Early Blood Brain Barrier Damage in Ischemic Stroke

Background and Purpose: Fear of symptomatic intracerebral hemorrhage (ICH) has been the primary reason for withholding tPA thrombolysis from acute ischemic stroke patients. Early blood brain barrier (BBB) damage is appreciated to be closely associated with post-thrombolysis ICH, while it remains a technical challenge for rapid assessment of BBB damage before tPA administration. Our recent data showed that cerebral ischemia induced rapid degradation of tight junction protein occludin in ischemic cerebromicrovessels. This study further investigates whether the cleaved occludin is released into the blood stream and how blood occludin levels correlate to the extent of ischemic BBB damage. Methods: Male Sprague Dawley rats were subjected to 1.5, 3, 4.5, 12 and 24 hours of middle cerebral artery occlusion (MCAO), followed by 5-min reperfusion. Blood samples were taken before and after MCAO. Blood occludin was assessed by ELISA. BBB permeability was measured by Evans blue dye leakage. Occludin cleavage was identified on immunoblots. Results: MCAO induced Evans blue dye leakage and blood occludin increase in a duration-dependent manner. Blood occludin increase concurrently occurred with the loss of occludin from ischemic cerebral microvessels. Western blot analysis identified two cleaved occludin fragments (31- and 55- kDa) in the blood. Lastly, blood occludin levels remained significantly higher than its basal level within the first 24 hours after MCAO onset. Conclusions: Our results indicate that blood occludin levels correlate well with the extents of BBB damage and thus may serve as a potential biomarker for evaluating the risk of hemorrhagic transformation before tPA administration.

Thrombolysis with Low-Dose Tissue Plasminogen Activator 3-4.5 h After Acute Ischemic Stroke in Five Hospital Groups in Japan.

Clinical data from Japan on the safety and real-world outcomes of alteplase (tPA) thrombolysis in the extended therapeutic window are lacking. The aim of this study was to assess the safety and real-world outcomes of tPA administered within 3-4.5 h of stroke onset. The study comprised consecutive acute ischemic stroke patients (n = 177) admitted across five hospitals between September 2012 and August 2014. Patients received intravenous tPA within <3 or 3-4.5 h of stroke onset. Endovascular therapy was used for tPA-refractory patients. In the 3-4.5 h subgroup (31.6 % of patients), tPA was started 85 min later than the <3 h group (220 vs. 135 min, respectively). However, outcome measures were not significantly different between the <3 and 3-4.5 h subgroups for recanalization rate (67.8 vs. 57.1 %), symptomatic intracerebral hemorrhage (2.5 vs. 3.6 %), modified Rankin Scale score of 0-1 at 3 months (36.0 vs. 23.4 %), and mortality (6.9 vs. 8.3 %). We present data from 2005 to 2012 using a therapeutic window <3 h showing comparable results. tPA following endovascular therapy with recanalization might be superior to tPA only with recanalization (81.0 vs. 59.1 %). Compared with administration within 3 h of ischemic stroke onset, tPA administration within 3-4.5 h of ischemic stroke onset in real-world stroke emergency settings at multiple sites in Japan is as safe and has the same outcomes.

A Thrombotic Stroke Model Based On Transient Cerebral Hypoxia-ischemia

Stroke research has endured many setbacks in translating neuroprotective therapies into clinical practice. In contrast, the real-world therapy (tPA thrombolysis) rarely produces benefits in mechanical occlusion-based experimental models, which dominate preclinical stroke research. This split between the bench and bedside suggests the need to employ tPA-responsive models in preclinical stroke research. To this end, a simple and tPA-reactive thrombotic stroke model is invented and described here. This model consists of transient occlusion of the unilateral common carotid artery and delivery of 7.5% oxygen through a face mask in adult mice for 30 min, while maintaining the animal rectal temperature at 37.5 ± 0.5 °C. Although reversible ligation of the unilateral carotid artery or hypoxia each suppressed cerebral blood flow only transiently, the combination of both insults caused lasting reperfusion deficits, fibrin and platelet deposition, and large infarct in the middle cerebral artery-supplied territory. Importantly, tail-vein injection of recombinant tPA at 0.5, 1, or 4 hr post-tHI (10 mg/kg) provided time-dependent reduction of the mortality rate and infarct size. This new stroke model is simple and can be standardized across laboratories to compare experimental results. Further, it induces thrombosis without craniectomy or introducing pre-formed emboli. Given these unique merits, the tHI model is a useful addition to the repertoire of preclinical stroke research.

A Thrombotic Stroke Model Based On Transient Cerebral Hypoxia-ischemia.

Stroke research has endured many setbacks in translating neuroprotective therapies into clinical practice. In contrast, the real-world therapy (tPA thrombolysis) rarely produces benefits in mechanical occlusion-based experimental models, which dominate preclinical stroke research. This split between the bench and bedside suggests the need to employ tPA-responsive models in preclinical stroke research. To this end, a simple and tPA-reactive thrombotic stroke model is invented and described here. This model consists of transient occlusion of the unilateral common carotid artery and delivery of 7.5% oxygen through a face mask in adult mice for 30 min, while maintaining the animal rectal temperature at 37.5 ± 0.5 °C. Although reversible ligation of the unilateral carotid artery or hypoxia each suppressed cerebral blood flow only transiently, the combination of both insults caused lasting reperfusion deficits, fibrin and platelet deposition, and large infarct in the middle cerebral artery-supplied territory. Importantly, tail-vein injection of recombinant tPA at 0.5, 1, or 4 hr post-tHI (10 mg/kg) provided time-dependent reduction of the mortality rate and infarct size. This new stroke model is simple and can be standardized across laboratories to compare experimental results. Further, it induces thrombosis without craniectomy or introducing pre-formed emboli. Given these unique merits, the tHI model is a useful addition to the repertoire of preclinical stroke research.

Normobaric hyperoxia slows blood-brain barrier damage and expands the therapeutic time window for tissue-type plasminogen activator treatment in cerebral ischemia.

Prolonged ischemia causes blood-brain barrier (BBB) damage and increases the incidence of neurovasculature complications secondary to reperfusion. Therefore, targeting ischemic BBB damage pathogenesis is critical to reducing neurovasculature complications and expanding the therapeutic time window of tissue-type plasminogen activator (tPA) thrombolysis. This study investigates whether increasing cerebral tissue PO2 through normobaric hyperoxia (NBO) treatment will slow the progression of BBB damage and, thus, improve the outcome of delayed tPA treatment after cerebral ischemia. Rats were exposed to NBO (100% O2) or normoxia (21% O2) during 3-, 5-, or, 7-hour middle cerebral artery occlusion. Fifteen minutes before reperfusion, tPA was continuously infused to rats for 30 minutes. Neurological score, mortality rate, and BBB permeability were determined. Matrix metalloproteinase-9 was measured by gelatin zymography and tight junction proteins (occludin and cluadin-5) by Western blot in the isolated cerebral microvessels. NBO slowed the progression of ischemic BBB damage pathogenesis, evidenced by reduced Evan blue leakage, smaller edema, and hemorrhagic volume in NBO-treated rats. NBO treatment reduced matrix metalloproteinase-9 induction and the loss of tight junction proteins in ischemic cerebral microvessels. NBO-afforded BBB protection was maintained during tPA reperfusion, resulting in improved neurological functions, significant reductions in brain edema, hemorrhagic volume, and mortality rate, even when tPA was given after prolonged ischemia (7 hours). Early NBO treatment slows ischemic BBB damage pathogenesis and significantly improves the outcome of delayed tPA treatment, providing new evidence supporting NBO as an effective adjunctive therapy to extend the time window of tPA thrombolysis for ischemic stroke.

Abstract T P57: TEG Does Not Correlate with Clot Subtype or Clinical Response to tPA

Background: Thromboelastography (TEG) measures coagulation status in venous blood. tPA thrombolysis is affected by multiple variables including whether clots are erythrocyte or platelet-rich. We hypothesized that TEG would correlate with clot subtype and response to tPA including rapid clinical improvement (RCI), recanalization, and hemorrhagic transformation (HT). Methods: 176 acute ischemic stroke patients between 11/09 and 06/14 treated with tPA were prospectively enrolled. Venous blood for TEG was drawn before and 10 minutes after tPA bolus. Pre-tPA measures of speed and strength of clot formation (R, Delta, K, Angle, MA, and G) and post-tPA measure of clot lysis (LY30) were analyzed. Hyperdense artery (HDA) on CT was a biomarker for erythrocyte-rich clot. RCI was defined as 8 point improvement on NIHSS or total NIHSS of 0,1 at 36 hours. HT was defined as any blood on follow up imaging within 36 hours. Recanalization was defined as resolution of baseline vascular occlusion on follow up CT or MR angiogram within 36 hours. Multivariable linear regression models compared TEG parameters after adjusting for potential confounding and interactive effects. Results: No differences in pre- or post-tPA TEG were found between patients with (n=32) or without (n=102) RCI. Also, there was no correlation between TEG and HDA on CT. Clot strength was decreased in patients with recanalization (lower MA and G, p = 0.02 and p = 0.03). Clotting was slightly prolonged (longer delta, p = 0.046) in patients with HT. Discussion: Our data do not show a robust association between TEG and clot subtype or clinical response to tPA. It is likely that arterial clot lysis is determined by factors unrelated to coagulation status as measured by TEG in the venous circulation. Though we found a correlation between TEG and recanalization, the number of patients with recanalization data was too small to detect an effect on clinical outcome. Similar to our previous findings, speed of clot formation may be related to risk of bleeding. Conclusion: It is unlikely that TEG will be useful in guiding tPA therapy. Future research should focus on local arterial influences on clot lysis. Further study of TEG in hemorrhage is indicated.

Abstract W P27: Quantitative Measurement Of Blood Flow Around Intravascular Thrombus Using CT Perfusion T0 Maps

Introduction: Anterograde blood flow around thrombus and extent of retrograde collateral filling can affect thrombus lysis with IV tPA. Current assessment of blood flow around thrombus is however very subjective. The aim of the present study is to validate a newly devised method to quantify blood flow around thrombus using CT perfusion (CTP) T0 maps. Methods: From the Prove-IT stroke-imaging database, perfusion CT and DSA images of stroke patients treated with IV tPA and/or IA thrombolysis were analyzed. We generated maps that measure delay in arrival time of contrast within the intracranial arterial tree (T0 maps) from that of the chosen arterial input function. A “positive sloped” regression line of T0 values from distal clot interface to at least 14 pixels (median 68 pixels) along the artery profile indicated presence of occult anterograde flow. Anterograde flow thus measured using the T0 maps was compared with anterograde flow assessed on first angiography of subsequent IA procedure. Results: Of 37 patients (mean age 66 ± 13.5 years, 20 female), 35 (94.6%) were treated with IV tPA before DSA. Median time from CTP to first run angiography was 83 mins (IQR 53-100 mins). Positive slope were noted in 10 patients. Patients who had anterograde flow on first angiography were 10. Compared with anterograde flow on first run angio, positive slope on T0 map had a sensitivity of 80%, specificity of 92.6% and a positive predictive value of 80% and negative predictive value of 92.6%. In patients with anterograde flow on first angiography, median T0 time at proximal clot interface was 0.1 seconds (IQR 0-0.1) and at distal clot interface was 0.7 seconds (IQR 0.5-3.1). In patients without any anterograde flow on first angio, median T0 time at proximal clot interface was 0.1 seconds (IQR 0-0.3) while that at distal clot interface was 3.7 seconds (IQR 2.1-5.6). Conclusions: The slope method on CTP T0 maps and measurement of T0 values around clot reliably measure presence of anterograde blood flow through thrombus.

Abstract No. 511 - Minimally invasive management of post-operative chylous ascites

No. 512 Pharmacomechanical recanalization of caval thrombosis in patients with vena cava filter associated phlegmasia cerulea dolens R. Florek, E.K. Lang, Dr, R. Batson, F. Alessi, E. LaNassa, C. Sheehan; Radiology, Lourdes Regional Medical Center, Lafayette, LA; Radiology, West Jefferson Medical Center, Marrero, LA; Radiology, SUNY Downstate, New York, NY; Vascular Surgery, LSU Medical Center, New Orleans, LA Purpose: Occlusion of the inferior vena cava (IVC) occurs in 1-2.5% of chronically indwelling caval filters (1). IVC thrombosis results in impaired venous drainage from the lower extremities, and can present clinically as phlegmasia cerulea dolens (PCD) in chronic cases. Caval filter associated IVC thrombosis can be recanalized by mechanical clot disruption, aided by multi-day TPA thrombolysis with restoration of caval flow and resolution of PCD symptoms of swelling and discoloration. Materials and Methods: Six patients (ages 48-72, avg. 63) were reviewed who presented with chronic (more than 1 week) symptoms of PCD of the lower extremities after placement of a caval filter (6-49 mos. prior, avg. 25 mos; two placed by the primary author, four referred from outside institutions). All showed complete caval thrombosis with an indwelling caval filter. Mechanical disruption with balloon catheters and Trellis device thrombus disruption was used, in combination with TPA infusion (10 mg. loading dose, followed by overnight infusion of 1 mg/hr, followed by repeat mechanical disruption, over an average of three days). Results: Five of the six patients were recanalized and discharged after therapy. All showed resolution of lower extremity swelling and discoloration. One patient who was admitted with ongoing sepsis continued to worsen into multiorgan failure (MOF) and expired. Overall success rate was 83%, with one treatment failure due to ongoing sepsis resistant to multiple antibiotics, suggesting the IVC thrombus may have been superinfected. Conclusion: PCD secondary to caval filter occlusion is difficult to recanalize and both mechanical and thrombolytic therapy may be necessary over several days. Success rate in this series was 5 of 6 (83%).2. Sepsis in addition to caval thrombosis carries a higher risk of fatality due to resistant sepsis progressing to MOF, suggesting the presence of infected thrombus.

Abstract 179: International Survey of Clinical Case Vignettes in Acute Ischemic Stroke

Background and Purpose: To quantify consistency across stroke centers worldwide in the typical imaging and treatment decisions made when presented with independent clinical case vignettes including various imaging findings across specific time from onset intervals. Methods: Stroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA)-Imaging circulated an online survey of clinical case vignettes through its website, through the websites of national professional societies from multiple countries as well as through email distribution lists from STIR and participating societies. Vignettes varied in terms of patient’s age, time from onset, neurological symptoms and NIHSS. The survey displayed the imaging findings offered by the imaging strategy selected, and the responders selected the appropriate therapy considering time from onset, clinical presentation and imaging findings. Results: We received responses from 30 countries including 260 centers. The specific onset interval presented: 0-3 hours, 6 hours, 10 hours or wake-up, influenced the type of imaging work-up selected rather than the clinical scenario. CT was used more often than MRI across all time intervals. For cases with M1 occlusion and large penumbra, vascular imaging was most common (36%) in 0-3 hours and perfusion imaging more frequently used in 6 hours (62%) and wake-up stroke (65%). For large penumbra cases with M1 or ICA occlusion, combination, IV tPA thrombolysis followed by endovascular\IA, treatment (81%) was most common in 0-3 hours. Endovascular treatment was selected the most at 6 hours (43%) for M1 occlusion and large penumbra cases but still selected in 27% of patients up to 10 hours for ICA occlusion and large penumbra cases. For M1 occlusion and large penumbra cases imaged with MRI only, treatment of wake-up stroke increased to 89% from 58% cases imaged with CT alone. Sites that obtained more imaging tended to be more aggressive in terms of revascularization treatment, particularly endovascular therapy. Conclusions: Adding vascular and\or perfusion imaging increased the likelihood of thrombolysis across all time intervals. Usage of MRI perfusion imaging was associated with an increased likelihood of enrollment into a randomized trial up to 83%.

Towards reperfusion-centric preclinical stroke research: outside the box of "reperfusion injury".

Stroke is a major health issue of increasing significance for any society with an aging population. Globally, stroke is the second-leading cause of death with approximately 5.9 million fatal events in 2010, equivalent to 11.1% of all deaths. Yet, despite years of preclinical research on neuroprotection and a multitude of clinical trials, tissue plasminogen activator (tPA)-mediated recanalization remains the mainstay of acute ischemic stroke therapy, whereas tPA thrombolysis rarely provides benefits in the mechanical occlusion-based stroke models. This split between the bench and bedside raised the concern over the clinical applicability of neuroprotection in acute ischemic stroke. In this perspective commentary, we call for attention to the differences between mechanical-occlusion and thromboembolic stroke models in cerebral hemodynamics (Figure ​Figure1A,1A, ​,BB), the implications of these differences in view of progressive pathobiology of ischemic stroke (Figure 1C), and the need and strategies towards reperfusion-centric preclinical stroke research.

Portomesenteric Venous Thrombosis As First Presentation of Thrombophilic Disorders in Adolescents

IntroductionPortomesenteric venous thrombosis is rare in children and adolescents. Rapid recognition of this uncommon phenomenon is essential to prevent resultant bowel ischemia and necrosis. Prior studies have shown that most cases are associated with central venous lines, abdominal trauma, autoimmunity, malignancy, or inflammatory bowel disease. Here we present a series of four adolescent patients with no significant past medical history or previously identified thrombophilia who presented with subacute abdominal pain and were ultimately found to have portomesenteric venous thrombosis.MethodsWe conducted a retrospective analysis of adolescent patients diagnosed with portomesenteric venous thrombosis at our center between July 2012 and July 2014. We evaluated baseline demographics, diagnostic workup, radiologic findings, therapy, and clot resolution.ResultsWe identified four patients (3 female, 1 male) with a median age of 15 years (range 14-17). No patients had history of clots, known thrombophilias, or predisposing conditions. All patients had presented to the general pediatric inpatient service with the chief complaint of acute to subacute abdominal pain originating 2-4 weeks prior and accompanied by diarrhea and/or constipation, anorexia, and nausea/emesis. After extensive preliminary diagnostic investigations, three patients’ clots were eventually discovered on computed tomography, and one patient’s clot was found on ultrasound. The thrombosis sites among the four patients were superior mesenteric (n=4), portal (n=3), splenic (n=2), inferior mesenteric (n=1), hepatic (n=1), inferior vena cava (n=1), and renal (n=1) veins. Two patients’ clots were completely occlusive; however, no patients had bowel necrosis requiring surgical intervention.All patients were treated with standard anticoagulation while inpatient. One patient additionally underwent direct tPA thrombolysis and thrombectomy and required repeat direct thrombolysis and continuous tPA infusion due to clot extension. All patients were discharged on therapeutic anticoagulation with at least partial resolution of their clots. Median followup was 7 months (4-9 months). One patient later developed an upper extremity deep vein thrombosis associated with a peripheral line inserted for heparin delivery; no other patients developed clots at new sites or experienced extension of their original clots. All workups remained negative for inflammatory bowel disease, malignancies, and rheumatologic conditions.All patients were evaluated for underlying thrombophilic conditions, each undergoing a variable set of laboratory tests during hospitalization and followup. One patient had a durable protein C deficiency. Another patient was heterozygous for the factor V Leiden mutation and had a transient lupus anticoagulant during and until four months after hospitalization. A third patient who smoked had no detectable thrombophilia during hospitalization but experienced elevated fibrinogen and anti-β2-glycoprotein I antibodies four months after initial presentation. A fourth patient who smoked as well as had initiated an estrogen patch within the past month had a positive hexagonal lipid neutralization during early hospitalization.ConclusionWe demonstrate that portomesenteric venous thrombosis can be the first presentation of a thrombophilic disorder in previously healthy adolescents. As it is a rare diagnosis with significant long-term complication potential, future work should standardize diagnostic approaches to adolescent subacute abdominal pain to enable rapid thrombosis recognition and prompt anticoagulation initiation. Furthermore, given the prevalence of thrombophilias identified in our patients despite variable laboratory testing regimens, it is imperative to develop a systematic approach for comprehensive thrombophilic testing in adolescents diagnosed with portomesenteric venous thrombosis. DisclosuresNo relevant conflicts of interest to declare.

Early ischemic blood brain barrier damage: a potential indicator for hemorrhagic transformation following tissue plasminogen activator (tPA) thrombolysis?

Tissue plasminogen activator (tPA) thrombolysis, remains to be the only United States Food and Drug Administration (FDA) approved treatment for acute ischemia stroke. However, the use of tPA has been profoundly constrained due to its narrow therapeutic time window and the increased risk of potentially deadly hemorrhagic complications. TPA-associated hemorrhagic transformation (HT) often occurs as a result of catastrophic failure of the blood brain barrier (BBB), wherein the affected cerebral capillaries can no longer hold blood constituents. Due to its direct contribution to edema and HT, reperfusion-associated BBB damage has been extensively studied, while BBB damage that occurs within the thrombolytic time window is largely neglected. Of note, ischemia-induced BBB damage in the early stroke stages is increasingly appreciated to negatively affect the safety and efficacy profiles of thrombolytic therapy for ischemic stroke. In this review, we discussed the recent findings of spatio-temporal evolution of BBB injury in the early stages of cerebral ischemia and its association with intracerebral hemorrhage following tPA thrombolysis. The increased understanding of early ischemic BBB damage and its close link to tPA-associated HT is of particular importance for developing new preventive and therapeutic strategies to reduce the hemorrhagic complications in stroke thrombolysis.

Translational stroke: a rapidly expanding area!

Stroke is so disappointing a disease for both neurologists and patients. In most cases, the effective managements are lacking. We prescribe aspirin, statin, and anti-hypertension treatment. A significant statistic difference in favor of these therapies can be achieved in clinical trials with large sample size, but their effects are often not observed for an individual. Recombinant tPA thrombolysis can reverse neurological deficits in some patients within hours, but only few patients have chance to accept tPA treatment due to the short time window.

Endovascular Treatment of Cerebral Venous Sinus Thrombosis with Combination of Rheolytic Thrombectomy, Angioplasty and tPA Thrombolysis Reversed Severely Elevated ICP Syndrome: A Case Study. (P2.295)

Endovascular Treatment of Cerebral Venous Sinus Thrombosis with Combination of Rheolytic Thrombectomy, Angioplasty and tPA Thrombolysis Reversed Severely Elevated ICP Syndrome: A Case Study. (P2.295)

Abstract W P48: Marked Regional Variation in Acute Stroke Treatment in Medicare Beneficiaries

Objective: Regionalization of stroke care has occurred sporadically across the U.S, so determining realistic goal treatment rates for individual regions or the nation as a whole is challenging. Studies of a single hospital or region vary widely in estimates of eligibility for acute therapy and may have limited generalizability or biases. We hypothesized that the proportion of U.S. Medicare beneficiaries receiving acute stroke therapy varies by region. Treatment rates in high performing regions may represent realistic national goals and inform policy to increase treatment rates. Methods: All Medicare beneficiaries with a principal diagnosis of ischemic stroke (ICD-9 433.x1, 434.x1, 436) admitted through the emergency department were identified using MEDPAR files from 2007-2010. Receipt of IV tPA (DRG 559, MS-DRG 61-63, ICD-9 procedure code 99.10) or IA thrombolysis (CPT code 37184-6, 37201, 75896 via linked Medicare Carrier files) was determined. Patients were assigned to one of 3,436 Hospital Service Areas (HSA; local health care markets for hospital care) by zip code. Regional acute stroke treatment rates were calculated and the lowest and highest quintiles were compared. Multi-level logistic regression was used to adjust for individual demographics as well as regional population density, education, median income, and unemployment using linked census data. Model-based adjusted regional acute stroke treatment rates were estimated. Results: Of 916,232 stroke admissions 3.6% received IV tPA only and 0.6% received IA or combined therapy. Unadjusted treatment rates by region ranged from 0.8% (minimum) to 14.8% (maximum). Regional rates ranged from 1.7% (quintile 1) to 5.4% (quintile 5). Regions with higher education, population density and income had higher treatment rates (p &lt;= 0.001). After adjustment, regional differences were attenuated slightly _ 1.9% (quintile 1) to 5.1% (quintile 5). Conclusions: Marked variation exists in acute stroke treatment rates by region, even after adjusting for patient and regional characteristics, supporting the perception that a major opportunity exists to improve acute stroke treatment within many HSAs.

Low-dose Tissue Plasminogen Activator is as Effective as Standard Tissue Plasminogen Activator Administration for the Treatment of Acute Ischemic Stroke

We compared the efficacy of intravenous (IV) combination of low-dose tissue plasminogen activator (tPA) and urokinase (UK) versus either classical IV tPA or UK alone for acute ischemic stroke (AIS) within 4.5 h of symptom onset. One-hundred fifty-three AIS patients were treated with 1 of 3 different IV thrombolytic therapies within a 4.5-h time window. Clinical data included age, gender, type of therapy, NIHSS score, time from onset to needle, ASPECTS, mRS at 90 days, and medical history. The outcomes were ΔNIHSS-a (the difference between NIHSS scores at admission and 24 h); ΔNIHSS-b (difference between NIHSS scores at admission and 7 days), and mRS at 90 days. Multivariate logistic regression (MLR) was used to determine if treatments or other variables could predict these outcomes. Of 153 patients, 60.1% had a good outcome and 39.9% had a poor outcome. The most important predictors of 90-day mRS were AF history (p < 0.001) and NIHSS score at admission (p = 0.001). Age (p = 0.004) and treatment type (p = 0.043) that were also significantly associated with 90-day mRS. IV tPA yielded the best outcome, compared to low-dose tPA/UK (OR = 1.17) and UK alone (OR = 1.42). Low-dose tPA/UK also resulted in better outcome than UK alone did (OR = 1.12). We conclude that low-dose IV tPA with UK administered within a 4.5-h time window was effective and likely comparable to classical IV tPA thrombolysis.

Abstract WP66: Metalloproteinase-9 Higher Increase After Thrombolysis Is Associated With Hemorrhagic Transformation Of Lesion And With Poor Stroke Outcome

Background and Purpose: In experimental animals metallo-proteinases (MMPs) play a detrimental role related to severity and hemorrhagic transformation of the ischemic lesion. tPA enhances and MMPs inhibitors (TIMPs) antagonize such effects. This study aimed to expand clinical evidence in this connection. Methods: Blood was taken at baseline and 24 hours after from 327 patients (mean age 68, mean NIHSS 11.9) with acute ischemic stroke, all treated with i.v. tPA thrombolysis within 4.5 hours. MMPs 1, 2, 3, 7, 8, 9, and TIMPs 1, 2, 4 were measured (in ng/ml) using Bio-plex suspension array system and R&amp;D kits. Delta median values [(post tPA-baseline)/baseline] of each MMP or TIMP were analyzed related to symptomatic hemorrhage (SICH), death, 3 month mRS (3-6 vs. 0-2), and correlated with baseline, 24 hours and 7 days NIHSS. Results: delta increases: 1) SICH vs. non SICH: significant for MMP9 and TIMP4 [MMP-9: 0.38 vs. -0.18 p 0.006; TIMP4 0.67 vs. 0.22 p 0.015]. 2) Death vs. survival: significant for MMPs 1, 8, 9 and TIMP1 [MMP1: 0.01 vs. -0.14 p .048; MMP8: 0.46 vs. -0.09 p .011; MMP9: 0.37 vs. -0.17 p .007; TIMP1 0.17 vs. -0.02 p .011]. 3) mRS 3-6 vs. 0-2: significant for MMPs 8, 9, and TIMP 4 [MMP8: 0.12 vs. -0.17 p&lt;.001; MMP9: 0.11 vs. -0.21 p&lt;.001; TIMP4 0.50 vs 0.16, p&lt;.001]. Both MMP-9 and TIMP4 deltas were strongly correlated with baseline, 24h, and 7 days NIHSS (Spearman p ranging from .003 to .001). Adjusting for demographics, baseline glucose or NIHSS, infection and atrial fibrillation, only MMP-9 remained an independent determinant of death [OR (95% CI) 1.55 (1.08-2.21)], SICH [OR (95% CI) 1.38 (1.01-1.90)], or mRS 3-6 [OR (95% CI) 1.35 (1.01-1.80)]. Conclusions: our data add substantial clinical evidence about MMP-9 as detrimental factor in ischemic stroke treated with thrombolysis, and may prompt RCTs testing of TIMPs in combination with tPA.

Treatment of Acute Stroke in Patients on Dabigatran: A Survey of US Stroke Specialists

There are no guidelines for thrombolysis in stroke patients taking dabigatran, or dabigatran reversal strategies in patients with ICH. We sought to assess how vascular neurologists plan to care for these patients. An Internet-based questionnaire was sent to US board-certified vascular neurologists. Case scenarios for patients on dabigatran with acute ischemic stroke or ICH were presented; questions assessed preferred treatment strategies. In all, 221 vascular neurologists responded. For a typical ischemic stroke patient eligible for intravenous (IV) tissue plasminogen activator (tPA) except for use of dabigatran (time of last dose unknown), 49% would not treat with tPA regardless of PTT, 28% would treat if PTT was normal, 9% would treat if PTT was less than 40 seconds, and 4% would treat regardless of PTT. Even more variability in responses was seen when presented with a normal PTT but variable times from last dabigatran dose. Between 8%-14% of respondents were not sure what they would do. For catheter-based thrombolysis, 25% indicated they would treat with IV tPA but would prefer catheter thrombolysis, 30% would use IV tPA and consider catheter thrombolysis as for any patient, 36% would only use catheter thrombolysis, and 9% would not use IV tPA or catheter thrombolysis. For a patient with dabigatran-associated ICH, 73% said they would attempt reversal of dabigatran with the following modalities: FFP 53%; factor VIIa 24%; prothrombin complex concentrates 61%; platelet transfusion 7%; and hemodialysis 24%. There is a remarkable lack of consensus among vascular neurologists regarding the assessment and treatment of acute stroke patients on dabigatran.

Recombinant ADAMTS13 reduces tissue plasminogen activator‐induced hemorrhage after stroke in mice

Tissue plasminogen activator (tPA) is approved for treatment of acute ischemic stroke, but it increases the risk of cerebral hemorrhage. Accumulating evidence suggests that von Willebrand factor (VWF) plays a pivotal role in thrombus formation and microcirculatory disturbances after ischemic stroke. By cleaving VWF, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) protects mice from stroke. Therefore, we hypothesized that recombinant ADAMTS13 (rADAMTS13) could increase the safety of tPA thrombolysis in stroke. We examined blood-brain barrier (BBB) permeability after intraventricular injection of tPA, VWF, and rADAMTS13 in nonischemic mice. We investigated the role of rADAMTS13 on reducing tPA-induced BBB dysfunction and cerebral hemorrhage in a mouse stroke model. Intraventricular injection of tPA or VWF under nonischemic conditions resulted in a significant increase in BBB permeability. In contrast, rADAMTS13 blocked both tPA- and VWF-induced BBB opening. BBB disruption following stroke was exacerbated by intravenous administration of tPA, but this was attenuated by injection of rADAMTS13. Correspondingly, tPA-associated hemorrhage after stroke was significantly reduced by rADAMTS13. The antihemorrhagic effect of rADAMTS13 was reversed by injection of recombinant VWF. We also showed that rADAMTS13 inhibited tPA-mediated upregulation of vascular endothelial growth factor (VEGF) in vascular endothelium after stroke. The upregulation of VEGF was suppressed by either an Akt inhibitor wortmannin or a Rho kinase inhibitor fasudil. Furthermore, rADAMTS13 downregulated tPA-induced phosphorylation of Akt and activation of RhoA. These findings demonstrate that the VWF-cleaving protease rADAMTS13 reduced tPA-induced hemorrhage by regulating BBB integrity, and suggest that this effect may occur through the Akt/RhoA-mediated VEGF pathways.

Early Insulin Glycemic Control Combined With tPA Thrombolysis Reduces Acute Brain Tissue Damages in a Focal Embolic Stroke Model of Diabetic Rats

Therapeutic effects of early insulin glycemic control for poststroke hyperglycemia in combination with tissue-type plasminogen activator (tPA) thrombolytic therapy have not yet been studied but are of great clinical interest. In this study, we tested the effects of insulin plus tPA combination in a model of focal embolic stroke in Type I diabetic rats. Streptozotocin was used to produce Type I diabetes in male Wistar rats for 6 weeks and then embolic focal strokes were induced. All rats were treated with insulin or saline at 1 hour followed by tPA or saline at 1.5 hour after stroke. Mortality, infarction, hemispheric swelling, hemorrhagic transformation, and perfusion defects were examined at 24 hours after stroke. Total plasma plasminogen activator inhibitor-1 antigen and activity levels were measured before stroke and 1.5, 3, and 6 hours after stroke by ELISA. Early insulin glycemic control alone or tPA thrombolysis alone had no significant effects on ischemic infarction. However, early insulin glycemic control combined with tPA significantly reduced brain infarction and swelling, ameliorated tPA-associated hemorrhagic transformation, and improved plasma perfusion at 24 hours after stroke. We also found that the combination significantly decreased plasma plasminogen activator inhibitor-1 antigen level at 6 hours and plasminogen activator inhibitor-1 activity at 1.5 and 6 hours after stroke. Early insulin glycemic control may be beneficial in combination with tPA thrombolysis for ischemic stroke with diabetes mellitus or poststroke hyperglycemia.